Bacille Calmette-Guérin Therapy Research Articles

Bilateral Panuveitis following Intravesical BCG Immunotherapy for Bladder Carcinoma

Purpose: To report a case of bilateral panuveitis following local treatment with Bacille Calmette-Guérin (BCG) immunotherapy for superficial bladder carcinoma.Design: Case report and literature review.Methods: A 70-year-old female presented with severe bilateral anterior chamber inflammation 5 days after intravesical BCG instillation. Despite topical steroids and mydriatics, inflammation worsened and bilateral optic nerve swelling developed.Results: Oral corticosteroids settled the ocular inflammation, and optic nerve function recovered. A trial of steroid cessation caused rebound uveitis, so she remains on maintenance doses of oral corticosteroid.Conclusions: Ocular inflammations following BCG therapy for bladder cancer are rare, and little is known about the management of such cases. This is the first report of bilateral panuveitis with optic nerve edema following such treatment.

The effect of gender on response to bacillus Calmette‐Guérin therapy for patients with non‐muscle‐invasive urothelial carcinoma of the bladder

To determine the influence of gender on the outcome of patients with high-risk non-muscle-invasive bladder cancer treated with intravesical bacille Calmette-Guérin (BCG) therapy, as the role of hormone status in the pathogenesis of urothelial carcinoma and the response to treatment remains subject to debate. We reviewed 1021 consecutive patients (756 men and 265 women) who were treated with induction BCG between 1978 and 2006 for multiple or recurrent high-grade Ta, T1, and/or carcinoma in situ (CIS) bladder cancer. All patients had > or = 5 years of follow-up. The endpoints of initial response to BCG and the time to disease recurrence and progression were correlated with gender using Kaplan-Meier methods and multivariate Cox regression models. Men were significantly more likely to present with high grade (P = 0.003) tumours and with CIS (P < 0.001), while age and clinical stage at presentation were similar between men and women. There was no significant difference in the initial response to BCG by gender, as 593/756 (78.4%) men and 219/265 (82.6%) women had no evidence of disease at 6 months after BCG treatment (P = 0.14). The median time to recurrence after BCG therapy was also similar for men and women (20 vs 21 months, P = 0.51). Likewise, there was no evidence of a significant association between gender and the risk of disease progression after BCG therapy, such that the 5-year estimated freedom from progression was 77% and 82%, respectively, for men and women (P = 0.08). Moreover, on a multivariate analysis controlling for patient age and tumour stage, grade and CIS, gender was not associated with the risk of recurrence (hazard ratio 0.94, 95% confidence interval 0.79-1.11; P = 0.44) or progression (1.18, 0.85-1.63; P = 0.33) after BCG. When the outcomes for women treated with BCG were stratified by age <50 years (the median age of menopause in the USA) vs > or = 50 years, again there were no differences in the risk of tumour recurrence (P = 0.95) or progression (P = 0.35). These data suggest that the outcomes of men and women with high risk non-muscle-invasive urothelial carcinoma treated with BCG are similar. As such, further studies are required to determine the clinical relevance of preclinical evidence that has suggested a potential role for sex steroids in the pathophysiology of bladder cancer.

Gemcitabine versus bacille Calmette‐Guérin after initial bacille Calmette‐Guérin failure in non‐muscle‐invasive bladder cancer

The efficacy of intravesical gemcitabine was evaluated compared with repeated administration of bacille Calmette-Guérin (BCG) after BCG failure in high-risk, non-muscle-invasive bladder cancer (BC). In this multicenter, prospective, randomized, phase 2 trial, eligible patients were those with high-risk non-muscle-invasive BC, failing 1 course of BCG therapy. All patients were randomly allocated to Group A, receiving intravesical gemcitabine (at a dose of 2000 mg/50 mL) twice weekly for 6 consecutive weeks and then weekly for 3 consecutive weeks at 3, 6, and 12 months, or Group B, receiving intravesical BCG (Connaught strain, 81 mg/50 mL) over a 6-week induction course and each week for 3 weeks at 3, 6, and 12 months. Outcome measures were recurrence rate, time to first recurrence, and progression rate. Treatment-related complications were also evaluated. Eighty participants were enrolled, 40 for each group 52.5% in Group A developed disease recurrence versus 87.5% of those in Group B (P = .002). There was no statistically significant difference in mean time to the first recurrence (Group A, 3.9 months; Group B, 3.1 months; P = .09). Kaplan-Meier analysis of 2-year recurrence-free survival showed significant differences between Group A and B (19% and 3%, respectively, P < .008). Seven of 21 (33%) patients in Group A and 13 of 35 (37.5%) patients in Group B had disease progression and underwent radical cystectomy (P = .12). Both intravesical administrations were generally well tolerated. Gemcitabine might represent a second-line treatment option after BCG failure in high-risk non-muscle-invasive BC patients.

Hexylaminolaevulinate fluorescence cystoscopy in patients previously treated with intravesical bacille Calmette‐Guérin

OBJECTIVE To determine if hexylaminolaevulinate fluorescence cystoscopy (HAL-FC) has the potential to improve the diagnosis of bladder cancer in patients who have been treated with bacille Calmette-Guérin (BCG). PATIENTS AND METHODS Patients scheduled for rigid cystoscopy after BCG therapy were recruited prospectively between April 2005 and February 2006. Patients received HAL (Hexvix, PhotoCure ASA, Oslo, Norway) and the D-light system (Storz, Tuttlingen, Germany) was used to detect fluorescence. The bladder was mapped and biopsies taken under white light and then using HAL-FC. The main outcome was the frequency and nature of additional pathology detected by HAL-FC. Twenty-seven patients (21 men and six women; median age 70 years, range 49-82) underwent 32 HAL-FC. RESULTS Recurrent bladder cancer was detected in 11 of the 32 (34%) examinations. HAL-FC detected additional pathology in five of the 27 (19%) patients. In two of these cases the additional pathology was clinically significant (one pT4G3 intraprostatic transitional cell carcinoma and one intravesical pT1G2 + carcinoma in situ), whereas in three cases the pathology was hyperplasia/dysplasia. Overall, the false-positive biopsy rate with HAL-FC was 63%. In the presence of positive voided urine cytology six of eight patients had recurrent bladder tumour and the false-positive biopsy rate was only 34%. Urine cytology was positive in four of five of the patients in whom additional pathology was detected by HAL-FC. CONCLUSIONS Clinically significant occult pathology can be detected using HAL-FC after BCG therapy, but in <10% of cases. The rate of false-positive biopsies is high but in our hands appears to be lower than with white-light guided biopsies after BCG. Our pragmatic approach is to use HAL-FC after BCG when clinical suspicion is high, and when the preoperative voided urine cytology is positive.

Narrow‐band imaging cystoscopy to evaluate the response to bacille Calmette‐Guérin therapy: preliminary results

Diagnostic (exploratory cohort). 2b. To evaluate whether narrow-band imaging cystoscopy (NBIC) can identify bladder tumour suspected on follow-up white-light cystoscopy (WLC) after intravesical bacille Calmette-Guérin (BCG) therapy, as BCG causes an intense reaction in the bladder, appearing as red lesions on WLC, which might be residual tumour or BCG-induced inflammation. Sixty-one patients with high-risk non-muscle-invasive bladder tumours were evaluated 3 months after starting induction BCG therapy. All patients had abnormal erythematous lesions on WLC, suspected to be residual carcinoma in situ. After WLC, they were evaluated by NBIC, urine cytology and biopsy, followed by transurethral resection of all visible lesions. Of the 61 patients, 22 (36%) had residual tumour. NBIC correctly identified tumour in 21 patients, but another 10 had unnecessary biopsy (NBIC positive, negative biopsy). Only one of 30 patients who had negative NBIC findings had tumour. NBIC outperformed urine cytology in detecting residual tumour after BCG therapy. NBIC appears to better identify patients who have suspected residual tumour on follow-up WLC at 3 months after BCG therapy.

Bacille Calmette-Guérin (BCG) Immunotherapy-Induced Celiac Crisis: A First Manifestation of Silent Celiac Disease in an Elderly Patient

Purpose: Introduction: Celiac disease (CD) is an immune-mediated glutensensitive enteropathy with various clinical presentations. BCG, in addition to its role as a vaccine against tuberculosis, has been used as an immunotherapeutic agent in patients with bladder cancer by intravesical instillation. We present an elderly patient with new onset of celiac disease after intravesical treatment with BCG, the first such report to our knowledge. Case Report: An 81-year-old woman with recently diagnosed superficial bladder cancer, treated with resection and intravesical BCG instillation, was seen because of multiple episodes of spurious non-bloody diarrhea for 3 days associated with colicky abdominal pain, nausea and non-bilious vomiting with no fever. On arrival, she was hypotensive requiring aggressive intravenous hydration. Physical examination was otherwise unremarkable. Similar episodes occurred twice 3 months ago, 2 weeks after her fourth BCG dose, requiring hospitalization and fluid resuscitation. At that time she was treated empirically for Clostridium difficile colitis and discharged without any definitive diagnosis. This admission, work up revealed normocytic anemia, +fecal WBC, and negative findings for C. difficile toxin and stool culture tests for cryptosporidia and ova and parasites. CT scan of the abdomen was unremarkable. Tissue transglutaminase antibody and gliadin IgG were mildly elevated. Endoscopy-guided small intestinal biopsy showed typical pathological characteristics of CD. The patient responded to a gluten-free diet with marked improvement in her symptoms. The diagnosis of latent CD was subsequently reconfirmed by genetic analysis. Discussion: The exact mechanism of BCG action is unknown, but intravesical instillation triggers a variety of local immune responses including stimulation of CD4 T cells, macrophages, cytokines and IFN-γ resulting in tumor destruction. The systemic response to intravesical BCG instillation has not been studied and has been thought to have only local effect. However, rare cases of BCG-induced HLA B27-positive arthritis have been reported. We propose that this new emergence of latent CD shortly after BCG therapy in our elderly patient is not just a coincidence. The impact of systemic immune response and possibly new onset of autoimmune disorders, such as CD, with intravesical BCG needs to be investigated. Clinicians should consider the diagnosis of activated CD (perhaps including other inflammatory bowel diseases) in patients with a new onset of unexplainable diarrhea after BCG therapy. More studies will need to be done to further validate this relationship, which suggests wider risks of activating remote immune reactions with BCG.

Intravesical Bacille Calmette-Guérin Therapy for Non-Muscle-Invasive Bladder Cancer: Effects of Concurrent Statin Therapy

Recent studies provide conflicting evidence about the association of statin use and decreased efficacy of intravesical bacille Calmette-Guérin (BCG) therapy for bladder cancer. Because statin drugs have immunomodulatory properties that could reduce the effectiveness of BCG, we investigated whether concurrent use of statin drugs was associated with worsened clinical outcomes in patients undergoing BCG treatment for non-muscle-invasive bladder cancer. We retrospectively analyzed records of 120 patients undergoing BCG treatment during 1997 through 2007 at a single Department of Veterans Affairs Medical Center. Tumor-progression events, total recurrences, disease-specific and overall mortality were the outcomes relative to statin use. Fisher's exact, Student's t-tests, and logistic regression were used to compare the groups. Among the 90 evaluable patients, there were no significant differences between groups with regard to tumor grade and stage distribution or smoking status. Statins were used during BCG therapy by 47.8% of patients. Comparing patients with no use versus use of statins, 8.5% versus 11.6% had local tumor progression (p = 0.44); 10.6% versus 9.3% underwent cystectomy, chemotherapy, or radiation therapy (p = 0.56); and metastatic disease developed in 6.7% versus 11.6% (p = 0.33). Of the 27 patients who died of any cause, 12.5% (2 of 16) versus 27.3% (3 of 11) in the nonstatin versus statin groups, respectively, died of disease (p = 0.32). Concurrent statin use was not associated with adverse outcomes for patients undergoing BCG treatment for bladder cancer. While statins have a plausible biologic mechanism to reduce BCG efficacy, no differences were seen in this small pilot study.

Commentary on The results of concurrent chemo-radiotherapy for recurrence after treatment with bacillus Calmette Guerin for non-muscle-invasive bladder cancer: Is immediate cystectomy always necessary?: Wo JY, Shipley WU, Dahl DM, Coen JJ, Heney NM, Kaufman DS, Zietman AL, Harvard Radiation Oncology Program, and Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA

To report our original experience in patients in whom bacille Calmette-Guerin (BCG) therapy has failed for T1 bladder cancer with subsequent progression to T2 disease treated with chemo-radiotherapy, as the management of recurrent high-grade T1 bladder cancer after failed BCG therapy is challenging, and radical cystectomy is the standard treatment because there are no well established second-line bladder-preserving therapies. From 1988 to 2002, 18 patients with T2 recurrence after failure of BCG therapy for T1 bladder cancer were treated with chemo-radiotherapy at the authors' institution. Patients received a visibly complete transurethral resection of the bladder tumor (TURBT) and concurrent chemo-radiotherapy with a mid-treatment evaluation after 40 Gy. Patients with less than a complete response had a prompt cystectomy; the others completed radiotherapy to 64–65 Gy. The primary treatment outcome was freedom from cystectomy due to recurrence not treatable by conservative measures; secondary outcomes included disease-specific (DSS) and overall survival (OS). With a median follow-up of 7.0 years, only 1 patient had persistent tumor at restaging TURBT, and had an immediate cystectomy. Of the remaining 17 patients, 10 (59%) were free of any bladder recurrence. The actuarial 7-year DSS and OS were 70% and 58%, respectively. At 7 years, 54% of patients were alive with intact bladders and free of invasive recurrence. In this study, we specifically evaluated patients with apparently small muscle-invasive recurrences after BCG treatment for T1 bladder cancer. Selective bladder preservation with chemo-radiotherapy is possible, with low morbidity and a high chance of long-term bladder control. If successful in treating T2 recurrences after BCG therapy, it now seems timely to critically evaluate chemo-radiotherapy as an alternative to immediate cystectomy in the management of patients with T1 recurrences after BCG.

The results of concurrent chemo‐radiotherapy for recurrence after treatment with bacillus Calmette‐Guérin for non‐muscle‐invasive bladder cancer: is immediate cystectomy always necessary?

To report our original experience in patients in whom bacille Calmette-Guérin (BCG) therapy has failed for T1 bladder cancer with subsequent progression to T2 disease treated with chemo-radiotherapy, as the management of recurrent high-grade T1 bladder cancer after failed BCG therapy is challenging, and radical cystectomy is the standard treatment because there are no well established second-line bladder-preserving therapies. From 1988 to 2002, 18 patients with T2 recurrence after failure of BCG therapy for T1 bladder cancer were treated with chemo-radiotherapy at the authors' institution. Patients received a visibly complete transurethral resection of the bladder tumour (TURBT) and concurrent chemo-radiotherapy with a mid-treatment evaluation after 40 Gy. Patients with less than a complete response had a prompt cystectomy; the others completed radiotherapy to 64-65 Gy. The primary treatment outcome was freedom from cystectomy due to recurrence not treatable by conservative measures; secondary outcomes included disease-specific (DSS) and overall survival (OS). With a median follow-up of 7.0 years, only one patient had persistent tumour at re-staging TURBT and had an immediate cystectomy. Of the remaining 17 patients, 10 (59%) were free of any bladder recurrence. The actuarial 7-year DSS and OS were 70% and 58%, respectively. At 7 years, 54% of patients were alive with intact bladders and free of invasive recurrence. In this study we specifically evaluated patients with apparently small muscle-invasive recurrences after BCG treatment for T1 bladder cancer. Selective bladder preservation with chemo-radiotherapy is possible, with low morbidity and a high chance of long-term bladder control. If successful in treating T2 recurrences after BCG therapy, it now seems timely to critically evaluate chemo-radiotherapy as an alternative to immediate cystectomy in the management of patients with T1 recurrences after BCG.

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.

Discontinuance of Bacille Calmette-Guérin Instillation Therapy for Nonmuscle-invasive Bladder Cancer Has Negative Effect on Tumor Recurrence

To investigate whether the occurrence of side effects or discontinuance of bacille Calmette-Guérin (BCG) therapy because of side effects is associated with its therapeutic efficacy. We analyzed the data from 145 patients who had had nonmuscle-invasive bladder cancer (Stage pTa, pT1, or pTis) and had undergone an initial course of adjuvant BCG therapy after transurethral resection of bladder tumor from 1996 and 2006 at Keio University Hospital. Side effects were classified as minor and major, and the association between the occurrence of side effects or discontinuance of BCG therapy because of side effects and tumor recurrence or progression was analyzed. Side effects occurred in 106 patients (73.1%) during BCG instillation. Of these 106 patients, 38 had major side effects and 95 had minor; 27 patients had both. BCG therapy was discontinued in 19 patients (13.1%) because of severe hematuria in 2, high fever in 8, and severe lower urinary tract symptoms in 9. Multivariate analyses demonstrated that discontinuance of BCG therapy (P = .018) was an independent predictor for tumor recurrence, in addition to multiplicity (P = .043). However, the occurrence of side effects was not an independent predictor for tumor recurrence (P = .935). Multivariate analyses also demonstrated that neither discontinuance of BCG therapy (P = .308) nor the occurrence of side effects (P = .333) was an independent predictor for tumor progression. Discontinuation of BCG therapy has a significantly deleterious effect on reducing the incidence of tumor recurrence. When major side effects occur, it might be preferable to attempt to mitigate the major side effects to maintain the BCG therapy on schedule.

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.

Impact of Previous Bacille Calmette-Guérin Failure Pattern on Subsequent Response to Bacille Calmette-Guérin Plus Interferon Intravesical Therapy

To evaluate the effect of the bacille Calmette-Guérin (BCG) failure pattern in patients with non-muscle-invasive bladder cancer on the subsequent response to intravesical immunotherapy. Data from the national Phase II multicenter trial for BCG plus interferon-alpha intravesical therapy for non-muscle-invasive bladder cancer were analyzed. The cancer-free rates for BCG-naive (BCG-N) and BCG-failure (BCG-F) patients with different failure patterns were compared using Kaplan-Meier analysis. At a median follow-up of 24 months, the BCG-N and BCG-F patients had a cancer-free rate of 59% and 45%, respectively. The BCG-F patients with immediate recurrence (refractory disease), within 6, 6 to 12, 12 to 24, and longer than 24 months had a cancer-free rate of 34%, 41%, 43%, 53%, and 66%, respectively (P = 0.005 for trend). No statistically significant difference was found in the cancer-free rates between patients with failure after 12 months and those with failure after 24 months or between BCG-N patients and those with failure after 12 and 24 months. A multivariate analysis of patients with failure after 12 months revealed that the number of previous courses of BCG did not significantly affect the treatment response. Patients with non-muscle-invasive bladder cancer with disease recurrence more than 1 year after BCG treatment and who were treated with low-dose BCG plus interferon-alpha had response rates similar to those of BCG-N patients treated with regular-dose BCG plus interferon. Although cystectomy should still be strongly considered, these patients might benefit from another trial with intravesical immunotherapy. In contrast, recurrence within 1 year of BCG treatment should lead to consideration of either cystectomy or alternative intravesical therapies.

Age and Outcome of Superficial Bladder Cancer Treated with Bacille Calmette-Guérin Therapy

To determine the influence of age on the outcomes of high-risk superficial bladder cancer treated with intravesical bacille Calmette-Guérin (BCG) therapy. A total of 805 patients with multiple or recurrent high-grade Ta, T1, and/or carcinoma in situ bladder cancer received BCG therapy. The endpoints were the initial response to BCG and cancer-free survival correlated with age among patients followed up for a minimum of 2 to 5 years. No difference was observed in the first response to BCG or cancer-free survival at 2 years among patients less than 50, 50 to 59, 60 to 69, 70 to 79, or 80 years or older. After 5 years, 27% of patients older than 70 years were cancer free compared with 37% younger than 70 years (P = 0.005). The results of our study have shown that aging has a measurable, but small, impact on the overall outcomes of high-risk superficial bladder cancer.

Phase I/II study of topical imiquimod and intralesional interleukin-2 in the treatment of accessible metastases in malignant melanoma

Patients with metastatic skin disease in malignant melanoma can be difficult to treat effectively, often requiring repeated treatments with different modalities in an attempt to control their disease. Treatment of nonsurgically resectable melanoma deposits is unsatisfactory, as they are often multiple and recurring. Anecdotal evidence from individual use of imiquimod in superficial metastases and intralesional interleukin (IL)-2 in subcutaneous deposits suggests that the combination may be more effective in bulky subcutaneous disease. To investigate the combination of topical imiquimod and, for selected lesions, intralesional IL-2, to treat a small cohort of patients with accessible melanoma metastases resistant to other treatments. Thirteen patients were recruited: all had evidence of multiple cutaneous and/or subcutaneous metastases. Imiquimod was applied to the metastases on a daily basis for 4 weeks, before the introduction of intralesional IL-2. This was injected up to three times a week, into selected lesions, with 0.1 mL injected per lesion at a concentration of 3.6 MIU mL(-1), a total of 1 mL being given at each session. The treated lesions were assessed individually at intervals of 3 months. Thirteen patients were treated, with 10 being eligible for assessment. In total, 182 lesions were treated: 137 purely cutaneous lesions and 41 subcutaneous lesions. Overall, a clinical response was seen in 92 lesions (50.5%) with 74 (40.7%) of these being a complete response (CR) with 91% of the CRs being in the cutaneous lesions. New lesions did appear during the treatment course; however, patients with cutaneous disease experienced a marked slowing of the appearance of new cutaneous lesions. No cutaneous lesions that responded reappeared on cessation of treatment. The combination of imiquimod and IL-2 is effective in controlling this mixed cutaneous and subcutaneous disease, and is well tolerated. Imiquimod alone is often enough to elicit a response in purely cutaneous lesions. The addition of intralesional IL-2 increases the response rates in subcutaneous lesions, and in otherwise refractory cutaneous lesions.

Phase II Trial of Intravesical Gemcitabine in Bacille Calmette-Guérin–Refractory Transitional Cell Carcinoma of the Bladder

The aim of this phase II study was to determine the efficacy of gemcitabine administered as an intravesical agent in patients with bacille Calmette-Guérin (BCG) -refractory transitional cell carcinoma of the bladder. Patients with superficial bladder cancer refractory or intolerant to intravesical BCG therapy and refusing a cystectomy were considered eligible for the trial. Eligible patients received two courses of intravesical gemcitabine twice weekly at a dose of 2,000 mg/100 mL for 3 consecutive weeks, with each course separated by 1 week of rest. Patients were evaluated for response at 8 weeks, then every 3 months to 1 year. Thirty eligible patients were included on study. The median follow-up for all the patients was 19 months (range, 0 to 35 months). Of the 30 patients, 15 (50%; 95% CI, 32% to 68%) achieved a complete response (CR). Twelve patients had tumor recurrence with a median recurrence-free survival time of 3.6 months (95% CI, 2.9 to 11.0 months). Two patients maintained a CR at 23 and 29 months, respectively. The 1-year recurrence-free survival rate for patients with a CR was 21% (95% CI, 0% to 43%). Two patients progressed to a higher stage while receiving gemcitabine treatment. The median follow-up for patients who did not have a progression or a cystectomy was 19 months (range, 2 to 35 months). Eleven patients (37%) underwent a cystectomy subsequent to gemcitabine therapy. Gemcitabine has activity in a high-risk patient population and remains a viable option for some patients who refuse cystectomy.

Intravesical interleukin-12 gene therapy in an orthotopic bladder cancer model

Objectives To evaluate the antitumor effect of intravesical cationic liposome-mediated interleukin-12 (IL-12) gene delivery in an orthotopic murine bladder cancer model, and to investigate the immunologic memory against tumors between IL-12 gene therapy and bacille Calmette-Guérin (BCG) therapy. Methods Orthotopic murine bladder tumors were established by implanting 5 × 10 5 MBT-2 cells into the bladder of syngeneic female C3H mice. Intravesical IL-12 gene therapy was evaluated at varying doses: 0 μg (control) and 3, 5, and 10 μg (n = 8 for each group). Intravesical treatments were performed every 3 days and repeated six times beginning 5 days after tumor implantation. To compare the long-term, tumor-specific immunity between IL-12-treated mice (n = 18) and BCG-treated mice (n = 20), the animals surviving at day 60 and 10 new control mice were rechallenged with MBT-2 cells and received no additional treatment. On day 120, all surviving mice were killed and underwent necropsy. Results In the IL-12 groups at doses of 0, 3, 5, and 10 μg, 0, 2, 3, and 3 mice survived, respectively. Mice in the 5-μg and 10-μg IL-12 groups survived significantly longer than did the control group. All mice cured by IL-12 treatment successfully rejected the rechallenge with MBT-2 cells; however, mice cured by BCG and the new control mice died of the rechallenged bladder tumors. Conclusions Intravesical IL-12 gene therapy, which induced long-lasting tumor-specific immunologic memory compared with BCG therapy, improved survival in an orthotopic bladder cancer model.

Clinical study of bladder cancer: Proteinuria as a predictor of recurrence and efficacy of intravesical bacille Calmette-Guerin therapy.

We studied the clinical characteristics of bladder cancer, with special attention to the clinical and pathological variables that affect tumor stage, relapse and efficacy of intravesical therapy. We reviewed the medical records of 152 patients of the Saiseikai Central Hospital who had been diagnosed as having bladder cancer between 1981 and 2001. The age of the patients ranged from 24 to 88 years, with a median of 63.5 years. The median follow up was 52.4 months (range, 0.5-259.5 months). There was no difference in the incidence of gross hematuria as a presenting symptom among the patients with invasive cancer, superficial cancer and carcinoma in situ (CIS). However, the incidence of urinary frequency and painful urination did differ significantly between patients. Although patients with invasive cancer had a longer time to hospital visit than those with superficial cancer, this time difference was not statistically significant. Presence of proteinuria, multifocality and intravesical bacille Calmette-Guerin (BCG) therapy were the significant predictors of relapse after transurethral resection (TUR). Presence of proteinuria was shown to adversely affect the efficacy of intravesical BCG therapy. In the BCG-treated group, 3-year relapse-free survival was 78.4% for patients without proteinuria and 40.0% for those with proteinuria; this difference was statistically significant (P = 0.0277). Time to hospital visit did not influence the pathological stage of cancer in patients included in the present study. Presence of proteinuria, multifocality and BCG therapy were the significant predictors of relapse after TUR. Presence of proteinuria was shown to adversely affect the efficacy of intravesical BCG therapy. Proteinuria might be helpful in predicting tumor relapse and efficacy of intravesical BCG therapy in clinical settings, along with other markers.

Long-term effects of bacille calmette-guérin perfusion therapy for treatment of transitional cell carcinoma in situ of upper urinary tract

Objectives To report our experience with bacille Calmette-Guérin (BCG) perfusion therapy for transitional cell carcinoma in situ of the upper urinary tract. BCG perfusion therapy is widely used to treat transitional cell carcinoma in situ of the upper urinary tract. However, it has not yet been established as a standard treatment. Methods Ten patients diagnosed with transitional cell carcinoma in situ of the upper urinary tract were treated with BCG perfusion therapy from January 1990 to May 2002. BCG was instilled weekly for 6 weeks, with a median dose of 65 mg at 1.17 mg/mL (Tokyo 172 strain, dissolved in normal saline). Results The mean follow-up period was 50.9 months (range 12 to 134). The initial response to therapy was excellent, and cytology became negative in all patients after one course of BCG perfusion. Five patients developed recurrence after 5, 11, 24, 26, and 45 months, and all died after 46, 12, 41, 134, and 79 months, respectively. The mortality rate was 50% and was 100% in those with recurrence. The mean recurrence-free period was 22.2 months (range 5 to 45). Complications included bladder irritation-related symptoms in all patients, fever greater than 38°C (n = 9), hematuria (n = 2), hydronephrosis (n = 2), and lumbago (n = 1) but all were transient and did not affect long-term prognosis. Conclusions BCG perfusion therapy for carcinoma in situ of the upper urinary tract is safe, and the short-term response is excellent. However, the long-term results were not satisfactory. Therefore, this therapy should be considered experimental, although it may have potential benefits in delaying progression and possibly providing local control for patients in poor condition. Long-term studies are required for additional evaluation of BCG therapy.

Effect of intravesical instillation on performance of uCYT+ test

Objectives To assess the influence of intravesical instillation of epirubicin or bacille Calmette-Guérin (BCG) in patients with bladder cancer on the clinical performance of the uCyt+ test, which traces the three monoclonal antibodies M344, LDQ 10, and 19A211 in urothelial cells. Methods A total of 267 patients with a mean age of 70.5 years (range 35 to 87) were included in this prospective study. All patients were being followed up after complete transurethral resection of superficial urothelial cancer. All patients received a single instillation of 80 mg epirubicin within 24 hours of transurethral resection and 163 underwent subsequent cycles of chemotherapy with epirubicin or immunotherapy with BCG. This was because of multifocality, high-recurrence, or high-grade urothelial cancer. At the next control, all patients underwent urinary cytology, with the uCyt+ test performed on liquid-based cytology (ThinPrep), subsequent cystoscopy, and evaluation of any suspicious lesion by biopsy. Patients who underwent intravesical BCG therapy underwent random bladder cold biopsy after every instillation series. Results Of the 267 patients, 8 could not be evaluated by uCyt+ because of insufficient cells. Of the remaining 259 patients under assessment, 86 had proven urothelial cancer. In the 101 patients under assessment with only a single intravesical instillation of epirubicin (group 1), the overall sensitivity for cytology and the uCyt+ test was 44.7% and 76.6%, respectively. Cytology had a specificity of 90.7% and uCyt+ of 64.8%. The negative predictive value for cytology and uCyt+ was 65.3% and 76.1%, respectively. Of the 158 patients under evaluation who were treated with long-term intravesical therapy (group 2), the overall sensitivity and specificity for cytology and the uCyt+ test was 37.8% and 84.6% and 94.9% and 70.6%, respectively. The negative predictive value for cytology and the uCyt+ test was 83.1% and 93.3%, respectively. Statistical analysis showed no statistically significant difference between the overall sensitivity ( P = 0.512) and specificity ( P = 0.558) for the uCyt+ test in the two groups of patients. Conclusions The sensitivity and specificity of the uCyt+ test are not significantly affected by intravesical long-term treatment with epirubicin or BCG.