Long-term complete remission inbladder carcinoma in situ with intravesical tice bacillus Calmette guerin: Overview analysis of six phase II clinical trials

doi:10.1016/0090-4295(91)80166-5

Urology

Volume 38, Issue 6, December 1991, Pages 507-513

https://doi.org/10.1016/0090-4295(91)80166-5 Get rights and content

Abstract

Carcinoma in situ is a form of superficial transitional cell carcinoma, which is characterized by a lateral spread along the bladder epithelium, with high-grade malignancy and poor prognosis. Early radical cystectomy is considered the definitive treatment even in the absence of associated invasive cancer. In six prospective phase II studies, 123 carcinoma in situ patients were administered intravesical TICE bacillus Calmette-Guerin (BCG). Treatment consisted of at least six weekly instillations (induction) followed by twelve monthly instillations (maintenance) of BCG (50 mg: 1 to 8 × 10⁸ colony-forming units). Of 119 evaluable patients, 90 (76%) achieved complete remission including 45 of 63 (71 %) patients who received prior intravesical chemotherapy. Forty-five responders (50 %) remain in complete remission with negative urine cytology with a median duration of response projected to be ≥ forty-eight months. There is no difference in survival between BCG responders and nonresponders, but there is a significant difference in cystectomy rates: 10 of 90 (11 %) responders vs. 16 of 29 (55 %) nonresponders (P < 0. 0001, Fisher's exact test) and time to cystectomy (31 vs. 74 mos.) (P <0.001, log-rank test). Delaying cystectomy does not seem to affect survival and improves quality of life. Treatment was well tolerated with some major adverse effects. Intravesical TICE BCG is an effective treatment for bladder carcinoma in situ patients with or without prior chemotherapy.

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Intravesical Bacille Calmette–Guérin (BCG) therapy after removal of prominent bladder tumor masses by transurethral resection is aimed to prevent recurrence of bladder cancer and to reduce disease progression to muscle-invasive bladder cancer. The indication of BCG therapy is high-grade Ta, T1, and/or carcinoma in situ, and multifocal, large, low-grade Ta or recurrent low-grade Ta tumors. BCG is administered directly into the bladder at weekly intervals for an initial course of 6–8 weeks with 81 mg or 27 mg of BCG. Greater reduction in recurrences can be obtained by using maintenance courses of three instillations at three monthly, then six monthly intervals with a recommended dosing of 27 mg BCG for at least 1 year. BCG, however, has more toxicity and systemic side effects that can be life threatening than other cytotoxic agents, causing many patients to discontinue treatment. The results of BCG usually need to be assessed by repeat biopsies.
Immunotherapy: Bacille Calmette-Guérin
2017, Bladder Cancer
Intravesical Bacille Calmette–Guérin (BCG) therapy after removal of prominent bladder tumor masses by transurethral resection is aimed to prevent recurrence of bladder cancer and to reduce disease progression to muscle-invasive bladder cancer. The indication of BCG therapy is high-grade Ta, T1, and/or carcinoma in situ, and multifocal, large, low-grade Ta or recurrent low-grade Ta tumors. BCG is administered directly into the bladder at weekly intervals for an initial course of 6–8 weeks with 81 mg or 27 mg of BCG. Greater reduction in recurrences can be obtained by using maintenance courses of three instillations at three monthly, then six monthly intervals with a recommended dosing of 27 mg BCG for at least 1 year. BCG, however, has more toxicity and systemic side effects that can be life threatening than other cytotoxic agents, causing many patients to discontinue treatment. The results of BCG usually need to be assessed by repeat biopsies.
Natural product derived immune-regulatory agents
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Citation Excerpt :
Treatment with BCG delays progression to muscle-invasive and/or metastatic disease, improves bladder preservation, and decreases the risk of death from bladder cancer [16]. Although intravesical BCG may not prolong overall survival (OS) for carcinoma in situ, it does result in complete response rates of about 70%, decreasing the need for salvage cystectomy [17] and delaying tumor recurrence and progression [18]. Meta-analyses have documented that BCG reduces recurrence and progression rates [19] and in comparison to IFN-α has similar efficacy [20].
We can now declare that the clinical goal of immune intervention as a therapeutic strategy for neoplastic, infectious, autoimmune and inflammatory diseases, has been achieved and in many instances obtained regulatory approval. Although, interest in and optimism for this approach has fluctuated, in the last 20 years, immunotherapy has progressed from trials with crude microbial mixtures and extracts to the sophisticated use of pure cultured bacterial, synthetized active moieties identified from crude extracts, analogues therefrom and agonists and antagonists identified during screening resulting in reproducible pharmacologically active compounds with multiple mechanisms of action. Our current understanding of the mechanism of action for immunoregulatory agents contributes to the future discovery of improved strategies to use these and future immunotherapies. In this review we have identified and discussed, those drugs that have been approved and or are in clinical development as immunoregulatory agents, emphasizing those derived from or associated with natural product.
Diagnosis and management of urothelial carcinoma in situ of the lower urinary tract: A systematic review
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As with all high-risk NMIBC, a balance must be struck between overtreatment with RC and undertreatment with subsequent disease progression when administering BCG [2,75,90]. It has not been demonstrated that an initial trial of BCG immunotherapy, followed by salvage RC for patients who fail to achieve a CR or who recur, affects overall survival compared with immediate RC [91–93]. However, progression to invasive disease likely occurs in a delayed fashion in patients with CIS.
Urothelial carcinoma in situ (CIS) has a high propensity for progression. It is usually reported within the heterogeneous context of non–muscle-invasive bladder cancer (NMIBC) but warrants special consideration.
To review the contemporary literature on the diagnosis and management of CIS.
A systematic search using broad terms to capture the diagnosis and treatment of CIS was performed according to Preferred Reporting Items for Systematic Reviews and Meta-analysis criteria. Full-text original articles, reviews, and editorials from 1966 to 2014 in English were included. References from selected articles, relevant guidelines, and conference abstracts were searched. Abstracts were excluded.
A total of 1887 articles were identified, of which 120 were used in this review. Most reports were retrospective and heterogeneous in caseload. There is a lack of standardised classification of CIS. Many studies consider CIS in the context of NMIBC without a clear separation of the subset with CIS. Recent prospective phase 2 and 3 studies have improved the evidence base.
We are beginning to understand that CIS has a spectrum of biologic potential. Bacillus Calmette-Guérin immunotherapy appears superior to other intravesical agents and may alter the natural history of CIS. New imaging modalities, agents, and treatment strategies have emerged in recent years with the aim of better identification of CIS, more bladder-preserving treatments, and prevention of surgical overtreatment.
Improvements in imaging techniques combined with new bladder-preserving treatments will continue to have an impact on the outcomes of bladder carcinoma in situ.
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Scientific articleLong-term complete remission inbladder carcinoma in situ with intravesical tice bacillus Calmette guerin: Overview analysis of six phase II clinical trials

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Scientific article
Long-term complete remission inbladder carcinoma in situ with intravesical tice bacillus Calmette guerin: Overview analysis of six phase II clinical trials