ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Treatment of primary non-muscle invasive urothelial bladder cancer

Treatment of primary non-muscle invasive urothelial bladder cancer
Literature review current through: Jan 2024.
This topic last updated: Jun 14, 2022.

INTRODUCTION — Globally, bladder cancer accounts for approximately 390,000 cases and 150,000 deaths each year [1]. In developed areas of the world, such as North America and Western Europe, these bladder cancers are predominantly urothelial (formerly called transitional cell). (See "Epidemiology and risk factors of urothelial (transitional cell) carcinoma of the bladder", section on 'Epidemiology'.)

Approximately 70 percent of new urothelial bladder cancer cases are classified as non-muscle invasive [2]. Non-muscle invasive bladder cancer includes Ta (papillary), T1 (submucosal invasive), and Tis (carcinoma in situ [CIS]) (table 1), which account for approximately 70, 20, and 10 percent of non-muscle invasive cancers, respectively. (See "Pathology of bladder neoplasms", section on 'Noninvasive urothelial neoplasms'.)

The prognostic factors, risk stratification, and initial management of primary non-muscle invasive bladder cancer are discussed here, while the management of recurrent or persistent non-muscle invasive bladder cancer is discussed separately. (See "Management of recurrent or persistent non-muscle invasive bladder cancer".)

Other related topics include:

(See "Clinical presentation, diagnosis, and staging of bladder cancer".)

(See "Overview of the initial approach and management of urothelial bladder cancer".)

INITIAL MANAGEMENT

Transurethral resection — The initial treatment of presumed non-muscle invasive bladder tumors is a complete transurethral resection of all visible bladder tumor (TURBT) with adequate depth to include muscularis propria. The quality of the TURBT is of primary importance. An examination under anesthesia (EUA) should also be performed since the presence of induration or a palpable mass suggests muscle invasive disease. A single postoperative instillation of intravesical chemotherapy is recommended in appropriately selected patients.

Resection should also include biopsy of focal areas of suspected carcinoma in situ (CIS), and abnormal areas in the prostatic urethra and bladder neck. Most patients can be successfully managed conservatively; however, a minority will require more aggressive surgery. (See 'Cystectomy' below.)

If the initial TURBT reveals muscle invasive disease, more aggressive treatment is indicated. (See "Overview of the initial approach and management of urothelial bladder cancer", section on 'Muscle invasive disease'.)

Restaging transurethral resection — A restaging transurethral resection (TUR) should be performed four to six weeks after the initial resection when the initial TUR is incomplete or if the tumor is high-grade T1, especially if muscularis propria is absent in the specimen.

Restaging transurethral resection provides more tissue for pathologic examination and more accurate staging, as well as insight into the biology of the disease. Approximately 30 percent of apparent T1 tumors will be found to have been understaged (ie, T2 or greater) by TURBT [3-7]. Thus, a repeat TURBT is strongly recommended in order to decrease the likelihood of understaging in patients whose tumors involve the lamina propria, even if the initial resection was thought to be complete [3,4,8-12].

The importance of a restaging TUR is illustrated by a retrospective analysis of 1021 patients with high-risk non-muscle invasive bladder cancer [13]. Viable tumor was found in 55 percent of patients at restaging TURBT. A follow-up of these patients by TUR at three months found that patients who had a restaging TURBT had significantly fewer recurrences compared with those with a single resection (9.6 versus 44.3 percent). Restaging TUR was associated with fewer recurrences (62 versus 77 percent) and significantly prolonged progression-free survival (82 versus 67 percent) at five-year follow-up.

Enhanced imaging techniques — Both fluorescence endoscopy (blue light cystoscopy) and narrow band imaging (NBI) are enhanced imaging techniques that can be used in conjunction with TURBT to improve the detection of non-muscle invasive disease and to decrease recurrence risk. However, neither approach has been shown to impact progression-free or overall survival

Fluorescence endoscopy — Fluorescence endoscopy with blue light after intravesical instillation of a porphyrin, such as hexaminolevulinate (HAL) or 5-aminolevulinic acid (ALA), appears to be more effective than white light endoscopy for the detection of multifocal tumors and CIS, and they may improve outcomes of TURBT [14-21].

A meta-analysis that included 2906 patients from 14 randomized trials comparing HAL or ALA with white light cystoscopy in patients with known or suspected non-muscle invasive bladder cancer found that fluorescent cystoscopy improved tumor detection and decreased risk of subsequent recurrences [22]. However, it is unclear whether this benefit persists for patients who receive immediate instillation of mitomycin following TURBT. A randomized trial that compared HAL photodynamic-assisted TURBT plus a single instillation of postoperative mitomycin with standard white light cystoscopy found no significant difference in recurrence rates at three months and one year [23].

Fluorescence endoscopy with blue light is also feasible for surveillance flexible cystoscopy and is more effective at detecting recurrences. In a phase III trial, patients with a history of multiple, recurrent, or high-grade urothelial tumors were randomized after initial white light cystoscopy to proceed with immediate blue cystoscopy or to undergo only the white light cystoscopy [24]. Those with evidence of recurrence proceeded to TURBT within six weeks of cystoscopy. TURBT was performed with both white and blue light in all patients. Of the 103 patients who underwent TURBT, a recurrent tumor was confirmed in 63, including 13 cases (21 percent) in which malignancy was detected only by blue light flexible cystoscopy. At the time of TURBT, blue light detected tumors that were missed by white light in 29 cases (46 percent). False positive rates were the same for both cystoscopy methods (9.1 percent). Flexible fluorescent cystoscopy was approved by the US Food and Drug Administration (FDA) and Health Canada in early 2018.

The improved early detection and treatment of tumors with fluorescence endoscopy needs to be balanced by a slightly higher false positive rate (mainly due to inflammation and scarring), the requirement for a special lens system, the need to instill the photosensitizer one hour prior to cystoscopy, as well as potentially higher costs.

Narrow band imaging — NBI is an enhanced imaging technique that can be used as an adjunct to white-light cystoscopy and to potentially improve outcomes of TURBT [25-30]. This technique uses a specific wavelength of light to accentuate the visibility of blood vessels and enhance the visualization of tumors. NBI also can be integrated into the procedure, as some cystoscopes can be easily switched from white light to NBI mode. It also does not require bladder instillation of a photosensitizer, unlike fluorescence endoscopy. The use of NBI to reduce recurrence risk must be weighed against the limited data on survival outcomes.

Although the data are less robust, in a systematic review of randomized trials that included over 1200 patients with non-muscle invasive bladder cancer, NBI-guided TURBT reduced the risk of disease recurrence compared with white light-guided TURBT (HR 0.63, 95% CI 0.45-0.89) with no difference in adverse events [28]. However, the impact of postoperative chemotherapy instillation or intravesical therapy was not integrated into this analysis, since their use differed between studies. In contrast, a separate meta-analysis of randomized trials that included 921 patients did not demonstrate a difference in recurrence rates for NBI compared with white light cystoscopy [30].

PROGNOSTIC FACTORS — An estimated 40 to 80 percent of non-muscle invasive bladder cancers recur within 6 to 12 months when managed with a transurethral resection of all visible bladder tumor (TURBT) without additional therapy, and 10 to 25 percent will progress to muscle invasive, regional, or metastatic disease [31]. Thus, additional therapy is often indicated even though an initial complete TURBT is possible.

The most important prognostic factors are histologic stage and grade. Other factors that have been assessed include number of tumors, the frequency of recurrence, the tumor size, and the presence or absence of concomitant Tis disease (also called carcinoma in situ [CIS]) [32,33]. Other factors include the presence of variant histology [34,35] and lymphovascular invasion [36-39].

Stage — Non-muscle invasive bladder cancers are classified into three stages based upon their growth pattern and depth of invasion: Ta, Tis, and T1 (table 1). (See "Pathology of bladder neoplasms", section on 'Pathologic tumor staging'.)

Ta tumors — Ta tumors are noninvasive papillary lesions that are confined to the urothelium and have not penetrated the basement membrane. These papillary tumors usually present as low-grade lesions that frequently recur multiple times prior to becoming invasive. The natural history of patients with Ta tumors without other evidence of invasive disease or Tis was illustrated by a retrospective series of 363 patients, in which only 6 percent eventually died of bladder cancer [40]. The fraction of patients who eventually progress to a high-grade lesion and require more aggressive treatment ranges from 6 to 28 percent in different series [40,41].

Tis — Tis (also called CIS) is characterized by severe cellular dysplasia in the absence of discrete tumor formation. Areas of mucosal involvement with Tis are often found in association with invasive disease. The presence of Tis in the mucosa adjacent to a Ta or T1 tumor appears to increase the risk for muscle invasive disease [42-45].

The potential prognostic significance associated with Tis is illustrated by a multicenter series of 243 patients who underwent radical cystectomy for Tis without more invasive disease [44]. Staging based upon the cystectomy specimen revealed that no disease (T0) was found in 8 percent, and Tis and Ta were identified in 48, and 8 percent of cases, respectively. However, T1, T2, T3, and T4 disease was detected in 13, 12, 5, and 6 percent of cases, respectively. Lymphovascular invasion and positive lymph nodes were found in 9 and 6 percent, respectively.

Tis is associated with a high incidence of subsequent progression to invasive disease. In a retrospective single-institution series of 155 patients managed with transurethral resection and BCG, the five-year cumulative incidence of progression to clinical T1 or higher stage disease was 45 percent (95% CI 37-55) [45]. Diffuse and extensive involvement of the mucosa with Tis is associated with particularly aggressive disease. Invasive bladder cancer develops in 60 to 80 percent of such patients [46,47].

T1 lesions — T1 tumors are by definition invasive cancers and are characterized by extension into the underlying lamina propria (also known as the submucosa) but without involvement of the muscularis propria, the true detrusor muscle of the bladder.

Virtually all T1 tumors are high grade, and approximately one-third to one-half have associated Tis. Recurrence rates at one, three, and five years can reach up to 50, 70 to 80, and 90 percent, respectively, and 20 to 25 percent progress to more invasive (T2 or greater) disease [48,49]. Conflicting data exist on whether nonprimary T1 lesions (occurring in patients who had a prior tumor resection for Tis or Ta disease) have a higher frequency of progression after BCG treatment compared with those with an initial presentation with T1 disease [50,51].

Because of the risk of progression, T1 tumors are generally treated with intravesical BCG, which reduces the rates of recurrence and progression by 30 to 40 percent [36,52]. (See 'Bacillus Calmette-Guerin' below.)

Grade — In addition to tumor stage (Tis, Ta, or T1), histologic grade influences the rate of recurrence and, ultimately, survival for patients with non-muscle invasive bladder cancer [53,54].

In 2004, the World Health Organization (WHO) revised its 1973 grading system in an attempt to improve interobserver agreement and provide better prognostic information, and this was updated in 2016 [31]. The WHO system employs the terms papillary urothelial neoplasm of low malignant potential (PUNLMP), low-grade urothelial carcinoma, and high-grade urothelial carcinoma. This has become the standard methodology for grading non-muscle invasive bladder cancer, although some community practices still report using the older grade 1 to 3 classification. (See "Pathology of bladder neoplasms".)

The importance of histologic grade was illustrated in a systematic review conducted by the European Association of Urology (EAU) [31]. In an analysis of 20 series that included all 2809 patients with evaluable data, the risk of progression to more advanced disease for patients with PUNLMP, low-grade urothelial carcinoma, and high-grade urothelial carcinoma was 1.7, 4.4, and 18.8 percent, respectively, while the risk of recurrence in the 1865 evaluable patients was 28, 43, and 58 percent, respectively.

In this systematic review, the risk of progression and recurrence was also analyzed based upon the 1973 criteria for grade 1, 2 and 3 lesions [31]. In patients with non-muscle invasive bladder cancer, the risk of progression to more advanced disease for the 2012 patients with data was 3, 9, and 28 percent, respectively, for grade 1, 2, and 3 lesions, and the risk of recurrence for the 1197 patients with data was 33, 44, and 65 percent, respectively.

Patients with grade 1 or 2 papillary (Ta) lesions who remain free of recurrence for at least five years usually have a good prognosis. In a series of 198 such patients diagnosed between 1991 and 1996, 89 percent of those who were disease-free at five years subsequently remained free of recurrence [55]. However, active surveillance is still required because of the risk of recurrence.

Multicentricity and frequency of recurrence — Patients who have multiple papillary tumors at the time of presentation have higher rates of both non-muscle invasive and invasive recurrence [53,54,56], but not necessarily worse survival [57]. As an example, the risk in one series for progression to muscle invasive disease for multiple and solitary lesions was 14 and 5 percent, respectively [56].

Tumor size — Patients who have large tumors (>3 cm) are associated with a higher risk of recurrence and progression to muscle-invasive disease [58].

Molecular markers — Molecular markers in tissue samples may provide an additional way to identify non-muscle invasive bladder cancers that are likely to progress to muscle invasive or high-grade disease [59-62]. The earliest studies focused on chromosomal abnormalities, and these provided the basis for identifying specific genetic alterations.

The presence of mutations in fibroblast growth factor receptor 3 (FGFR3) appears to identify a subgroup of patients with a favorable prognosis [63-65]. Some studies have suggested that abnormalities in p53 are associated with a less favorable prognosis in patients with non-muscle invasive disease, but these findings require confirmation [66-68].

Gene expression profiling may offer another approach to identifying those patients who are most likely to progress to muscle invasive disease and thus would benefit from more aggressive treatment [69-72]. More recently, stratification of T1 tumors into molecular subtypes (basal, or luminal-like characteristics) has been shown to improve the identification of patients with progressing tumors [73,74].

RISK STRATIFICATION — Once the diagnosis is confirmed, patients should be stratified by clinical factors to determine their risk of recurrence and/or progression. Incorporation of information about the depth of invasion (stage), histologic grade, and the presence or absence of multifocal disease, carcinoma in situ, or lymphovascular invasion are important factors in determining whether management should consist of TURBT alone, TURBT plus intravesical therapy, or cystectomy. Appropriate stratification of non-muscle invasive bladder tumors provides important information to guide subsequent therapy.

Based upon the 2019 European Association of Urologists (EAU) guidelines, the risk of progression is stratified into low (0 to 4 percent), intermediate (10 to 15 percent), and high (30 to 40 percent) based on tumor grade, invasion into lamina propria, tumor size, and whether the tumor is recurrent and multifocal [12,75]:

Low – Primary, solitary, low-grade Ta tumor, <3 cm in diameter, no carcinoma in situ (CIS).

Intermediate – All tumors not meeting the criteria for low risk or high risk.

High – Any of the following: CIS, high-grade disease, or T1 lesion. In addition, low-grade Ta tumors having all of the following are classified as high risk: multiple, recurrent, and large (>3 cm).

Similar criteria for risk stratification have been established by the American Urological Association (AUA) [11], although there are important differences. For example, both high-grade Ta tumors measuring <3 cm and low-grade T1 tumors are considered intermediate risk in the AUA classification but high risk in the EAU classification.

Rates of recurrence in patients have been characterized by the European Organisation for Research and Treatment of Cancer (EORTC) risk tables [32], although the accuracy of this prognostic tool has been questioned [76,77]. After a median follow-up of 3.9 years, 1240 of 2596 patients (47.8 percent) had at least one recurrence. The median time to first recurrence was 2.7 years. Progression to muscle-invasive disease was observed in 279 (11 percent) patients. These summary statistics, however, mask a wide spectrum of risk in this heterogenous patient population, which included primary and recurrent disease.

This spectrum of risk of recurrence and progression in patients with primary non-muscle-invasive bladder cancer is illustrated by the following examples:

A patient with one small (<3 cm), solitary, low-grade Ta has a 15 and 31 percent risk of additional recurrence at one and five years and a 0.2 and 0.8 percent risk of progression at one and five years.

A patient with multifocal (two to seven tumors), small, high-grade Ta bladder cancer in the absence of CIS has a 38 and 62 percent risk of additional recurrence at one and five years and a 5 and 17 percent risk of progression at one and five years.

A patient with one solitary, high-grade T1 tumor measuring >3 cm and concomitant CIS has a 38 and 62 percent risk of recurrence at one and five years and a 17 and 45 percent risk of progression at one and five years.

A quantitative calculator to more accurately predict the risk of both recurrence and progression has been developed by the EORTC [32,78]. Risk is calculated using a scoring system based on six factors: number of tumors, tumor size, prior recurrence rate (ie, first time occurrence versus recurrence >1 year from prior diagnosis versus recurrent tumor <1 year from prior diagnosis), T category, CIS, and grade. The five-year probabilities of recurrence or progression, based on total score, ranged from 30 to 80 percent and 1 to 45 percent, respectively.

However, the EORTC risk calculator probably overestimates the risk of recurrence and disease progression as very few patients in this database received intravesical bacillus Calmette-Guerin (BCG). More recently, the same group evaluated prognostic factors for recurrence and progression, as well as survival for patients with non-muscle invasive bladder cancer treated with BCG induction with one to three years of maintenance therapy [33].

The Spanish Urological Club for Oncological Treatment (CUETO) developed a similar risk stratification tool for patients who received BCG [79], which has been validated by other international groups [76,80]. The CUETO model is limited by the unusual dosing regimen (weekly induction for six weeks followed by biweekly instillation for 12 weeks) and the lack of maintenance BCG.

The EORTC subsequently proposed a new nomogram for patients treated with one or three years of maintenance BCG [33], based on the EORTC 30962 trial [81]. In this trial of 1812 patients, 762 (42.1 percent) recurred, 173 (9.5 percent) progressed, and 520 (28.7 percent) died after a median follow-up of 7.4 years. Death was due to bladder cancer in 83 (4.6 percent) cases.

MANAGEMENT BASED ON RISK OF RECURRENCE — Initial management is based on risk stratification (algorithm 1):

Low risk – For patients with low-risk disease, no adjuvant systemic treatment is required, and a single dose of intravesical chemotherapy is often administered after the transurethral resection and is allowed to dwell for 60 minutes. (See 'Initial management' above and 'Single postoperative instillation' below.)

Intermediate risk – For patients with intermediate-risk disease, intravesical therapy is suggested following transurethral resection of all visible bladder tumor (TURBT). Options include Bacillus Calmette-Guerin (BCG) or intravesical chemotherapy [82]. (See 'Bacillus Calmette-Guerin' below.)

High risk – For high-risk patients with stage T1 tumors (and select patients with high-grade Ta tumors with an incomplete or suspected incomplete initial TURBT), a restaging TURBT is performed four to six weeks after the initial cystoscopy/TURBT to determine whether radical cystectomy may be indicated. (See 'Restaging transurethral resection' above and 'Cystectomy' below.)

For patients with high-risk disease not undergoing cystectomy, a course of intravesical therapy is indicated. The agent of choice for high-risk patients is BCG. (See 'Bacillus Calmette-Guerin' below.)

Careful surveillance following treatment is recommended for all patients. (See 'Posttreatment surveillance' below.)

INTRAVESICAL THERAPY — Intravesical therapy permits high local concentrations of a therapeutic agent within the bladder, potentially destroying viable tumor cells that remain following transurethral resection of all visible bladder tumor (TURBT). The decision to proceed with intravesical therapy depends primarily upon the likelihood of a recurrence and/or progression. (See 'Risk stratification' above and 'Management based on risk of recurrence' above.)

Intravesical therapy is generally used as an adjuvant following complete TURBT to prevent recurrence. Intravesical therapy may also be given to treat residual disease that remains in the bladder following TURBT, but this situation is relatively infrequent, except in cases with diffuse carcinoma in situ (CIS).

All intravesical therapies can cause symptoms of bladder irritation (dysuria and frequency). In addition, systemic effects may occur if the agent is absorbed through the mucosa. The latter phenomenon depends partly upon the size of the molecule and the pH in the bladder at the time of instillation.

The presence of mucosal damage at the time of instillation can also permit systemic absorption of the agent. Intravesical therapy may be initiated two to three weeks postoperatively and no later than four weeks after completing TURBT, as this allows healing and reduces the likelihood of severe local or systemic toxicities.

Bacillus Calmette-Guerin (BCG), a live attenuated form of Mycobacterium bovis, is the most widely used intravesical agent. A number of chemotherapy agents, including in particular mitomycin, epirubicin, and gemcitabine, are widely used as alternatives.

Bacillus Calmette-Guerin — BCG is a live attenuated form of Mycobacterium bovis; BCG is the most commonly used agent for intravesical therapy. A number of other intravesical agents have been compared with BCG, but most are inferior, and none has consistently proven to be superior [83-88].

For all patients with high-risk non-muscle invasive bladder cancer, a course of intravesical BCG following a restaging TURBT is indicated rather than intravesical chemotherapy. Intravesical BCG is also an option for appropriately selected patients with intermediate-risk disease. This is consistent with the American Urological Association (AUA), the European Association of Urology (EAU), and the Canadian Urological Association (CUA) bladder cancer guidelines [11,58,89]. This recommendation is based on meta-analyses that consistently report that BCG decreases the risk of recurrence and progression compared with chemotherapy when at least a year of maintenance treatment is administered [52,83,86,90]. (See 'Efficacy' below.)

Mechanism of action of Bacillus Calmette-Guerin — While gaps in our knowledge remain, we continue to learn more about BCG's antitumor action [91]. Intravesical instillation of BCG triggers a variety of local immune responses that may persist for a number of months and which appear to correlate with antitumor activity [92-94]. These include:

Induction of a mononuclear cell infiltrate that consists predominantly of CD4 T cells and macrophages.

Increased expression of interferon gamma (IFNg) in the bladder. Expression of IFNg induces expression of class II major histocompatibility (MHC) molecules on bladder cancer cells, including HLA-DR and intercellular adhesion molecule (ICAM)-1. IFNg can also increase the sensitivity of bladder tumor cells to BCG by activating lymphokine-activated killer (LAK) cells and antigen-presenting cells.

Elevated urinary cytokine levels, including interleukin (IL)-1, IL-2, IL-6, IL-8, IL-12, IFNg, tumor necrosis factor (TNF)-alpha, and tumor necrosis factor apoptosis inducing ligand (TRAIL).

Direct suppression of tumor growth in a dose-dependent fashion [95].

The persistence of BCG in the bladder may facilitate an ongoing immune activation, but also potentially increases the risk of a late systemic infection. In one study of uncomplicated intravesical instillation in 49 patients, BCG was detected in 96, 68, and 27 percent of urine specimens from two hours, 24 hours, and seven days following instillation, respectively [96].

Dose and schedule

Induction therapy – BCG is typically instilled into the bladder weekly for six weeks for patients with intermediate- and high-risk disease, generally starting two to six weeks after TURBT. Each dose consists of a vial of reconstituted Connaught BCG (81 mg) or one 2 mL ampule of Tice BCG (50 mg), plus 50 mL of sterile saline injected into the bladder through a catheter and retained for two hours.

Maintenance therapy – Maintenance BCG is given weekly for three weeks at months 3, 6, 12, 18, 24, 30, and 36 for patients with high-risk disease. For patients with intermediate-risk disease, maintenance therapy is continued for only one year.

To diminish the risk of systemic infection, intravesical BCG should not be administered to patients with traumatic catheterization, active cystitis, or persistent gross hematuria following TURBT [97]. (See "Infectious complications of intravesical BCG immunotherapy", section on 'Systemic complications'.)

Several trials suggest that a lower dose of BCG may be as effective but less toxic [98-100]. The effect of dose was illustrated by a trial in which 155 patients with non-muscle invasive bladder cancer (T1 grade 3 or Tis (table 1)) were randomly assigned to six weekly instillations of standard or reduced-dose BCG (81 and 27 mg, respectively) following complete TURBT [98]. At a median follow-up of 61 months, there were no differences between the groups with respect to disease recurrence, time to recurrence, need for deferred cystectomy, or disease-specific survival.

A European Organisation for the Research and Treatment of Cancer (EORTC) trial demonstrated that the full dose BCG may be associated with lower recurrence [81]. Full-dose BCG may be particularly relevant in the North American population where tuberculosis vaccine or previous exposure to the mycobacterium is much less prevalent.

Maintenance therapy — Both the AUA, EAU, and CUA support a maintenance treatment duration of at least one year for patients being managed with intravesical BCG [11,58,89]. Although individual randomized trials assessing the role of maintenance therapy have given mixed results, multiple meta-analyses have confirmed the improved results in trials that used at least a year of maintenance therapy [52,83,86,90].

To address the question of optimal dose and duration of maintenance BCG therapy, the EORTC conducted a four-arm trial in which patients with intermediate and high risk disease were randomly assigned to full- or reduced-dose BCG [81]. In addition, patients underwent a second random assignment to maintenance therapy administered over one or three years. The main results were:

There were no significant differences in the toxicity profiles between full and reduced doses of BCG.

Treatment at full dose for three years significantly decreased the risk of recurrence compared with reduced dose for one year (hazard ratio [HR] for disease-free survival 0.75, 95% CI 0.59-0.94).

There was no additional benefit to three years of maintenance treatment compared with one year for patients with intermediate-risk disease given full-dose BCG.

For patients with high-risk disease, the administration of full-dose BCG for one year increased the risk of recurrence compared with treatment over three years (HR 1.61, 95% CI 1.13-2.30). Despite this, there was no difference in either disease progression or survival.

Dose reduction of BCG during maintenance therapy and/or the use of a fluoroquinolone given 8 and 20 hours after BCG dosing may improve the rates of treatment completion [101,102]. (See "Infectious complications of intravesical BCG immunotherapy".)

For patients receiving intravesical chemotherapy, the protocol and duration for maintenance therapy are not standardized. One commonly used maintenance protocol includes a single monthly instillation for one year.

Bacillus Calmette-Guerin shortage — In the setting of a BCG shortage, the following strategies may be used to conserve BCG use and decrease the pool of patients receiving treatment:

Limit BCG use to high-risk patients only.

Prioritize the full dose for induction and maintenance treatments (when supply is adequate).

Reduced doses of BCG are preferable to reduced frequency of BCG administration [103]. Consider using a one-third BCG dose for maintenance doses and limit the duration of maintenance to one year (when supply is not adequate).

Offer radical cystectomy to patients with very high-risk disease (T1 with adverse features). (See 'Cystectomy' below.)

If BCG becomes unavailable, alternatives include sequential intravesical gemcitabine/docetaxel [104] or other regimens (standard or electromotive administration of mitomycin, gemcitabine, epirubicin). (See 'Mitomycin' below.)

Posttreatment evaluation — A repeat cystoscopy is indicated approximately six weeks after completing the induction cycle with BCG (three months after the start of treatment). Urine cytology should be done routinely [105].

Persistent CIS following an induction course of BCG should not be considered treatment failure. Instead, one round of maintenance therapy (or repeat induction therapy) should be administered prior to determining treatment failure. In a randomized trial, the complete response rate improved from 55 to 84 percent after a three-week round of maintenance BCG [106].

Efficacy — Intravesical BCG is the most efficacious agent for non-muscle invasive bladder cancer. BCG therapy has been shown to delay tumor progression to a more advanced stage, decrease the need for subsequent cystectomy, and improve overall survival.

BCG is considered the treatment of choice for patients with CIS. In a 2005 meta-analysis of 700 patients with CIS, 68 percent achieved a complete response with BCG versus 51 percent with chemotherapy. Furthermore, the long-term 3.6-year durability of response to BCG was significantly better than with mitomycin (47 versus 26 percent) [83].

In a systematic review, the activity of intravesical BCG was analyzed in six randomized trials that included 585 eligible patients with Ta or T1 disease [107]. Those treated with TURBT plus BCG had significantly fewer recurrences at 12 months compared with those managed with TURBT alone (odds ratio [OR] 0.30, 95% CI 0.21-0.43).

The long-term outcome following intravesical BCG therapy for non-muscle invasive bladder cancer has been assessed in a number of trials [108-110]. As an example, 86 high-risk patients (Ta, Tis, or T1) were randomly assigned to BCG or no BCG following TURBT [108]. At a 10-year follow-up, the progression-free rate was longer for patients who had received BCG (62 versus 37 percent without BCG). Disease-specific survival was also significantly increased (75 versus 55 percent).

The 70 to 86 percent survival rate at four to five years following BCG is similar to that achieved after immediate cystectomy and supports the choice of TURBT plus BCG rather than immediate cystectomy for the initial management in these patients [111,112]. Although additional late relapses are observed, intravesical BCG does delay tumor progression and death in patients who present with non-muscle invasive bladder cancer.

Similar results have been reported in observational studies [109,110]. As an example, in one report of 98 patients with high-risk or recurrent non-muscle invasive bladder cancer and a minimum follow-up of 10 years, 67 percent were progression-free, 59 percent had a retained bladder, and the disease-specific survival was 85 percent [109].

Complications — Minor noninfectious symptoms following BCG administration are common (up to 85 percent of patients) [113]. These include fever, malaise, and bladder irritation (urination frequency, dysuria, or mild hematuria) within a few hours of BCG instillation [114]. Urinalysis and culture do not demonstrate evidence of infection. Such manifestations generally resolve within 48 hours and reflect a hypersensitivity reaction rather than an infectious complication of BCG. Management consists of analgesics and/or nonsteroidal antiinflammatory drugs (NSAIDs) [115]. Symptoms usually resolve within 48 hours, after which BCG may be resumed.

In a systematic review of six randomized trials that included 585 patients, toxicities associated with intravesical BCG included increased urinary frequency (71 percent), cystitis (67 percent), fever (25 percent), and hematuria (23 percent) [107]. There were no BCG-associated deaths in this review, and BCG-associated deaths are rare [115].

In addition to acute toxicities, both localized and systemic infectious complications can occur after intravesical administration of BCG. The infectious complications of intravesical BCG are discussed separately. (See "Infectious complications of intravesical BCG immunotherapy".)

To diminish the risk of systemic infection, intravesical BCG should not be administered to patients with traumatic catheterization, active cystitis, or persistent gross hematuria following TURBT, which appears to be associated with the greatest risk of systemic infection with BCG [97].

The presence of a prosthetic device (eg, pacemakers, artificial heart valves, orthopedic hardware) is not a contraindication to intravesical BCG. While there are individual case reports of prosthetic device infections after BCG therapy, this type of event is very uncommon [116-119]. As an example, in one observational study of 143 patents with non-muscle invasive bladder cancer and a prosthetic device treated with intravesical BCG therapy, none developed infective endocarditis or hardware infection [120]. (See "Infectious complications of intravesical BCG immunotherapy".)

BCG is contraindicated in patients who are immunocompromised due to use of TNF antagonists, which are used to treat conditions such as psoriasis, Crohn disease, and rheumatoid arthritis. Administration of BCG in older adult patients and transplant recipients may be associated with higher toxicity and decreased efficacy. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects".)

Interactions with statins — Statins (HMG CoA reductase inhibitors) are known to have immunosuppressive effects that might theoretically counteract the immunotherapeutic effect of BCG [121,122]. Whether this has clinical implications for patients with bladder cancer remains uncertain. Retrospective studies have given conflicting results. Although one study initially suggested that statins may be harmful in patients receiving BCG [123], two other studies found no effect [124,125].

Mitomycin — Mitomycin is one of the more commonly used intravesical chemotherapeutic agents. Mitomycin has an established role as a single intravesical administration following resection of low-risk non-muscle invasive bladder cancer. Mitomycin also has been used as an adjuvant given as multiple treatments following TURBT.

The optimal volume of administration and dwell time have not been definitively established. An "optimized" regimen using a decreased volume in which 40 mg is instilled 20 cc, in which urine volume was decreased by dehydration and complete bladder emptying, and in which the urine was alkalinized to stabilize the drug was demonstrated to be superior to the administration of 20 mg diluted in 20 mL volume in a randomized trial using six weekly instillations of mitomycin [126].

Single postoperative instillation — Single-dose intravesical chemotherapy given in the immediate postoperative period is recommended following TURBT for low-grade papillary disease. In a 2007 meta-analysis of two randomized trials including 427 patients, single-dose postoperative instillation of chemotherapy reduced early tumor recurrence rates by 17 percent compared with TURBT alone [127]. A randomized trial in 2243 patients compared mitomycin instillation within 24 hours versus at two weeks and demonstrated definitively that early administration is more effective [128]. The toxicity of mitomycin is discussed below. (See 'Toxicity' below.)

Other agents that had been evaluated in the trials included in the meta-analysis were epirubicin, thiotepa, gemcitabine, and pirarubicin.

An individual patient data meta-analysis of randomized trials demonstrated that a single postoperative instillation of intravesical chemotherapy does not benefit patients who have >1 recurrence per year or multiple tumors where one of which is >3 cm [129]. Furthermore, a more recent randomized trial demonstrated that immediate single instillation after TURBT reduces the recurrence risk in non-muscle invasive bladder cancer patients independent of the number of adjuvant instillations [128].

In patients who are not able to receive the single postoperative instillation of chemotherapy, a randomized study shows that continuous saline bladder irrigation after TURBT may be beneficial [130]. The continuous saline irrigation, however, was administered over 16 hours, which would require admission of patients who would otherwise be managed as outpatients in many centers.

Multiple adjuvant instillations — For patients with low-grade disease that has previously recurred or is multifocal, six weekly courses of intravesical chemotherapy are considered a reasonable alternative to BCG for initial management [131]. This is typically followed by intravesical mitomycin monthly as maintenance therapy.

The activity of mitomycin with extended maintenance therapy was illustrated in a multicenter trial in which 495 patients were randomly assigned to intravesical therapy with BCG (weekly for six doses), mitomycin (20 mg weekly for six weeks), or mitomycin (20 mg weekly for six weeks, then monthly for three years) [132]. The three-year recurrence-free rates with six-week courses of either BCG or mitomycin were inferior to that achieved with maintenance mitomycin (66 and 69 percent versus 86 percent).

Alternative administration approaches — Two approaches have been used to increase the effectiveness of intravesical mitomycin in various clinical settings. These include the use of hyperthermia and the use of an electromotive gradient to increase the transport of mitomycin into the bladder.

Hyperthermia – The creation of hyperthermia within the bladder has been used to improve transport and penetration of mitomycin into the bladder wall. Randomized trials have suggested that this approach can improve outcomes compared with BCG alone or mitomycin without hyperthermia [133-136]. In the largest of these trials, 190 patients with intermediate- or high-risk non-muscle invasive bladder cancer were randomly assigned to hyperthermia with mitomycin or to BCG [136]. Relapse-free survival was improved with chemotherapy plus hyperthermia compared with BCG (78 versus 65 percent).

Electromotive drug administration (EMDA) – The use of an electromotive gradient in conjunction with intravesical mitomycin is believed to increase transport of drug across the mucosal membrane. This approach has been evaluated in randomized trials, either alone, sequentially after intravesical BCG, and prior to TURBT [135,137-139].

As an example, a phase III study demonstrated improved recurrence and progression rates in 108 patients with T1 disease treated with sequential BCG and electromotive mitomycin administration compared with BCG alone [138]. After a median follow-up of 88 months, electromotive mitomycin used sequentially with intravesical BCG demonstrated a significantly decreased recurrence (42 versus 58 percent), progression (9 versus 22 percent), cancer-specific mortality (6 versus 16 percent), and overall mortality (21.5 versus 32.4 percent) compared with BCG alone. Sequential BCG/EMDA MMC have been shown to be cost-effective as well [138].

Toxicity — Mitomycin is an alkylating agent that is minimally absorbed from the bladder into the systemic circulation. As a result, myelosuppression following the intravesical use of this agent is uncommon [140].

Other toxicities that have been reported following intravesical administration include:

A self-limited chemical cystitis has been reported in approximately 40 percent of patients receiving intravesical mitomycin [90]. Only rarely does this progress to shrunken, contracted bladder.

A rash primarily involving the palms, soles, and genitalia is thought to be a manifestation of a hypersensitivity reaction [141].

Both the chemical cystitis and the rash generally respond to treatment with corticosteroids.

In addition, wounds in the bladder do not heal properly once intravesical mitomycin is started. Such areas do not completely epithelialize and can undergo dystrophic calcification. Although usually asymptomatic, these lesions can take months or years to fully resolve.

Gemcitabine — Gemcitabine appears to have similar efficacy to mitomycin and has a better toxicity profile [142,143].

The most extensive data on the role of gemcitabine come from the SWOG 0337 trial, in which 406 eligible patients were randomly assigned to a single instillation of gemcitabine or normal saline after resection of tumor that had a cystoscopic appearance consistent with low-grade non-muscle invasive urothelial cancer [144]. Overall, 63 percent of patients were treated at their initial occurrence, and 37 percent were treated for a recurrence. Patients were then followed with cystoscopy every three months for two years, followed by every six months for at least two additional years.

In the intention-to-treat analysis of the entire study population, there was a 34 percent decrease in the risk of recurrence (four-year estimated recurrence rate 35 versus 47 percent, HR 0.66, 95% CI 0.48-0.90). There was progression to muscle-invasive disease in 5 patients treated with gemcitabine and 10 in the saline group (2.5 versus 4.9 percent, HR 0.51, 95% CI 0.17-1.49).

In the prespecified target population of those with low-grade disease, there was a similar decrease in the rate of recurrence (four-year estimated recurrence rate 34 versus 54 percent, HR 0.53, 95% CI 0.35-0.81).

Treatment was well tolerated, with no difference in the incidence of serious (grade 3) adverse events (2.4 percent with gemcitabine versus 3.4 percent with saline).

Due to the comparable efficacy with lower toxicity [142], gemcitabine has become the preferred agent for single-dose postoperative intravesical chemotherapy.

In another trial, 355 patients were randomly assigned to either a single dose of gemcitabine or a saline placebo [145]. There was no improvement in relapse-free survival in those given gemcitabine (median 37 versus 40 months). In this trial, the dwell time for gemcitabine was only 35 minutes, compared with 60 minutes in the SWOG 0337 trial. In addition, both groups received 20 hours of continuous saline irrigation of the bladder after study drug instillation in this trial. Both factors likely contributed to the difference in observed efficacy.

Other agents

Epirubicin — Epirubicin can be used as an alternative to mitomycin as first-line therapy in patients with low- and intermediate-risk disease, either as immediate postoperative or as adjuvant multiple instillations.

Epirubicin has limited systemic absorption following intravesical instillation. Although epirubicin is more active than either placebo or interferon (IFN) alfa [57,146,147], it was less active than BCG in a trial of 957 patients with intermediate- and high-risk Ta and T1 papillary bladder cancer [148]. Patients were randomly assigned to intravesical epirubicin (50 mg weekly for six weeks) or BCG (Tice strain, weekly for six weeks). Both groups then received maintenance treatment with three weekly intravesical doses of either agent every three months for 36 months. The main results were that:

Treatment with BCG resulted in a significantly longer time to first recurrence compared with epirubicin and a higher three-year recurrence-free survival (65 versus 49 percent).

At a median follow-up of 9.2 years, risks of first recurrence and distant metastases were significantly lower with BCG compared with epirubicin (38 versus 53 percent and 5.0 versus 8.6 percent, respectively).

Death from all causes and death from bladder cancer were significantly reduced with BCG compared with epirubicin (31 versus 38 percent and 3.4 versus 6.8 percent, respectively) [149].

Thiotepa — Thiotepa was the first intravesical agent to be used for non-muscle invasive bladder cancer and is one of the few actually approved for use in the United States for intravesical administration by the US Food and Drug Administration (FDA). However, it is seldom used because of its side effect profile and risk for late complications.

A randomized trial conducted by the National Bladder Cancer Collaborative Group showed that intravesical thiotepa (30 or 60 mg) was associated with a significant reduction in recurrence rate [150]. However, it can cause irritative voiding symptoms in up to 69 percent of patients [140].

Because of its relatively small molecular weight (186 daltons), thiotepa is absorbed systemically, and the incidence of myelosuppression may be as high as 54 percent [140,151]. Furthermore, thiotepa is a potent carcinogen and has been linked to the development of secondary leukemia in patients treated for non-muscle invasive bladder cancer [152].

CYSTECTOMY — For patients with high-risk non-muscle invasive bladder cancer who have undergone restaging transurethral resection of bladder tumor (TURBT), and an appropriate performance status, radical cystectomy is an option for initial treatment under specific circumstances. (See 'Management based on risk of recurrence' above.)

Indications for cystectomy include the following:

Extensive bladder involvement, unable to attain complete resection of all visible disease despite multiple attempts at TURBT.

Men with carcinoma in situ (CIS) involving the prostatic ducts/acini.

Pure squamous cell or adenocarcinoma histology.

T1 tumor with lymphovascular invasion or variant histology, such as micropapillary, sarcomatoid or neuroendocrine/small cell, features. Patients with neuroendocrine or small cell carcinoma of the bladder typically receive neoadjuvant chemotherapy prior to cystectomy. (See "Small cell carcinoma of the bladder", section on 'Neoadjuvant chemotherapy plus cystectomy'.)

T1, grade 3 tumors that are large/diffuse/multifocal or persistent lesions identified on re-resection.

T1b tumors (ie, deep or extensive involvement of the lamina propria).

UpToDate contributors have different approaches to patients with T1 high-grade tumors and concomitant CIS. Some contributors offer a discussion about the risks and benefits of radical cystectomy, especially with larger T1 high-grade tumors combined with CIS, which is consistent with guidelines from the American Urological Association (AUA), the European Association of Urology (EAU), and the Canadian Urological Association (CUA) [11,58,89].

Limited data from one randomized feasibility trial suggest that approximately 10 percent of patients with high-risk non-muscle invasive bladder cancer have lethal disease in the short term that is better managed with radical cystectomy than intravesical Bacillus Calmette-Guerin (BCG) [153]. However, the same study also suggests that radical cystectomy overtreats most patients with high-risk disease.

Radical cystectomy may also be indicated for patients crippled by symptoms related to bladder cancer pathology (eg, intolerable urinary frequency, pain, incontinence, and hemorrhage) that cannot be adequately managed medically. More aggressive therapy (eg, chemotherapy, radiation therapy, surgery) is also indicated if the initial TURBT or restaging TURBT reveals muscle invasive disease. (See "Neoadjuvant treatment options for muscle-invasive urothelial bladder cancer" and "Bladder preservation treatment options for muscle-invasive urothelial bladder cancer".)

The use of radical cystectomy in patients with BCG-unresponsive disease is discussed separately. (See "Management of recurrent or persistent non-muscle invasive bladder cancer".)

RADIATION THERAPY — External beam radiation therapy (RT), with or without platinum-based chemotherapy, has been evaluated as an alternative to intravesical therapy for patients with high-grade T1 lesions following transurethral resection of all visible bladder tumor (TURBT).

The role of RT was reported in a retrospective study that included 141 patients with stage T1 disease, 60 percent of which were high grade, who were treated with RT alone (n = 28) or RT plus chemotherapy (n = 113). Major outcomes with RT (alone or with concomitant chemotherapy) resulted in:

A complete response rate of 88 percent

Rates of tumor progression of 19 and 30 percent at five and 10 years, respectively

Rates for disease-specific survival of 82 and 73 percent at five and 10 years, respectively

More than 80 percent of survivors preserved their bladder and 70.4 percent were "delighted" or "pleased" with their urinary function [154]. However, in a randomized trial of 210 patients with high-grade T1NXMO disease, radical RT (60 Gy in 30 fractions) alone had no advantages over observation in terms of progression-free or overall survival for patients with unifocal disease, or over Bacillus Calmette-Guerin (BCG) for those with multifocal disease or carcinoma in situ (CIS) [155].

CHEMOPREVENTION — Systemic chemopreventive biologic agents, rather than or in addition to intravesical therapy, have been evaluated to prevent recurrence of low-risk non-muscle invasive bladder cancers. Although some data supporting these agents are suggestive, no role has been established for any chemopreventive agent in patients with previously treated non-muscle invasive bladder cancer. (See "Chemoprevention of urothelial carcinoma of the bladder", section on 'Chemopreventive agents'.)

POSTTREATMENT SURVEILLANCE — Careful follow-up is required for all patients with non-muscle invasive bladder cancer. Second primary urothelial carcinoma can develop anywhere along the genitourinary epithelium, including the renal pelvis, ureters, prostate and urethra, as well as the bladder. (See "Urethral cancer" and "Malignancies of the renal pelvis and ureter".)

Although there are no definitive guidelines for optimal surveillance [11,58], the recommendations from the International Bladder Cancer Network (IBCG) provide a useful framework based upon risk of recurrence [156]. For patients with low-risk tumors, these recommendations include annual cystoscopy but do not require cytology or evaluation of the upper urinary tract except at the time of diagnosis. For those with high-risk tumors, a more intensive schedule is required: in addition to frequent cytology, this includes cystoscopy every three months for two years, followed by every six months for two additional years, and then annually with imaging of the upper urinary tract at one year and then every two years thereafter. For intermediate-risk tumors, intensity of follow-up varies depending on the number of IBCG risk factors present. (See 'Imaging of the urinary tract' below.)

Adherence to surveillance recommendations is often suboptimal, as illustrated in a series of 6717 patients aged 65 or older with non-muscle invasive bladder cancer identified in the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database of the National Cancer Institute [157]. During the five contiguous six-month intervals following initial diagnosis, only 40 percent of patients had an examination during all five periods, while 18 percent were examined during two or fewer of these periods. Among the factors that were independently associated with a lower intensity of surveillance were age ≥75 years, favorable tumor histology (ie, well-differentiated versus poorly differentiated), a high degree of comorbidity, and being from a Black or other population, rather than from a White population.

Patients should be encouraged to discontinue smoking because of the association between smoking and urothelial cancer incidence and recurrence. (See "Epidemiology and risk factors of urothelial (transitional cell) carcinoma of the bladder", section on 'Smoking cessation'.)

On the basis of an ongoing drug safety review, the US Food and Drug Administration (FDA) has recommended against the use of pioglitazone in patients with active bladder cancer and to use it with caution in patients with a history of bladder cancer because of an association between the use of pioglitazone and bladder cancer. (See "Thiazolidinediones in the treatment of type 2 diabetes mellitus", section on 'Bladder cancer'.)

Imaging of the urinary tract — In large series, the incidence of renal pelvis and ureteral tumors has ranged from 1 to 4 percent [158-162]. The median time to discovery of such tumors following the diagnosis of bladder cancer has varied from three to seven years [158,159,162]. Factors that may increase the risk of developing an upper tract tumor include urethral involvement, vesicoureteral reflux, the presence of multiple tumors or Tis, high-grade disease, previous Bacillus Calmette-Guerin (BCG) treatment, and occupational exposure [159,160,162-164]. (See "Malignancies of the renal pelvis and ureter", section on 'Diagnosis'.)

The use of imaging (ie, intravenous pyelogram, computed tomography [CT] urography, retrograde pyelography, or magnetic resonance imaging [MRI] urogram) is individualized based on the risk for development of an upper tract tumor:

There are no data to support routine upper tract imaging for patients with single, nonrecurrent, low-grade, small, papillary tumors [131].

For patients with no obvious intravesical tumor and positive urinary cytology, we suggest random bladder and prostatic urethral biopsies, or targeted biopsies using blue light cystoscopy [165], as well as careful periodic evaluation of the upper tracts [166]. CT urography has replaced intravenous pyelogram as the preferred imaging modality in this situation. This may be combined with ureteroscopy for any suspicious lesions.

For patients with intermediate- to high-risk disease after transurethral resection of all visible bladder tumor (TURBT) and a negative urine cytology, we suggest imaging of the upper urinary tracts every one to two years to exclude involvement with metachronous lesions [167-169]. This should be continued for five years in patients with intermediate-risk disease and even longer for patients with high-risk disease. (See 'Risk stratification' above and 'Management based on risk of recurrence' above.)

Evaluation of the prostatic urethra — In addition to bladder and upper urinary tract recurrences, second primary tumors in the prostatic urethra and ducts are not uncommon.

In a series of 186 men followed for 15 years, 39 percent had a relapse in the prostatic urethra, with 15 percent showing stromal invasion of the prostate [170]. More than one-half of the relapses occurred in the first five years, but 39 percent were diagnosed between 5 and 15 years. A high index of suspicion is needed for early diagnosis of a urethral recurrence with the most common symptom being urinary tract obstruction. Patients suspected of urethral cancer require cystourethroscopy and further pelvic imaging as necessary. Furthermore, urethral involvement is the most significant variable predicting muscle invasive cancer [171]. A further discussion of urethral cancer in men is discussed separately. (See "Urethral cancer".)

Urine biomarkers — A wide range of urinary biomarkers are being evaluated for their utility in surveillance following initial treatment of non-muscle invasive bladder cancer. However, none of these tests has been proven to have sufficient diagnostic reliability to eliminate the need for cystoscopy.

In the United States, several of these urine tests (eg, bladder tumor antigen [BTA] stat, BTA TRAK, UroVysion, nuclear matrix protein [NMP] 22) are approved for the detection of tumor recurrence. Major problems with these assays include the lack of sensitivity for small tumors and particularly low-grade lesions, as well as a higher number of false positives.

The data supporting the use of these assays and their potential role in bladder cancer surveillance are discussed separately. (See "Urine biomarkers for the detection of urothelial (transitional cell) carcinoma of the bladder", section on 'Urine biomarkers'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Bladder cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Beyond the Basics topics (see "Patient education: Bladder cancer treatment; non-muscle invasive (superficial) cancer (Beyond the Basics)" and "Patient education: Bladder cancer treatment; muscle invasive cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Diagnosis – The initial diagnosis and management of most patients with presumed non-muscle invasive bladder cancer (Ta, Tis, and T1 (table 1)) includes a complete transurethral resection of bladder tumor (TURBT), examination under anesthesia, and a single postoperative instillation of intravesical chemotherapy (algorithm 1). Although the transurethral resection may be complete, these patients remain at high risk for recurrent disease. (See 'Initial management' above and 'Single postoperative instillation' above.)

Risk stratification – After initial TURBT, patients with non-muscle invasive bladder cancer are stratified for risk of recurrence and progression (low, intermediate, high) based on stage, grade, and the number and size of tumors. (See 'Prognostic factors' above and 'Risk stratification' above.)

Treatment – The approach to additional intravesical adjuvant therapy is based on risk stratification for disease recurrence (see 'Management based on risk of recurrence' above and 'Intravesical therapy' above):

Low-risk disease – For patients with low-risk disease, we recommend a single postoperative intravesical instillation of chemotherapy (Grade 1B), followed by surveillance. No further adjuvant therapy is indicated. (See 'Mitomycin' above.)

Intermediate-risk disease – For patients with intermediate-risk disease, we suggest induction with either intravesical chemotherapy or Bacillus Calmette-Guerin (BCG), followed by one year of maintenance therapy (Grade 2B). In the setting of BCG shortage, we offer intravesical chemotherapy rather than BCG. (See 'Dose and schedule' above and 'Maintenance therapy' above and 'Bacillus Calmette-Guerin shortage' above.)

High-risk disease – For high-risk patients with stage T1 tumors (and select patients with high-grade Ta tumors with an incomplete or suspected incomplete initial TURBT), a restaging TURBT is performed four to six weeks after the initial cystoscopy/TURBT to determine whether a radical cystectomy may be indicated. (See 'Restaging transurethral resection' above and 'Cystectomy' above.)

For patients with high-risk disease who are managed conservatively, we recommend treatment with intravesical BCG rather than observation only (Grade 1B). BCG is administered as an induction course, followed by a three-year course of maintenance therapy. (See 'Dose and schedule' above and 'Maintenance therapy' above.)

Contraindications to intravesical BCG – Intravesical BCG should not be administered to patients with traumatic catheterization, active cystitis, or persistent gross hematuria following TURBT, in order to minimize the risk of systemic infection. BCG is never given in the perioperative setting. (See "Infectious complications of intravesical BCG immunotherapy".)

Posttreatment surveillance – All patients being treated for non-muscle invasive bladder cancer require careful surveillance, and the intensity of such follow-up should be adapted to the risk of disease recurrence. Key components of such surveillance include periodic cystoscopy, urine cytology, and imaging of the upper urinary tract. (See 'Posttreatment surveillance' above.)

Recurrent or persistent disease – The management of patients with recurrent or persistent non-muscle invasive bladder cancer is discussed separately. (See "Management of recurrent or persistent non-muscle invasive bladder cancer".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Michael O'Donnell, MD, who contributed to earlier versions of this topic review.

  1. Antoni S, Ferlay J, Soerjomataram I, et al. Bladder Cancer Incidence and Mortality: A Global Overview and Recent Trends. Eur Urol 2017; 71:96.
  2. Kirkali Z, Chan T, Manoharan M, et al. Bladder cancer: epidemiology, staging and grading, and diagnosis. Urology 2005; 66:4.
  3. Herr HW. Restaging transurethral resection of high risk superficial bladder cancer improves the initial response to bacillus Calmette-Guerin therapy. J Urol 2005; 174:2134.
  4. Herr HW. The value of a second transurethral resection in evaluating patients with bladder tumors. J Urol 1999; 162:74.
  5. Gendy R, Delprado W, Brenner P, et al. Repeat transurethral resection for non-muscle-invasive bladder cancer: a contemporary series. BJU Int 2016; 117 Suppl 4:54.
  6. Gordon PC, Thomas F, Noon AP, et al. Long-term Outcomes from Re-resection for High-risk Non-muscle-invasive Bladder Cancer: A Potential to Rationalize Use. Eur Urol Focus 2019; 5:650.
  7. Audenet F, Retinger C, Chien C, et al. Is restaging transurethral resection necessary in patients with non-muscle invasive bladder cancer and limited lamina propria invasion? Urol Oncol 2017; 35:603.e1.
  8. Lee SE, Jeong IG, Ku JH, et al. Impact of transurethral resection of bladder tumor: analysis of cystectomy specimens to evaluate for residual tumor. Urology 2004; 63:873.
  9. Klän R, Loy V, Huland H. Residual tumor discovered in routine second transurethral resection in patients with stage T1 transitional cell carcinoma of the bladder. J Urol 1991; 146:316.
  10. Dalbagni G, Herr HW, Reuter VE. Impact of a second transurethral resection on the staging of T1 bladder cancer. Urology 2002; 60:822.
  11. Chang SS, Boorjian SA, Chou R, et al. Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer: AUA/SUO Guideline. J Urol 2016; 196:1021.
  12. Babjuk M, Burger M, Compérat EM, et al. European Association of Urology Guidelines on Non-muscle-invasive Bladder Cancer (TaT1 and Carcinoma In Situ) - 2019 Update. Eur Urol 2019; 76:639.
  13. Sfakianos JP, Kim PH, Hakimi AA, Herr HW. The effect of restaging transurethral resection on recurrence and progression rates in patients with nonmuscle invasive bladder cancer treated with intravesical bacillus Calmette-Guérin. J Urol 2014; 191:341.
  14. Kausch I, Sommerauer M, Montorsi F, et al. Photodynamic diagnosis in non-muscle-invasive bladder cancer: a systematic review and cumulative analysis of prospective studies. Eur Urol 2010; 57:595.
  15. Daniltchenko DI, Riedl CR, Sachs MD, et al. Long-term benefit of 5-aminolevulinic acid fluorescence assisted transurethral resection of superficial bladder cancer: 5-year results of a prospective randomized study. J Urol 2005; 174:2129.
  16. Denzinger S, Burger M, Walter B, et al. Clinically relevant reduction in risk of recurrence of superficial bladder cancer using 5-aminolevulinic acid-induced fluorescence diagnosis: 8-year results of prospective randomized study. Urology 2007; 69:675.
  17. Filbeck T, Roessler W, Knuechel R, et al. Clinical results of the transurethreal resection and evaluation of superficial bladder carcinomas by means of fluorescence diagnosis after intravesical instillation of 5-aminolevulinic acid. J Endourol 1999; 13:117.
  18. Schmidbauer J, Witjes F, Schmeller N, et al. Improved detection of urothelial carcinoma in situ with hexaminolevulinate fluorescence cystoscopy. J Urol 2004; 171:135.
  19. Hungerhuber E, Stepp H, Kriegmair M, et al. Seven years' experience with 5-aminolevulinic acid in detection of transitional cell carcinoma of the bladder. Urology 2007; 69:260.
  20. Grossman HB, Gomella L, Fradet Y, et al. A phase III, multicenter comparison of hexaminolevulinate fluorescence cystoscopy and white light cystoscopy for the detection of superficial papillary lesions in patients with bladder cancer. J Urol 2007; 178:62.
  21. Fradet Y, Grossman HB, Gomella L, et al. A comparison of hexaminolevulinate fluorescence cystoscopy and white light cystoscopy for the detection of carcinoma in situ in patients with bladder cancer: a phase III, multicenter study. J Urol 2007; 178:68.
  22. Chou R, Selph S, Buckley DI, et al. Comparative Effectiveness of Fluorescent Versus White Light Cystoscopy for Initial Diagnosis or Surveillance of Bladder Cancer on Clinical Outcomes: Systematic Review and Meta-Analysis. J Urol 2017; 197:548.
  23. O'Brien T, Ray E, Chatterton K, et al. Prospective randomized trial of hexylaminolevulinate photodynamic-assisted transurethral resection of bladder tumour (TURBT) plus single-shot intravesical mitomycin C vs conventional white-light TURBT plus mitomycin C in newly presenting non-muscle-invasive bladder cancer. BJU Int 2013; 112:1096.
  24. Daneshmand S, Patel S, Lotan Y, et al. Efficacy and Safety of Blue Light Flexible Cystoscopy with Hexaminolevulinate in the Surveillance of Bladder Cancer: A Phase III, Comparative, Multicenter Study. J Urol 2018; 199:1158.
  25. Lee JY, Cho KS, Kang DH, et al. A network meta-analysis of therapeutic outcomes after new image technology-assisted transurethral resection for non-muscle invasive bladder cancer: 5-aminolaevulinic acid fluorescence vs hexylaminolevulinate fluorescence vs narrow band imaging. BMC Cancer 2015; 15:566.
  26. Zheng C, Lv Y, Zhong Q, et al. Narrow band imaging diagnosis of bladder cancer: systematic review and meta-analysis. BJU Int 2012; 110:E680.
  27. Naito S, Algaba F, Babjuk M, et al. The Clinical Research Office of the Endourological Society (CROES) Multicentre Randomised Trial of Narrow Band Imaging-Assisted Transurethral Resection of Bladder Tumour (TURBT) Versus Conventional White Light Imaging-Assisted TURBT in Primary Non-Muscle-invasive Bladder Cancer Patients: Trial Protocol and 1-year Results. Eur Urol 2016; 70:506.
  28. Lai LY, Tafuri SM, Ginier EC, et al. Narrow band imaging versus white light cystoscopy alone for transurethral resection of non-muscle invasive bladder cancer. Cochrane Database Syst Rev 2022; 4:CD014887.
  29. Kim SB, Yoon SG, Tae J, et al. Detection and recurrence rate of transurethral resection of bladder tumors by narrow-band imaging: Prospective, randomized comparison with white light cystoscopy. Investig Clin Urol 2018; 59:98.
  30. Gravestock P, Coulthard N, Veeratterapillay R, Heer R. Systematic review and meta-analysis of narrow band imaging for non-muscle-invasive bladder cancer. Int J Urol 2021; 28:1212.
  31. Soukup V, Čapoun O, Cohen D, et al. Prognostic Performance and Reproducibility of the 1973 and 2004/2016 World Health Organization Grading Classification Systems in Non-muscle-invasive Bladder Cancer: A European Association of Urology Non-muscle Invasive Bladder Cancer Guidelines Panel Systematic Review. Eur Urol 2017.
  32. Sylvester RJ, van der Meijden AP, Oosterlinck W, et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol 2006; 49:466.
  33. Cambier S, Sylvester RJ, Collette L, et al. EORTC Nomograms and Risk Groups for Predicting Recurrence, Progression, and Disease-specific and Overall Survival in Non-Muscle-invasive Stage Ta-T1 Urothelial Bladder Cancer Patients Treated with 1-3 Years of Maintenance Bacillus Calmette-Guérin. Eur Urol 2016; 69:60.
  34. Banerjee I, Yadav S, Priyadarshi S, Tomar V. Re: Clinical Outcomes of cT1 Micropapillary Bladder Cancer: D. L. Willis, M. I. Fernandez, R. J. Dickstein, S. Parikh, J. B. Shah, L. L. Pisters, C. C. Guo, S. Henderson, B. A. Czerniak, H. B. Grossman, C. P. Dinney and A. M. Kamat J Urol 2015;193:1129-1134. J Urol 2015; 194:1825.
  35. Spaliviero M, Dalbagni G, Bochner BH, et al. Clinical outcome of patients with T1 micropapillary urothelial carcinoma of the bladder. J Urol 2014; 192:702.
  36. Martin-Doyle W, Leow JJ, Orsola A, et al. Improving selection criteria for early cystectomy in high-grade t1 bladder cancer: a meta-analysis of 15,215 patients. J Clin Oncol 2015; 33:643.
  37. Cho KS, Seo HK, Joung JY, et al. Lymphovascular invasion in transurethral resection specimens as predictor of progression and metastasis in patients with newly diagnosed T1 bladder urothelial cancer. J Urol 2009; 182:2625.
  38. Resnick MJ, Bergey M, Magerfleisch L, et al. Longitudinal evaluation of the concordance and prognostic value of lymphovascular invasion in transurethral resection and radical cystectomy specimens. BJU Int 2011; 107:46.
  39. Streeper NM, Simons CM, Konety BR, et al. The significance of lymphovascular invasion in transurethral resection of bladder tumour and cystectomy specimens on the survival of patients with urothelial bladder cancer. BJU Int 2009; 103:475.
  40. Holmäng S, Andius P, Hedelin H, et al. Stage progression in Ta papillary urothelial tumors: relationship to grade, immunohistochemical expression of tumor markers, mitotic frequency and DNA ploidy. J Urol 2001; 165:1124.
  41. Bostwick DG. Natural history of early bladder cancer. J Cell Biochem Suppl 1992; 16I:31.
  42. Althausen AF, Prout GR Jr, Daly JJ. Non-invasive papillary carcinoma of the bladder associated with carcinoma in situ. J Urol 1976; 116:575.
  43. Pagano F, Garbeglio A, Milani C, et al. Prognosis of bladder cancer. I. Risk factors in superficial transitional cell carcinoma. Eur Urol 1987; 13:145.
  44. Tilki D, Reich O, Svatek RS, et al. Characteristics and outcomes of patients with clinical carcinoma in situ only treated with radical cystectomy: an international study of 243 patients. J Urol 2010; 183:1757.
  45. Chade DC, Shariat SF, Godoy G, et al. Clinical outcomes of primary bladder carcinoma in situ in a contemporary series. J Urol 2010; 184:74.
  46. Wallace DM, Hindmarsh JR, Webb JN, et al. The role of multiple mucosal biopsies in the management of patients with bladder cancer. Br J Urol 1979; 51:535.
  47. Farrow GM, Utz DC, Rife CC, Greene LF. Clinical observations on sixty-nine cases of in situ carcinoma of the urinary bladder. Cancer Res 1977; 37:2794.
  48. Herr HW, Jakse G, Sheinfeld J. The T1 bladder tumor. Semin Urol 1990; 8:254.
  49. Peyromaure M, Zerbib M. T1G3 transitional cell carcinoma of the bladder: recurrence, progression and survival. BJU Int 2004; 93:60.
  50. Alkhateeb SS, Van Rhijn BW, Finelli A, et al. Nonprimary pT1 nonmuscle invasive bladder cancer treated with bacillus Calmette-Guerin is associated with higher risk of progression compared to primary T1 tumors. J Urol 2010; 184:81.
  51. Segal R, Yafi FA, Brimo F, et al. Prognostic factors and outcome in patients with T1 high-grade bladder cancer: can we identify patients for early cystectomy? BJU Int 2012; 109:1026.
  52. Sylvester RJ, van der MEIJDEN AP, Lamm DL. Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials. J Urol 2002; 168:1964.
  53. Heney NM, Ahmed S, Flanagan MJ, et al. Superficial bladder cancer: progression and recurrence. J Urol 1983; 130:1083.
  54. Lutzeyer W, Rübben H, Dahm H. Prognostic parameters in superficial bladder cancer: an analysis of 315 cases. J Urol 1982; 127:250.
  55. Mariappan P, Smith G, Lamb AD, et al. Pattern of recurrence changes in noninvasive bladder tumors observed during 2 decades. J Urol 2007; 177:867.
  56. Lerman RI, Hutter RV, Whitmore WF Jr. Papilloma of the urinary bladder. Cancer 1970; 25:333.
  57. Oosterlinck W, Kurth KH, Schröder F, et al. A prospective European Organization for Research and Treatment of Cancer Genitourinary Group randomized trial comparing transurethral resection followed by a single intravesical instillation of epirubicin or water in single stage Ta, T1 papillary carcinoma of the bladder. J Urol 1993; 149:749.
  58. Babjuk M, Böhle A, Burger M, et al. EAU Guidelines on Non-Muscle-invasive Urothelial Carcinoma of the Bladder: Update 2016. Eur Urol 2017; 71:447.
  59. Wu XR. Urothelial tumorigenesis: a tale of divergent pathways. Nat Rev Cancer 2005; 5:713.
  60. Knowles MA. Molecular subtypes of bladder cancer: Jekyll and Hyde or chalk and cheese? Carcinogenesis 2006; 27:361.
  61. Pietzak EJ, Bagrodia A, Cha EK, et al. Next-generation Sequencing of Nonmuscle Invasive Bladder Cancer Reveals Potential Biomarkers and Rational Therapeutic Targets. Eur Urol 2017; 72:952.
  62. Hurst CD, Alder O, Platt FM, et al. Genomic Subtypes of Non-invasive Bladder Cancer with Distinct Metabolic Profile and Female Gender Bias in KDM6A Mutation Frequency. Cancer Cell 2017; 32:701.
  63. Burger M, van der Aa MN, van Oers JM, et al. Prediction of progression of non-muscle-invasive bladder cancer by WHO 1973 and 2004 grading and by FGFR3 mutation status: a prospective study. Eur Urol 2008; 54:835.
  64. van Rhijn BW, Vis AN, van der Kwast TH, et al. Molecular grading of urothelial cell carcinoma with fibroblast growth factor receptor 3 and MIB-1 is superior to pathologic grade for the prediction of clinical outcome. J Clin Oncol 2003; 21:1912.
  65. Hernández S, López-Knowles E, Lloreta J, et al. Prospective study of FGFR3 mutations as a prognostic factor in nonmuscle invasive urothelial bladder carcinomas. J Clin Oncol 2006; 24:3664.
  66. Hartmann A, Schlake G, Zaak D, et al. Occurrence of chromosome 9 and p53 alterations in multifocal dysplasia and carcinoma in situ of human urinary bladder. Cancer Res 2002; 62:809.
  67. Moonen PM, van Balken-Ory B, Kiemeney LA, et al. Prognostic value of p53 for high risk superficial bladder cancer with long-term followup. J Urol 2007; 177:80.
  68. Shariat SF, Lotan Y, Karakiewicz PI, et al. p53 predictive value for pT1-2 N0 disease at radical cystectomy. J Urol 2009; 182:907.
  69. Dyrskjøt L, Zieger K, Real FX, et al. Gene expression signatures predict outcome in non-muscle-invasive bladder carcinoma: a multicenter validation study. Clin Cancer Res 2007; 13:3545.
  70. Liu Y, Noon AP, Aguiar Cabeza E, et al. Next-generation RNA sequencing of archival formalin-fixed paraffin-embedded urothelial bladder cancer. Eur Urol 2014; 66:982.
  71. Dyrskjøt L, Reinert T, Algaba F, et al. Prognostic Impact of a 12-gene Progression Score in Non-muscle-invasive Bladder Cancer: A Prospective Multicentre Validation Study. Eur Urol 2017; 72:461.
  72. van Kessel KEM, van der Keur KA, Dyrskjøt L, et al. Molecular Markers Increase Precision of the European Association of Urology Non-Muscle-Invasive Bladder Cancer Progression Risk Groups. Clin Cancer Res 2018; 24:1586.
  73. Patschan O, Sjödahl G, Chebil G, et al. A Molecular Pathologic Framework for Risk Stratification of Stage T1 Urothelial Carcinoma. Eur Urol 2015; 68:824.
  74. Hedegaard J, Lamy P, Nordentoft I, et al. Comprehensive Transcriptional Analysis of Early-Stage Urothelial Carcinoma. Cancer Cell 2016; 30:27.
  75. Sylvester RJ, Rodríguez O, Hernández V, et al. European Association of Urology (EAU) Prognostic Factor Risk Groups for Non-muscle-invasive Bladder Cancer (NMIBC) Incorporating the WHO 2004/2016 and WHO 1973 Classification Systems for Grade: An Update from the EAU NMIBC Guidelines Panel. Eur Urol 2021; 79:480.
  76. Kohjimoto Y, Kusumoto H, Nishizawa S, et al. External validation of European Organization for Research and Treatment of Cancer and Spanish Urological Club for Oncological Treatment scoring models to predict recurrence and progression in Japanese patients with non-muscle invasive bladder cancer treated with bacillus Calmette-Guérin. Int J Urol 2014; 21:1201.
  77. Fernandez-Gomez J, Madero R, Solsona E, et al. The EORTC tables overestimate the risk of recurrence and progression in patients with non-muscle-invasive bladder cancer treated with bacillus Calmette-Guérin: external validation of the EORTC risk tables. Eur Urol 2011; 60:423.
  78. EORTC Risk Tables for Predicting Recurrence and Progression in Individual Patients with Stage Ta T1 Bladder Cancer. EORTC. Available at: http://www.eortc.be/tools/bladdercalculator/default.htm (Accessed on January 12, 2024).
  79. Fernandez-Gomez J, Madero R, Solsona E, et al. Predicting nonmuscle invasive bladder cancer recurrence and progression in patients treated with bacillus Calmette-Guerin: the CUETO scoring model. J Urol 2009; 182:2195.
  80. Rosevear HM, Lightfoot AJ, Nepple KG, O'Donnell MA. Usefulness of the Spanish Urological Club for Oncological Treatment scoring model to predict nonmuscle invasive bladder cancer recurrence in patients treated with intravesical bacillus Calmette-Guérin plus interferon-α. J Urol 2011; 185:67.
  81. Oddens J, Brausi M, Sylvester R, et al. Final results of an EORTC-GU cancers group randomized study of maintenance bacillus Calmette-Guérin in intermediate- and high-risk Ta, T1 papillary carcinoma of the urinary bladder: one-third dose versus full dose and 1 year versus 3 years of maintenance. Eur Urol 2013; 63:462.
  82. Kamat AM, Witjes JA, Brausi M, et al. Defining and treating the spectrum of intermediate risk nonmuscle invasive bladder cancer. J Urol 2014; 192:305.
  83. Sylvester RJ, van der Meijden AP, Witjes JA, Kurth K. Bacillus calmette-guerin versus chemotherapy for the intravesical treatment of patients with carcinoma in situ of the bladder: a meta-analysis of the published results of randomized clinical trials. J Urol 2005; 174:86.
  84. Martínez-Piñeiro JA, Jiménez León J, Martínez-Piñeiro L Jr, et al. Bacillus Calmette-Guerin versus doxorubicin versus thiotepa: a randomized prospective study in 202 patients with superficial bladder cancer. J Urol 1990; 143:502.
  85. Shelley MD, Court JB, Kynaston H, et al. Intravesical bacillus Calmette-Guerin versus mitomycin C for Ta and T1 bladder cancer. Cochrane Database Syst Rev 2003; :CD003231.
  86. Böhle A, Bock PR. Intravesical bacille Calmette-Guérin versus mitomycin C in superficial bladder cancer: formal meta-analysis of comparative studies on tumor progression. Urology 2004; 63:682.
  87. de Reijke TM, Kurth KH, Sylvester RJ, et al. Bacillus Calmette-Guerin versus epirubicin for primary, secondary or concurrent carcinoma in situ of the bladder: results of a European Organization for the Research and Treatment of Cancer--Genito-Urinary Group Phase III Trial (30906). J Urol 2005; 173:405.
  88. Schmidt S, Kunath F, Coles B, et al. Intravesical Bacillus Calmette-Guérin versus mitomycin C for Ta and T1 bladder cancer. Cochrane Database Syst Rev 2020; 1:CD011935.
  89. Kassouf W, Traboulsi SL, Kulkarni GS, et al. CUA guidelines on the management of non-muscle invasive bladder cancer. Can Urol Assoc J 2015; 9:E690.
  90. Böhle A, Jocham D, Bock PR. Intravesical bacillus Calmette-Guerin versus mitomycin C for superficial bladder cancer: a formal meta-analysis of comparative studies on recurrence and toxicity. J Urol 2003; 169:90.
  91. Pettenati C, Ingersoll MA. Mechanisms of BCG immunotherapy and its outlook for bladder cancer. Nat Rev Urol 2018; 15:615.
  92. Prescott S, Jackson AM, Hawkyard SJ, et al. Mechanisms of action of intravesical bacille Calmette-Guérin: local immune mechanisms. Clin Infect Dis 2000; 31 Suppl 3:S91.
  93. Böhle A, Brandau S. Immune mechanisms in bacillus Calmette-Guerin immunotherapy for superficial bladder cancer. J Urol 2003; 170:964.
  94. Mungan NA, Witjes JA. Bacille Calmette-Guérin in superficial transitional cell carcinoma. Br J Urol 1998; 82:213.
  95. Jackson A, Alexandroff A, Fleming D, et al. Bacillus-calmette-guerin (bcg) organisms directly alter the growth of bladder-tumor cells. Int J Oncol 1994; 5:697.
  96. Durek C, Richter E, Basteck A, et al. The fate of bacillus Calmette-Guerin after intravesical instillation. J Urol 2001; 165:1765.
  97. Catalona WJ, Ratliff TL. Bacillus Calmette-Guérin and superficial bladder cancer. Clinical experience and mechanism of action. Surg Annu 1990; 22:363.
  98. Martínez-Piñeiro JA, Martínez-Piñeiro L, Solsona E, et al. Has a 3-fold decreased dose of bacillus Calmette-Guerin the same efficacy against recurrences and progression of T1G3 and Tis bladder tumors than the standard dose? Results of a prospective randomized trial. J Urol 2005; 174:1242.
  99. Pagano F, Bassi P, Piazza N, et al. Improving the efficacy of BCG immunotherapy by dose reduction. Eur Urol 1995; 27 Suppl 1:19.
  100. Agrawal MS, Agrawal M, Bansal S, et al. The safety and efficacy of different doses of bacillus Calmette Guérin in superficial bladder transitional cell carcinoma. Urology 2007; 70:1075.
  101. Saint F, Irani J, Patard JJ, et al. Tolerability of bacille Calmette-Guérin maintenance therapy for superficial bladder cancer. Urology 2001; 57:883.
  102. Colombel M, Saint F, Chopin D, et al. The effect of ofloxacin on bacillus calmette-guerin induced toxicity in patients with superficial bladder cancer: results of a randomized, prospective, double-blind, placebo controlled, multicenter study. J Urol 2006; 176:935.
  103. Grimm MO, van der Heijden, Colombel M, et al. Treatment of high-grade non-muscle invasive bladder carcinoma by standard number and dose of BCG instillations versus reduced number and standard dose of BCG instillations: Results of the phase III clinical trial (NIMBUS). J Clin Oncol 2020; 38. 6S; Abstract 436.
  104. Steinberg RL, Thomas LJ, Brooks N, et al. Multi-Institution Evaluation of Sequential Gemcitabine and Docetaxel as Rescue Therapy for Nonmuscle Invasive Bladder Cancer. J Urol 2020; 203:902.
  105. Swietek N, Waldert M, Rom M, et al. The value of transurethral bladder biopsy after intravesical bacillus Calmette-Guérin instillation therapy for nonmuscle invasive bladder cancer: a retrospective, single center study and cumulative analysis of the literature. J Urol 2012; 188:748.
  106. Lamm DL, Blumenstein BA, Crissman JD, et al. Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol 2000; 163:1124.
  107. Shelley MD, Court JB, Kynaston H, et al. Intravesical Bacillus Calmette-Guerin in Ta and T1 Bladder Cancer. Cochrane Database Syst Rev 2000; :CD001986.
  108. Herr HW, Schwalb DM, Zhang ZF, et al. Intravesical bacillus Calmette-Guérin therapy prevents tumor progression and death from superficial bladder cancer: ten-year follow-up of a prospective randomized trial. J Clin Oncol 1995; 13:1404.
  109. Davis JW, Sheth SI, Doviak MJ, Schellhammer PF. Superficial bladder carcinoma treated with bacillus Calmette-Guerin: progression-free and disease specific survival with minimum 10-year followup. J Urol 2002; 167:494.
  110. Margel D, Tal R, Golan S, et al. Long-term follow-up of patients with Stage T1 high-grade transitional cell carcinoma managed by Bacille Calmette-Guérin immunotherapy. Urology 2007; 69:78.
  111. Herr HW. Tumour progression and survival in patients with T1G3 bladder tumours: 15-year outcome. Br J Urol 1997; 80:762.
  112. Brake M, Loertzer H, Horsch R, Keller H. Long-term results of intravesical bacillus Calmette-Guérin therapy for stage T1 superficial bladder cancer. Urology 2000; 55:673.
  113. Larsen ES, Joensen UN, Poulsen AM, et al. Bacillus Calmette-Guérin immunotherapy for bladder cancer: a review of immunological aspects, clinical effects and BCG infections. APMIS 2020; 128:92.
  114. Green DB, Kawashima A, Menias CO, et al. Complications of Intravesical BCG Immunotherapy for Bladder Cancer. Radiographics 2019; 39:80.
  115. Pérez-Jacoiste Asín MA, Fernández-Ruiz M, López-Medrano F, et al. Bacillus Calmette-Guérin (BCG) infection following intravesical BCG administration as adjunctive therapy for bladder cancer: incidence, risk factors, and outcome in a single-institution series and review of the literature. Medicine (Baltimore) 2014; 93:236.
  116. Metayer B, Menu P, Khatchatourian L, et al. Prosthetic joint infection with pseudo-tumoral aspect due to Mycobacterium bovis infection after Bacillus-Calmette-Guerin therapy. Ann Phys Rehabil Med 2018; 61:62.
  117. Chazerain P, Desplaces N, Mamoudy P, et al. Prosthetic total knee infection with a bacillus Calmette Guerin (BCG) strain after BCG therapy for bladder cancer. J Rheumatol 1993; 20:2171.
  118. Segal A, Krauss ES. Infected total hip arthroplasty after intravesical bacillus Calmette-Guérin therapy. J Arthroplasty 2007; 22:759.
  119. Stone DR, Estes NA 3rd, Klempner MS. Mycobacterium bovis infection of an implantable defibrillator following intravesical therapy with bacille Calmette-Guérin. Clin Infect Dis 1993; 16:825.
  120. Rosevear HM, Lightfoot AJ, Nepple KG, O'Donnell MA. Safety and efficacy of intravesical bacillus Calmette-Guérin plus interferon α-2b therapy for nonmuscle invasive bladder cancer in patients with prosthetic devices. J Urol 2010; 184:1920.
  121. Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator. Nat Med 2000; 6:1399.
  122. Greenwood J, Steinman L, Zamvil SS. Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nat Rev Immunol 2006; 6:358.
  123. Hoffmann P, Roumeguère T, Schulman C, van Velthoven R. Use of statins and outcome of BCG treatment for bladder cancer. N Engl J Med 2006; 355:2705.
  124. Orsola A, Cecchini L, Bellmunt J. Statins and the effect of BCG on bladder cancer. N Engl J Med 2007; 356:1276; author reply 1276.
  125. Berglund RK, Savage CJ, Vora KC, et al. An analysis of the effect of statin use on the efficacy of bacillus calmette-guerin treatment for transitional cell carcinoma of the bladder. J Urol 2008; 180:1297.
  126. Au JL, Badalament RA, Wientjes MG, et al. Methods to improve efficacy of intravesical mitomycin C: results of a randomized phase III trial. J Natl Cancer Inst 2001; 93:597.
  127. Hall MC, Chang SS, Dalbagni G, et al. Guideline for the management of nonmuscle invasive bladder cancer (stages Ta, T1, and Tis): 2007 update. J Urol 2007; 178:2314.
  128. Bosschieter J, Nieuwenhuijzen JA, van Ginkel T, et al. Value of an Immediate Intravesical Instillation of Mitomycin C in Patients with Non–muscle-invasive Bladder Cancer: A Prospective Multicentre Randomised Study in 2243 patients. Eur Urol 2017.
  129. Sylvester RJ, Oosterlinck W, Holmang S, et al. Systematic Review and Individual Patient Data Meta-analysis of Randomized Trials Comparing a Single Immediate Instillation of Chemotherapy After Transurethral Resection with Transurethral Resection Alone in Patients with Stage pTa-pT1 Urothelial Carcinoma of the Bladder: Which Patients Benefit from the Instillation? Eur Urol 2016; 69:231.
  130. Onishi T, Sugino Y, Shibahara T, et al. Randomized controlled study of the efficacy and safety of continuous saline bladder irrigation after transurethral resection for the treatment of non-muscle-invasive bladder cancer. BJU Int 2017; 119:276.
  131. Babjuk M, Oosterlinck W, Sylvester R, et al. EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder. Eur Urol 2008; 54:303.
  132. Friedrich MG, Pichlmeier U, Schwaibold H, et al. Long-term intravesical adjuvant chemotherapy further reduces recurrence rate compared with short-term intravesical chemotherapy and short-term therapy with Bacillus Calmette-Guérin (BCG) in patients with non-muscle-invasive bladder carcinoma. Eur Urol 2007; 52:1123.
  133. Colombo R, Da Pozzo LF, Salonia A, et al. Multicentric study comparing intravesical chemotherapy alone and with local microwave hyperthermia for prophylaxis of recurrence of superficial transitional cell carcinoma. J Clin Oncol 2003; 21:4270.
  134. Colombo R, Salonia A, Leib Z, et al. Long-term outcomes of a randomized controlled trial comparing thermochemotherapy with mitomycin-C alone as adjuvant treatment for non-muscle-invasive bladder cancer (NMIBC). BJU Int 2011; 107:912.
  135. Alfred Witjes J, Hendricksen K, Gofrit O, et al. Intravesical hyperthermia and mitomycin-C for carcinoma in situ of the urinary bladder: experience of the European Synergo working party. World J Urol 2009; 27:319.
  136. Arends TJ, Nativ O, Maffezzini M, et al. Results of a Randomised Controlled Trial Comparing Intravesical Chemohyperthermia with Mitomycin C Versus Bacillus Calmette-Guérin for Adjuvant Treatment of Patients with Intermediate- and High-risk Non-Muscle-invasive Bladder Cancer. Eur Urol 2016; 69:1046.
  137. Di Stasi SM, Giannantoni A, Giurioli A, et al. Sequential BCG and electromotive mitomycin versus BCG alone for high-risk superficial bladder cancer: a randomised controlled trial. Lancet Oncol 2006; 7:43.
  138. Bachir BG, Dragomir A, Aprikian AG, et al. Contemporary cost-effectiveness analysis comparing sequential bacillus Calmette-Guerin and electromotive mitomycin versus bacillus Calmette-Guerin alone for patients with high-risk non-muscle-invasive bladder cancer. Cancer 2014; 120:2424.
  139. Di Stasi SM, Giannantoni A, Stephen RL, et al. Intravesical electromotive mitomycin C versus passive transport mitomycin C for high risk superficial bladder cancer: a prospective randomized study. J Urol 2003; 170:777.
  140. Thrasher JB, Crawford ED. Complications of intravesical chemotherapy. Urol Clin North Am 1992; 19:529.
  141. Colver GB, Inglis JA, McVittie E, et al. Dermatitis due to intravesical mitomycin C: a delayed-type hypersensitivity reaction? Br J Dermatol 1990; 122:217.
  142. Addeo R, Caraglia M, Bellini S, et al. Randomized phase III trial on gemcitabine versus mytomicin in recurrent superficial bladder cancer: evaluation of efficacy and tolerance. J Clin Oncol 2010; 28:543.
  143. Han MA, Maisch P, Jung JH, et al. Intravesical gemcitabine for non-muscle invasive bladder cancer. Cochrane Database Syst Rev 2021; 6:CD009294.
  144. Messing EM, Tangen CM, Lerner SP, et al. Effect of Intravesical Instillation of Gemcitabine vs Saline Immediately Following Resection of Suspected Low-Grade Non-Muscle-Invasive Bladder Cancer on Tumor Recurrence: SWOG S0337 Randomized Clinical Trial. JAMA 2018; 319:1880.
  145. Böhle A, Leyh H, Frei C, et al. Single postoperative instillation of gemcitabine in patients with non-muscle-invasive transitional cell carcinoma of the bladder: a randomised, double-blind, placebo-controlled phase III multicentre study. Eur Urol 2009; 56:495.
  146. Rajala P, Liukkonen T, Raitanen M, et al. Transurethral resection with perioperative instilation on interferon-alpha or epirubicin for the prophylaxis of recurrent primary superficial bladder cancer: a prospective randomized multicenter study--Finnbladder III. J Urol 1999; 161:1133.
  147. Berrum-Svennung I, Granfors T, Jahnson S, et al. A single instillation of epirubicin after transurethral resection of bladder tumors prevents only small recurrences. J Urol 2008; 179:101.
  148. van der Meijden AP, Brausi M, Zambon V, et al. Intravesical instillation of epirubicin, bacillus Calmette-Guerin and bacillus Calmette-Guerin plus isoniazid for intermediate and high risk Ta, T1 papillary carcinoma of the bladder: a European Organization for Research and Treatment of Cancer genito-urinary group randomized phase III trial. J Urol 2001; 166:476.
  149. Sylvester RJ, Brausi MA, Kirkels WJ, et al. Long-term efficacy results of EORTC genito-urinary group randomized phase 3 study 30911 comparing intravesical instillations of epirubicin, bacillus Calmette-Guérin, and bacillus Calmette-Guérin plus isoniazid in patients with intermediate- and high-risk stage Ta T1 urothelial carcinoma of the bladder. Eur Urol 2010; 57:766.
  150. Prout GR Jr, Koontz WW Jr, Coombs LJ, et al. Long-term fate of 90 patients with superficial bladder cancer randomly assigned to receive or not to receive thiotepa. J Urol 1983; 130:677.
  151. Hollister D Jr, Coleman M. Hematologic effects of intravesicular thiotepa therapy for bladder carcinoma. JAMA 1980; 244:2065.
  152. Silberberg JM, Zarrabi MH. Acute nonlymphocytic leukemia after thiotepa instillation into the bladder: report of 2 cases and review of the literature. J Urol 1987; 138:402.
  153. Catto JWF, Gordon K, Collinson M, et al. Radical Cystectomy Against Intravesical BCG for High-Risk High-Grade Nonmuscle Invasive Bladder Cancer: Results From the Randomized Controlled BRAVO-Feasibility Study. J Clin Oncol 2021; 39:202.
  154. Weiss C, Wolze C, Engehausen DG, et al. Radiochemotherapy after transurethral resection for high-risk T1 bladder cancer: an alternative to intravesical therapy or early cystectomy? J Clin Oncol 2006; 24:2318.
  155. Harland SJ, Kynaston H, Grigor K, et al. A randomized trial of radical radiotherapy for the management of pT1G3 NXM0 transitional cell carcinoma of the bladder. J Urol 2007; 178:807.
  156. Kassouf W, Traboulsi SL, Schmitz-Dräger B, et al. Follow-up in non-muscle-invasive bladder cancer-International Bladder Cancer Network recommendations. Urol Oncol 2016; 34:460.
  157. Schrag D, Hsieh LJ, Rabbani F, et al. Adherence to surveillance among patients with superficial bladder cancer. J Natl Cancer Inst 2003; 95:588.
  158. Sanderson KM, Cai J, Miranda G, et al. Upper tract urothelial recurrence following radical cystectomy for transitional cell carcinoma of the bladder: an analysis of 1,069 patients with 10-year followup. J Urol 2007; 177:2088.
  159. Schwartz CB, Bekirov H, Melman A. Urothelial tumors of upper tract following treatment of primary bladder transitional cell carcinoma. Urology 1992; 40:509.
  160. Hurle R, Losa A, Manzetti A, Lembo A. Upper urinary tract tumors developing after treatment of superficial bladder cancer: 7-year follow-up of 591 consecutive patients. Urology 1999; 53:1144.
  161. Canales BK, Anderson JK, Premoli J, Slaton JW. Risk factors for upper tract recurrence in patients undergoing long-term surveillance for stage ta bladder cancer. J Urol 2006; 175:74.
  162. Wright JL, Hotaling J, Porter MP. Predictors of upper tract urothelial cell carcinoma after primary bladder cancer: a population based analysis. J Urol 2009; 181:1035.
  163. Herr HW, Cookson MS, Soloway SM. Upper tract tumors in patients with primary bladder cancer followed for 15 years. J Urol 1996; 156:1286.
  164. Miller EB, Eure GR, Schellhammer PF. Upper tract transitional cell carcinoma following treatment of superficial bladder cancer with BCG. Urology 1993; 42:26.
  165. Daneshmand S, Bazargani ST, Bivalacqua TJ, et al. Blue light cystoscopy for the diagnosis of bladder cancer: Results from the US prospective multicenter registry. Urol Oncol 2018; 36:361.e1.
  166. Schwalb MD, Herr HW, Sogani PC, et al. Positive urinary cytology following a complete response to intravesical bacillus Calmette-Guerin therapy: pattern of recurrence. J Urol 1994; 152:382.
  167. Evans CP. Follow-up surveillance strategies for genitourinary malignancies. Cancer 2002; 94:2892.
  168. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer. Version 2.2023. Available at: https://www.nccn.org/professionals/physician_gls/ https://www.nccn.org/professionals/physician_gls/ (Accessed on November 29, 2023).
  169. Rabbani F, Perrotti M, Russo P, Herr HW. Upper-tract tumors after an initial diagnosis of bladder cancer: argument for long-term surveillance. J Clin Oncol 2001; 19:94.
  170. Herr HW, Donat SM. Prostatic tumor relapse in patients with superficial bladder tumors: 15-year outcome. J Urol 1999; 161:1854.
  171. Huguet J, Crego M, Sabaté S, et al. Cystectomy in patients with high risk superficial bladder tumors who fail intravesical BCG therapy: pre-cystectomy prostate involvement as a prognostic factor. Eur Urol 2005; 48:53.
Topic 2996 Version 57.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟