Version July 2025
INTRODUCTION —
Bladder cancer accounts for approximately 600,000 cases and over 200,000 deaths each year globally [1]. The predominant histology for bladder cancer is urothelial carcinoma. Approximately 70 percent of new cases of urothelial bladder cancer are classified as non-muscle invasive bladder cancer (NMIBC) [2]. (See "Epidemiology and risk factors of urothelial carcinoma of the bladder".)
The initial management of primary NMIBC is discussed here. The management of recurrent or persistent NMIBC is discussed separately. (See "Treatment of recurrent or persistent non-muscle invasive urothelial carcinoma of the bladder".)
Other topics related to the clinical presentation, diagnosis, and management of bladder cancer include:
●(See "Clinical presentation, diagnosis, and staging of bladder cancer".)
●(See "Overview of the initial approach and management of urothelial bladder cancer".)
DEFINITION —
Non-muscle invasive bladder cancer (NMIBC) are tumors within the bladder that occur in the urothelium and lamina propria but do not invade into the muscularis propria. NMIBC includes Tis (ie, carcinoma in situ [CIS]) as well as Ta and T1 disease (ie, papillary disease) (figure 1 and table 1). (See "Pathology of bladder neoplasms", section on 'Noninvasive urothelial neoplasms'.)
●Tis – Tis tumors (also known as CIS), are flat, noninvasive flat lesions characterized by severe cellular dysplasia in the absence of discrete tumor formation. Areas of mucosal involvement with Tis are often found in association with muscle-invasive disease. Among all patients with NMIBC, the frequency of Tis disease is 10 percent.
●Papillary disease
•Ta – 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. Among all patients with NMIBC, the frequency of Ta disease is 70 percent.
•T1 – T1 tumors are papillary, submucosal invasive cancers that 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. Among all patients with NMIBC, the frequency of T1 disease is 20 percent.
DIAGNOSIS —
For patients with suspected non-muscle invasive bladder cancer (NMIBC), the diagnostic evaluation includes examination under anesthesia, a complete transurethral resection of bladder tumor (TURBT), and staging imaging studies to confirm the absence of locoregional or metastatic disease. The tissue specimen obtained from the TURBT is histopathologically evaluated to confirm the diagnosis and assess the tumor (T) stage and grade. Further details on the diagnosis and staging of bladder cancer are discussed separately. (See "Clinical presentation, diagnosis, and staging of bladder cancer".)
Transurethral resection of bladder tumor
Initial TURBT — The first step in the diagnosis of presumed NMIBC is a complete transurethral resection of all visible bladder tumor with adequate depth to include muscularis propria. The quality of the TURBT is of primary importance. An examination under anesthesia should also be performed since the presence of induration or a palpable mass suggests muscle invasive disease. (See "Clinical presentation, diagnosis, and staging of bladder cancer", section on 'Cystoscopy'.)
Resection should also include biopsy of focal areas of suspected Tis (carcinoma in situ [CIS]) and abnormal areas in the prostatic urethra and bladder neck. Most patients with NMIBC can be successfully managed conservatively; however, a minority will require more aggressive surgery. (See 'Very high-risk disease' below.)
The management of patients whose TURBT reveals muscle-invasive disease is discussed separately. (See "Overview of the initial approach and management of urothelial bladder cancer", section on 'Muscle invasive disease'.)
Indications for restaging TURBT — For patients with a confirmed diagnosis of NMIBC after initial TURBT, a restaging TURBT should be performed four to six weeks after the initial resection for the following indications:
●Incomplete resection with the initial TURBT (eg, resection is not visually complete; high-volume tumor; muscularis propria is absent in the histologic specimen)
●T1 tumor
●Select cases of high-grade Ta disease (eg, large and/or multiple tumors)
A restaging TURBT is not required for patients with very high-risk features on the initial TURBT who are being treated with radical cystectomy [3]. These features are defined below. (See 'Very high-risk disease' below.)
Restaging TURBT results in more accurate risk stratification of NMIBC (table 2) and is associated with improved outcomes such as lower recurrence rates and improved progression-free survival [4].
Restaging TURBT can also identify a muscle-invasive bladder cancer that was improperly diagnosed as NMIBC on the initial TURBT, which impacts management. As an example, in patients with T1 tumors (ie, tumors that involve the lamina propria), studies suggest that repeat TURBT may decrease the chances of cancer understaging, even if the initial resection was thought to be complete [5-12]. The management of muscle-invasive bladder cancer is discussed separately. (See "Neoadjuvant therapy for localized muscle-invasive urothelial carcinoma of the bladder" and "Bladder preservation treatment options for muscle-invasive urothelial bladder cancer".)
Enhanced imaging techniques — Photodynamic diagnosis (ie, fluorescent cystoscopy) and narrow band imaging (NBI) are enhanced imaging techniques that are performed in conjunction with cystoscopy and TURBT to improve the detection of bladder tumors.
Fluorescent cystoscopy (photodynamic diagnosis) — Fluorescent cystoscopy (ie, photodynamic diagnosis) uses an intravesical photosensitizer that is instilled prior to cystoscopy (such as hexyl aminolevulinic acid [HAL]), which makes tumors fluoresce under blue light. These tumors are then detected using a special lens system. (See "Clinical presentation, diagnosis, and staging of bladder cancer", section on 'Fluorescence cystoscopy'.)
Most data suggest that photodynamic diagnosis improves detection of multifocal tumors and CIS and decreased recurrence risk after TURBT when compared with white-light guided cystoscopy [13-23]. As an example, in a meta-analysis of 16 randomized trials that included 4325 patients with NMIBC, blue-light TURBT reduced the risk of disease recurrence (hazard ratio [HR] 0.66, 95% CI 0.54-0.81) and disease progression (HR 0.65, 95% CI 0.50-0.84) compared with white-light guided TURBT [23], with the magnitude of effect varying across risk stratification groups. However, many of these studies did not include immediate instillation of postoperative chemotherapy following TURBT. One randomized trial included in the meta-analysis did compare HAL photodynamic-assisted TURBT with standard white-light cystoscopy (both followed by a single instillation (SI) of postoperative mitomycin) but found no difference in recurrence rates at three months and one year [24].
A few studies have failed to demonstrate a recurrence-free survival (RFS) benefit for photodynamic diagnosis [24,25]. In a randomized trial (PHOTO), 538 patients with suspected initial diagnosis of intermediate- or high-risk NMIBC were randomly assigned to either photodynamic-guided or standard white-light guided TURBT [25]. Patients received postoperative instillation of chemotherapy in both arms. Although photodynamic-guided TURBT initially demonstrated an RFS benefit at one year over white-light guided TURBT, this RFS benefit did not persist with extended follow-up (three-year RFS 58 versus 62 percent, HR 0.94, 95% CI 0.69-1.28). Photodynamic diagnosis-guided TURBT was more costly with no difference in quality-adjusted-life years. One limitation of this study is the inclusion of intermediate- and high-risk tumors only, which limits its generalizability to tumors in other risk groups. In addition, CIS, a tumor type in which blue light detects the most "missed" tumors, was underrepresented in this study (present in only 13 percent of the resection specimen).
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 [26-31]. 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 cystoscopy.
Although the data are less robust, in a systematic review of randomized trials that included over 1200 patients with NMIBC, 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 [29]. However, the impact of postoperative chemotherapy instillation or a course of adjuvant 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 [31].
RISK STRATIFICATION —
Patients with a histologically confirmed diagnosis of non-muscle invasive bladder cancer (NMIBC) who complete transurethral resection of all visible bladder tumor (TURBT) still remain at risk for recurrent disease [32]. Based upon the American Urologic Association (AUA) risk stratification system for NMIBC, primary tumors are stratified into low risk, intermediate risk, and high-risk for disease progression (table 2) [33,34]. Recurrent tumors are stratified as either intermediate- or high-risk disease.
●Low risk:
•Papillary urothelial neoplasm of low malignant potential
•Low-grade solitary Ta tumor ≤3 cm in diameter
●Intermediate risk:
•Low-grade Ta and recurrence within one year
•Low-grade solitary Ta tumor >3 cm
•Low-grade multifocal Ta
•First occurrence, solitary, high-grade Ta tumor ≤3 cm in diameter
•Low-grade T1
●High risk:
•High-grade T1
•Any recurrent high-grade Ta
•High-grade Ta tumor >3 cm or multifocal
•Any carcinoma in situ (CIS)
•Any Bacille Calmette-Guérin (BCG) failure in a patient with a high-grade tumor
•Any variant histology
•Any lymphovascular invasion (LVI)
•Any high-risk prostatic urethral involvement
●Very high-risk disease – Although the AUA does not formally define this subcategory under their risk classification system, the guidelines do acknowledge a subset of patients with additional features that place them at the highest risk for disease progression. Such "very high-risk disease" includes the following features [3,33-35]:
•Extensive bladder involvement, unable to attain complete resection of all visible disease despite multiple attempts at TURBT.
•CIS involving the prostatic ducts/acini.
•Pure squamous cell or adenocarcinoma histology.
•T1 tumor with associated CIS, LVI, or variant histology, such as micropapillary, neuroendocrine/small cell, plasmacytoid, or sarcomatoid features.
•T1, grade 3 tumors that are large/diffuse/multifocal or persistent lesions identified on reresection.
•T1b tumors (ie, deep or extensive involvement of the lamina propria).
Alternative risk stratification systems for NMIBC are also available from the Canadian Urological Association (CUA) [3] and the European Association of Urology (EAU) [36,37]. For the EAU risk stratification system, an online calculator is available to determine the appropriate risk category and probability of progression [36,38]. The specific classification criteria used in these systems have some differences with the AUA system. For example, the EAU risk stratification system includes a very high-risk category and incorporates patient age.
PROGNOSIS —
Outcomes are generally excellent in patients with non-muscle invasive bladder cancer (NMIBC) [33]. Among all patients with NMIBC, five-year overall survival (OS) is approximately 96 percent. Among those with low-risk disease, cancer specific mortality is less than 1 percent; among those with higher-risk disease, cancer-specific survival ranges between 70 and 85 percent. As such, the most important clinical outcomes are disease recurrence and progression to muscle-invasive bladder cancer, especially for those with intermediate- and high-risk disease.
Prognostic factors — The most important prognostic factors for recurrence of NMIBC are tumor (T) stage and histologic grade. Other prognostic factors include number of tumors, the frequency of recurrence, the tumor size, concomitant Tis disease (also called carcinoma in situ [CIS]) [39,40], age [38], variant histology [41,42], and lymphovascular invasion(LVI) [43-46].
Tumor (T) stage
●Ta tumors – Ta 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 [47]. 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 [47,48].
●Tis tumors – Tis (CIS) tumors in the mucosa adjacent to a Ta or T1 tumor appears to increase the risk for muscle invasive disease [49-52].
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 [51]. 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. LVI 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 with CIS who were managed with transurethral resection and Bacille Calmette-Guérin (BCG), the five-year cumulative incidence of progression to clinical T1 or higher stage disease was 45 percent (95% CI 37-55) [52]. 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 [53,54].
●T1 tumors – Virtually all T1 tumors are high-grade, and approximately one-third to one-half have associated Tis [43,55,56]. In a meta-analysis of 56 cohort studies that included 15,215 patients with high-grade T1 NMIBC, the five-year rates of recurrence, progression, and cancer-specific survival were 42, 21, and 82 percent [43].
Grade — In addition to tumor stage (Tis, Ta, or T1), histologic grade influences the rate of recurrence and, ultimately, survival for patients with NMIBC [57,58].
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 [32]. The WHO 2004/2006 grading classification 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 NMIBC, although some community practices still report using the WHO 1973 grading classification system (grade 1 to 3). (See "Pathology of bladder neoplasms".)
The importance of histologic grade was illustrated in a systematic review from the European Association of Urology (EAU) [32]. 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 [32]. In patients with NMIBC, the risk of progression to more advanced disease for the 2012 patients with data were 3, 9, and 28 percent, respectively; for grade 1, 2, and 3 lesions, and the risk of recurrence for the 1197 patients with data were 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 [59,60]. As an example, in an observational study of 577 patients with low-risk NMIBC (ie, primary, solitary, low-grade, Ta bladder tumor measuring <3 cm), five-year recurrence-free survival (RFS) was 82 percent [60]. The recurrence rate after five years was 13 percent, and high-risk recurrences (ie, first recurrence of a high-grade and/or ≥T1 tumor) were rare after five years (3 percent).
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 [57,58,61]. 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 [61].
Tumor size — Patients who have large tumors (>3 cm) are associated with a higher risk of recurrence and progression to muscle-invasive disease [36,38].
What is the role of molecular markers? — Further studies are necessary to determine the impact of molecular markers on predicting prognosis for NMIBC.
Molecular markers in tissue samples may provide an additional way to identify NMIBCs that are likely to progress to muscle invasive or high-grade disease [62-65]. Initial studies focused on chromosomal abnormalities, and these provided the basis for identifying specific genetic alterations. Other pathogenic variants that have been studied include fibroblast growth factor receptor 3 (FGFR3), which may be associated with a favorable prognosis [66-68], and alterations in p53, which may be associated with a less favorable prognosis [69-71].
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 [72-75]. Stratification of T1 tumors into molecular subtypes (basal or luminal-like characteristics) has also been shown to improve the identification of patients with progressing tumors [76-79]. (See "Molecular biology of bladder cancer", section on 'Subtypes defined by gene expression profiling'.)
Prediction models — In addition to the available clinical risk stratification systems, other prediction models are available to calculate the risk progression and disease recurrence of NMIBC.
●Patients not treated with intravesical BCG – For patients with NMIBC who are not treated with intravesical BCG, a calculator was developed in 2006 by the European Organisation for Research and Treatment of Cancer (EORTC) to predict the risk of both disease recurrence and progression [39,80]. 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 greater than one year from prior diagnosis versus recurrent tumor less than one 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.
Risk tables are also available that characterize the rates of recurrence in NMIBC [39]. However, the accuracy of this prognostic tool has been questioned as the summary statistics mask the wide spectrum of risk in this heterogeneous patient population with both primary and recurrent disease. [81,82].
●Patients treated with BCG – For patients with NMIBC who are treated with one to three years of maintenance BCG, the EORTC proposed an updated 2016 nomogram for patients treated with one or three years of maintenance BCG [40]. The 2006 EORTC risk calculator is not used for this population as it probably overestimates the risk of recurrence and disease progression since very few patients in that database used to create the 2006 risk calculator received intravesical BCG. The 2016 EORTC nomogram was based on the EORTC 30962 trial [83]. In this trial of 1812 patients with NMIBC, 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.
For patients treated with BCG, the Spanish Urological Club for Oncological Treatment (CUETO) developed a risk stratification tool [84], which has been validated by other international groups [81,85]. 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 additional maintenance BCG.
MANAGEMENT —
The management of non-muscle invasive bladder cancer (NMIBC) is based on the risk of disease recurrence and progression (algorithm 1), as well as patient and provider preferences and drug availability. (See 'Risk stratification' above.)
Low-risk disease — For patients with suspected low-risk disease (table 2) or a European Organisation for Research and Treatment of Cancer (EORTC) recurrence score <5 (see 'Prediction models' above), we suggest a postoperative single instillation (SI) of intravesical chemotherapy rather than no treatment or other regimens, followed by surveillance. Among the available regimens, we suggest gemcitabine, with mitomycin, epirubicin, and pirarubicin as acceptable alternatives. (See 'Intravesical gemcitabine' below and 'Intravesical mitomycin, epirubicin, or pirarubicin' below.)
Single instillation of intravesical chemotherapy — SI of intravesical chemotherapy is administered immediately after transurethral resection of bladder tumor (TURBT; either in the operating room or within 24 hours of completing the procedure) and is allowed to dwell between one to two hours, depending upon the selected agent and dosing.
SI chemotherapy should not be administered after extensive resection or when bladder perforation is suspected. For patients who are unable to receive immediate SI of intravesical chemotherapy, continuous saline bladder irrigation over 16 hours is an alternative option. However, this approach requires inpatient admission of patients who would otherwise be managed in the outpatient setting at most centers [86].
Intravesical therapy permits high local concentrations of a therapeutic agent within the bladder, potentially destroying viable tumor cells that remain following TURBT. Several meta-analyses suggest that administering a SI of intravesical chemotherapy immediately after TURBT reduces the recurrence rate by 12 to 17 percent [87-91]. Early administration of SI intravesical therapy with mitomycin following TURBT within 24 hours is also more effective than delayed therapy (within two weeks), independent of the number of adjuvant instillations, based on a randomized trial [92,93].
Intravesical gemcitabine — For patients with low-risk disease, SI intravesical gemcitabine reduces recurrence risk and is well-tolerated [94,95]. In a phase III trial (SWOG 0337), 406 patients with suspected low-grade NMIBC who were treated with TURBT were randomly assigned to a single postoperative one-hour instillation of intravesical gemcitabine (2000 mg in 100 mL of saline) or normal saline alone [95]. A majority (63 percent) were treated as part of initial therapy, and the remainder (37 percent) were treated for recurrent disease. Patients were evaluated with cystoscopy every three months for two years, followed by every six months for at least two additional years. At a median follow-up of four years, relative to saline, SI intravesical gemcitabine demonstrated the following results:
●In the entire study population, lower risk of recurrence (four-year recurrence rate 35 versus 47 percent, hazard ratio [HR] 0.66, 95% CI 0.48-0.90). The risk of progression to muscle-invasive disease (2.5 versus 4.9 percent, HR 0.51, 95% CI 0.17-1.49) and death due to any cause (17 versus 25 deaths, HR 0.68, 95% CI 0.37-1.27) were similar between the two treatment arms.
●Among the subgroup of 215 patients with histologically confirmed low-grade disease, lower risk of recurrence (four-year recurrence rate 34 versus 54 percent, HR 0.53, 95% CI 0.35-0.81). This recurrence risk benefit was not seen among those with histologically confirmed high-grade disease (four-year recurrence rate 40 versus 45 percent, HR 0.84, 95% CI 0.45-1.6).
●Similar grade 3 toxicity rates (2.4 versus 3.4 percent).
In a separate phase III trial of 355 patients with papillary disease (stage Ta/T1, grade 1 to 3, no concomitant bladder carcinoma in situ [CIS]) who received TURBT followed by 20 hours of continuous saline irrigation of the bladder, a SI of gemcitabine did not improve relapse-free survival compared with saline placebo (median 37 versus 40 months) [96]. However, the dwell time for gemcitabine was only 35 minutes, compared with 60 minutes in the SWOG 0337 trial. In addition, the continuous prolonged saline irrigation of the bladder reduced the recurrence rate in the placebo arm to a degree that the trial was underpowered to demonstrate a difference with SI gemcitabine. Of note, saline irrigation over 20 hours is not feasible at most institution, and, therefore, not routinely used.
Intravesical mitomycin, epirubicin, or pirarubicin — In a systematic review and meta-analysis of 11 randomized trials that included 2278 patients with NMIBC, the addition of a SI of postoperative intravesical chemotherapy (either mitomycin, epirubicin, pirarubicin, or thiotepa) to TURBT reduced the five-year recurrence rate by 14 percent (five-year recurrence rate 58.8 versus 44.8 percent, HR 0.65, 95% CI 0.58-0.74) [88]. The addition of SI chemotherapy to TURBT improved time to first recurrence among those with a 2006 EORTC recurrence score <5 (HR 0.55, 95% CI 0.41-0.73 for recurrence score of 0; HR 0.69, 95% CI 0.56-0.85 for recurrence score of 1 to 4) but not among those with an EORTC recurrence score ≥5 (HR 0.93, 95% CI 0.68-1.28). The European Association of Urology (EAU) risk group was not an effect modifier for the impact of adding SI chemotherapy to TURBT on time to first recurrence. The addition of SI chemotherapy to TURBT did not prolong either the time to progression or death from bladder cancer but, paradoxically, increased the overall risk of death (five-year death rates 12 versus 11 percent; HR 1.26; 95% CI, 1.05-1.51); although this latter finding was mostly driven by patients with an EORTC recurrence score ≥5, there was no effect modification by EORTC recurrence score or EAU risk group.
Intermediate-risk disease — For patients with intermediate-risk disease, we suggest intravesical chemotherapy with gemcitabine followed by one year of maintenance therapy to reduce the risk of disease recurrence, rather than other agents or treatment approaches. (See 'Intravesical gemcitabine' below.)
Other options for intravesical chemotherapy include epirubicin or mitomycin. However, intravesical mitomycin is less preferred since it is significantly more toxic than intravesical gemcitabine. (See 'Intravesical epirubicin' below and 'Intravesical mitomycin' below.)
Although intravesical Bacille Calmette-Guérin (BCG) is an effective alternative, but it is also less preferred since progression is infrequent in intermediate-risk disease, BCG is more toxic than intravesical chemotherapy, and availability is limited due to an ongoing BCG shortage. (See 'Intravesical BCG (intermediate-risk disease)' below and 'Management during BCG shortages' below.)
Intravesical gemcitabine — In patients with primary intermediate-risk disease, intravesical gemcitabine is the preferred option for adjuvant chemotherapy at most institutions. Intravesical gemcitabine reduces recurrence risk compared with mitomycin although this is extrapolated from data in progressive or relapsed NMIBC [97]. Intravesical gemcitabine is also better tolerated than other intravesical regimens such as mitomycin [94,97] and BCG [98,99].
For intermediate-risk disease, intravesical gemcitabine is administered as follows [97]:
●Induction therapy – For induction therapy, six weekly courses are initiated approximately two to six weeks after TURBT [100]. This timing allows healing and reduces the likelihood of severe local or systemic toxicities though systemic absorption via the areas of mucosal damage.
●Maintenance therapy – Approximately six weeks after completing induction therapy, intravesical gemcitabine is administered as maintenance therapy for up to one year (10 monthly doses).
In a randomized trial, 120 patients with Ta to T1, grade 1 to 3 NMIBC who had either progressed, relapsed, or were ineligible for BCG were randomly assigned to induction with six weekly treatments of intravesical gemcitabine (2000 mg in 50 mL of saline) or four weekly treatments of intravesical mitomycin (40 mg in 50 mL of saline) [97]. In both arms, responders who remained free of recurrence subsequently received maintenance therapy with 10 monthly intravesical treatments of their assigned drug during the first year. At a median follow-up of 36 months, compared with mitomycin, gemcitabine resulted in a higher proportion of patients who were recurrence-free (72 versus 61 percent) and was better tolerated (adverse events of any grade 39 versus 72 percent), including lower rates of chemical cystitis (6 versus 21 percent) and dysuria (9 versus 20 percent).
Intravesical epirubicin — Intravesical epirubicin is an option for adjuvant therapy with limited systemic absorption in patients with intermediate-risk disease. Although intravesical epirubicin is more active than either placebo or interferon (IFN) alfa [101-103], it is less effective than intravesical BCG for intermediate-risk disease [104,105]. (See 'Intravesical BCG (intermediate-risk disease)' below.)
Intravesical mitomycin — For patients with intermediate-risk disease, intravesical mitomycin is an option for adjuvant therapy. However, intravesical mitomycin is less preferred since it causes more toxicity than intravesical gemcitabine [97].
Various induction dosing and administration schedules for intravesical mitomycin are available [106-108]. We prefer an optimized mitomycin dose (40 mg in a 20 mL volume), which is administered in six weekly instillations; the drug concentration is increased by decreasing the urine volume and alkalinizing the urine to stabilize the drug. In a randomized trial of patients with high-risk NMIBC, six weekly doses of mitomycin at the optimized dose increased the median time to recurrence (29 versus 12 months) and recurrence-free fraction (41 versus 25 percent) relative to 20 mg in a 20 mL volume [108]. No maintenance therapy was administered in this study.
In a randomized trial of 495 patients with intermediate- or high-risk NMIBC treated with TURBT, compared intravesical therapy using either induction BCG (weekly for six doses), induction mitomycin (20 mg weekly for six weeks), or induction plus maintenance mitomycin (20 mg weekly for six weeks, then monthly for three years) [109]. For the entire study population, inductions plus maintenance mitomycin improved recurrence-free rates relative to induction BCG or mitomycin (three-year recurrence free rate of 86 versus 66 and 69 percent, respectively) [110]. Of note, long-term survival outcomes were not reported in this study.
Toxicities associated with intravesical mitomycin include bladder irritation (dysuria, urinary frequency), a self-limited chemical cystitis [111], and a rash primarily involving the palms, soles, and genitalia, which is mainly due to hypersensitivity reaction [112]. Both the chemical cystitis and the rash generally respond to treatment with corticosteroids. 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. Myelosuppression is uncommon since intravesical mitomycin is minimally absorbed from the bladder into the systemic circulation due to its large molecular weight [113].
Intravesical BCG (intermediate-risk disease) — In patients with intermediate-risk NMIBC, intravesical BCG is an option for adjuvant therapy that reduces recurrence risk but generally carries more toxicity than intravesical chemotherapy [98,99,114,115]. In the setting of BCG shortage, we offer intravesical chemotherapy rather than BCG. (See 'Toxicity' below.)
Dose and schedule — For intermediate-risk disease, intravesical BCG is administered as follows:
●Induction therapy – Induction BCG is instilled into the bladder weekly for six weeks, generally starting two to six weeks after TURBT.
●Maintenance therapy – Upon completion of induction therapy, maintenance BCG is administered for one year (weekly for three weeks at months 3, 6, and 12).
Efficacy and toxicity — Data supporting these dosing schedules for intravesical BCG in intermediate-risk NMIBC are as follows:
●Intravesical BCG versus mitomycin – In an individual patient data meta-analysis of nine randomized trials conducted in patients with NMIBC (a majority with intermediate-risk disease, 74 percent), intravesical BCG regimens that included maintenance therapy reduced the risk of recurrence by 32 percent compared with intravesical mitomycin without maintenance [116]. Progression-free survival, cancer-specific survival, and overall survival (OS) were similar between the treatments.
However, in a separate meta-analysis, intravesical BCG had higher rates of local (44 versus 30 percent) and systemic toxicity (19 versus 12 percent) compared with mitomycin [115]. Other studies have demonstrated similar results [117]. (See 'Toxicity' below.)
●Intravesical BCG versus epirubicin – In a phase III trial (EORTC 30911), 957 patients with intermediate- (497 patients) and high-risk (323 patients) Ta and T1 papillary bladder cancer were randomly assigned to intravesical epirubicin (50 mg weekly for six weeks) or BCG (weekly for six weeks) [104,105]. Both groups then received maintenance treatment with three weekly intravesical doses of either agent every three months for 36 months.
At a median follow-up of 9.2 years, relative to epirubicin, intravesical BCG reduced the risk of first recurrence (38 versus 53 percent, HR 0.62, 95% CI 0.50-0.76), death from bladder cancer (3 versus 7 percent, HR 0.47, 95% CI 0.25-0.89), and death from all causes (31 versus 38 percent, HR 0.76, 95% 0.59-0.96) [105]. In a subgroup analysis by risk group, the benefits of intravesical BCG for patients with intermediate-risk disease were as large, if not larger, than those with high-risk disease.
However, a separate meta-analysis suggested that intravesical BCG had higher rates of toxicity compared with epirubicin, including cystitis (54 versus 31 percent), hematuria (31 versus 16 percent) and land systemic toxicity (35 versus 1 percent) [114]. (See 'Toxicity' below.)
●Benefits of maintenance intravesical BCG – Several meta-analyses of randomized trials that included patients with intermediate-risk disease consistently report that intravesical BCG regimens that include at least one year of maintenance therapy decrease the risk of recurrence compared with either TURBT alone or intravesical chemotherapy [111,115,118-120].
The optimal dose and duration of maintenance intravesical BCG for intermediate-risk disease was also demonstrated in a randomized, noninferiority trial conducted by the EORTC. In this trial, 1335 patients with intermediate-risk (789 patients) and high-risk (560 patients) disease were randomly assigned to full- or reduced-dose (ie, one-third dose) BCG, followed by a second random assignment to maintenance therapy administered over one versus three years [83]. Among patients with intermediate-risk disease who were treated with full-dose intravesical BCG, three years of maintenance therapy conferred no additional benefit over one year of maintenance therapy for risk of recurrence (HR 0.88, 95% CI 0.64-1.12). Results of this trial for the entire study population are discussed separately. (See 'Efficacy' below.)
High-risk disease — For most patients with high-risk disease, we suggest treatment with intravesical BCG rather than intravesical chemotherapy. BCG is administered as an induction course, followed by a three-year course of maintenance therapy. (See 'Intravesical BCG (high-risk disease)' below.)
For those who are ineligible for, decline, or do not have access to intravesical BCG, appropriate alternatives include immediate cystectomy, intravesical chemotherapy, or trimodality therapy (TMT; ie, maximal TURBT followed by chemoradiation) for high-risk T1 tumors. (See "Bladder preservation treatment options for muscle-invasive urothelial bladder cancer".)
Intravesical BCG (high-risk disease)
Mechanism of action — Intravesical BCG, a live attenuated form of Mycobacterium bovis, is one of the most frequently used agents for intravesical therapy. Intravesical instillation of BCG triggers a variety of local immune responses that may persist for a number of months and that appear to correlate with antitumor activity [121-123]. These include:
●Induction of a mononuclear cell infiltrate that consists predominantly of cluster of differentiation 4 (CD4) T cells and macrophages.
●Increased expression of IFN gamma (IFNg) in the bladder. Expression of IFNg induces expression of class II major histocompatibility (MHC) molecules on bladder cancer cells, including human leukocyte antigen (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 TNF apoptosis-inducing ligand (TRAIL).
●Direct suppression of tumor growth in a dose-dependent fashion [124].
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 [125].
Dose and schedule — For high-risk disease, intravesical BCG is administered as follows:
●Induction therapy – BCG is instilled into the bladder weekly for six weeks, generally starting two to six weeks after TURBT.
A cystoscopy is repeated approximately six weeks after completing the induction intravesical BCG (approximately three months after the start of treatment). A urine cytology is also obtained at this time [126]. For patients with persistent CIS or recurrent high-grade Ta tumor following induction BCG, one round of maintenance therapy (or repeat induction therapy) should be administered prior to classifying the tumor as BCG-unresponsive [127]. (See "Treatment of recurrent or persistent non-muscle invasive urothelial carcinoma of the bladder", section on 'Intravesical regimens for BCG-unresponsive disease'.)
●Maintenance therapy – Upon completion of induction therapy, maintenance BCG is administered for up to three years (weekly for three weeks at months 3, 6, 12, 18, 24, 30, and 36). Dose reductions of BCG during maintenance therapy may be useful to manage toxicity and improve the rate of treatment completion.
Efficacy — In patients with high-risk disease, intravesical BCG therapy reduces the risk of disease recurrence and/or progression and improves disease-specific survival.
●Intravesical BCG versus observation only – In a systematic review of six randomized trials that included 585 patients with intermediate- or high-risk Ta or T1 NMIBC, TURBT plus intravesical BCG reduced the risk of recurrence at 12 months compared with TURBT alone (odds ratio 0.30, 95% CI 0.21-0.43) [128].
Intravesical BCG therapy also has excellent long-term disease-specific survival outcomes in high-risk disease [129-131]. As an example, in one randomized trial of 86 patients with high-risk NMIBC (Ta, Tis, or T1) with 10 year follow-up, the addition of intravesical BCG to TURBT improved both progression-free (62 versus 37 percent) and disease-specific survival (75 versus 55 percent) [129].
●Intravesical BCG versus immediate cystectomy – For patients with high-risk disease, TURBT plus intravesical BCG have a four to five-year OS rate of 70 to 86 percent, which is similar to that achieved after immediate cystectomy [132,133]. Although additional late relapses are observed, intravesical BCG offers the opportunity for bladder preservation [130,131]. As an example, in one prospective observational study of 98 patients with high-risk or recurrent NMIBC who received TURBT followed by intravesical therapy, 59 percent were progression-free and retained their native bladder after a minimum follow-up of 10 years [130].
●Intravesical BCG versus other intravesical agents – For patients with high-risk disease, intravesical BCG reduces the risk of recurrence when compared against other intravesical agents including gemcitabine [98], mitomycin [117,119,120,134], epirubicin [119,135], and thiotepa [136]. As examples:
•In a meta-analysis of nine randomized trials that included 700 patients with CIS, intravesical BCG was compared to intravesical chemotherapy using either mitomycin, epirubicin, doxorubicin, or sequential mitomycin and doxorubicin [119]. Intravesical BCG improved the complete response rate compared to chemotherapy (68 versus 51 percent). These responses were also durable; at a median follow-up of 3.6 years, more patients had no evidence of disease recurrence with intravesical BCG than chemotherapy (47 versus 26 percent).
•In a subsequent systematic review of 12 randomized trials that included 932 patients with intermediate- and high-risk NMIBC, intravesical BCG had less recurrences at five years relative to mitomycin, although the difference was not statistically significant (41 fewer recurrences for BCG than mitomycin, HR 0.88, 95% CI 0.71-1.09) [117]. There was no difference in progression-free or overall survival between the treatments. BCG caused more toxicity than mitomycin.
●Benefits of maintenance intravesical BCG for high-risk disease – Several meta-analyses of randomized trials that included patients with high-risk disease consistently report that intravesical BCG regimens that include at least one year of maintenance therapy decrease the risk of recurrence and progression compared with TURBT alone or intravesical chemotherapy [111,115,118-120].
The optimal dose and duration of maintenance intravesical BCG therapy for high-risk disease was also demonstrated in a randomized trial conducted by the EORTC [83]. In this trial, 1335 patients with intermediate-risk (789 patients) and high-risk (560 patients) disease were randomly assigned to full- or reduced-dose (ie, one-third dose) BCG, followed by a second random assignment to maintenance therapy administered over one versus three years. At a median follow-up of approximately seven years, results were as follows:
•For the entire study population, disease-free survival (DFS) was similar for full-dose BCG versus reduced-dose BCG (five-year DFS 62 versus 59 percent, HR 1.15, 95% CI 0.98-1.35) and for three years of maintenance therapy versus one year of maintenance therapy (five-year DFS 63 versus 57 percent, HR 1.17, 95% CI 0.99-1.38).
•However, full-dose BCG with maintenance therapy for three years improved DFS compared with reduced-dose BCG with one year of maintenance therapy (five-year DFS 64 versus 54 percent, HR 0.75, 95% CI 0.59-0.94).
•In addition, for patients with high-risk disease treated with full-dose BCG, three years of maintenance therapy reduced the risk of recurrence compared with one year of maintenance therapy (HR 1.61, 95% CI 1.13-2.30, in favor of three years of maintenance therapy).
•Outcomes for patients with intermediate-risk disease treated with full-dose BCG are discussed separately. (See 'Efficacy and toxicity' above.)
•There was no difference between all four treatment arms for either progression-free or overall survival.
•There were no differences in the toxicity profiles between full and reduced doses of BCG.
Toxicity
●Acute symptoms – Minor acute symptoms following administration of intravesical BCG are common (up to 85 percent of patients) [137]. These include fever, malaise, and bladder irritation (urination frequency, dysuria, or mild hematuria) within a few hours of BCG instillation [138]. Urinalysis and culture do not demonstrate evidence of infection. Such symptoms generally resolve within 48 hours and reflect a hypersensitivity reaction rather than an infectious complication of BCG. Management consists of analgesics and/or nonsteroidal anti-inflammatory drugs (NSAIDs) [139]. BCG may be resumed once symptoms resolve.
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) [128]. There were no BCG-associated deaths. Other studies have also confirmed that BCG-associated deaths from intravesical therapy are rare [139].
●Infection – 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 [140]. BCG is never given in the perioperative setting.
A prosthetic device (eg, pacemakers, artificial heart valves, orthopedic hardware) is not a contraindication to intravesical BCG. While there are case reports of prosthetic device infections after BCG therapy, this event is very uncommon [141-144]. As an example, in one observational study of 143 patents with NMIBC and a prosthetic device treated with intravesical BCG therapy, none developed infective endocarditis or hardware infection [145]. (See "Infectious complications of intravesical BCG immunotherapy".)
●Immunocompromised patients – 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".)
Management during BCG shortages — In the setting of a BCG shortage, the following strategies may be used to conserve BCG use:
●Limit intravesical BCG use to patients with high-risk disease only. (See 'Intravesical BCG (high-risk disease)' above.)
●Prioritize the full dose for induction over maintenance treatments. Full-dose BCG may also be particularly important in patients with NMIBC who live in regions where the tuberculosis vaccine or previous exposure to Mycobacterium tuberculosis is less prevalent.
●Reduced doses of intravesical BCG are preferable to reduced frequency of intravesical BCG administration [146]. Consider using a one-third BCG dose for maintenance doses (if three patients can be treated during the same day with one open vial) and limit the duration of maintenance to one year (when supply is not adequate).
●Offer radical cystectomy to patients with high- or very high-risk disease. (See 'Risk stratification' above and 'Very high-risk disease' below.)
●If BCG becomes completely unavailable, alternatives include induction and maintenance intravesical chemotherapy with mitomycin, gemcitabine, or epirubicin, or sequential administration of gemcitabine and docetaxel [147,148]. (See 'Intermediate-risk disease' above.)
Studies suggest that a lower dose of BCG is well-tolerated and may be as effective as full-dose BCG [83,149-151]. As an example, in a randomized clinical trial of 155 patients with NMIBC (T1 grade 3 or Tis (table 1)) comparing six weekly instillations of standard- versus reduced-dose BCG (81 and 27 mg, respectively) following complete TURBT, there were no differences in disease recurrence or disease-specific survival between the two BCG doses [149]. Similarly, in a clinical trial conducted by the EORTC, DFS was similar for full-dose BCG relative to lower-dose BCG [83]. (See 'Efficacy' above.)
Very high-risk disease — For most patients with very high-risk features for disease progression, we suggest immediate radical cystectomy rather than intravesical therapy due to the extremely high risk of disease progression.
The extent of concomitant CIS is relevant when selecting therapy. For example, high-grade T1 tumors and concomitant focal CIS, it is uncertain whether radical cystectomy is necessary for all patients. In such cases, clinicians should offer a risk-benefit discussion of radical cystectomy versus more conservative management, such as intravesical therapy. By contrast, high-grade T1 tumors with diffuse CIS is a higher risk situation where radical cystectomy is generally warranted. Furthermore, 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. (See "Radical cystectomy".)
Alternative approaches include the following:
●TMT (maximal TURBT followed by chemoradiation) may be an appropriate alternative to radical cystectomy in select patients with a good functioning bladder who have T1 disease, lymphovascular invasion (LVI), and no CIS [152,153].
●Patients with T1 disease and neuroendocrine or small cell carcinoma of the bladder typically receive neoadjuvant chemotherapy prior to cystectomy. (See "Small cell carcinoma of the bladder", section on 'Selection of neoadjuvant therapy'.)
In a retrospective study of 3041 patients with NMIBC treated with or without intravesical therapy, among those with very high-risk NMIBC, the 1, 5- and 10-year probability of progression are 20, 44, and 59 percent [38]. These data suggest that more aggressive therapy with radical cystectomy is necessary. Limited data from one randomized trial also suggest that approximately 10 percent of patients with high- and very high-risk NMIBC have potentially lethal disease that is better managed with radical cystectomy than intravesical BCG [154]. However, the same study also suggests that radical cystectomy overtreats most patients with high-risk disease.
INVESTIGATIONAL APPROACHES —
Other approaches for the initial management of non-muscle invasive bladder cancer (NMIBC) either remain investigational or are not used in routine clinical practice.
●Intravesical chemohyperthermia – Intravesical chemohyperthermia improves transport and penetration of mitomycin into the bladder wall. Although initial studies in primary NMIBC suggested some benefit [155-158], randomized trials have failed to demonstrate a benefit for this approach over normothermic intravesical chemotherapy [159,160].
●Electromotive drug administration (EMDA) – EMDA uses an electromotive gradient in conjunction with intravesical mitomycin to increase transport of drug across the bladder wall. In randomized trials of primary NMIBC, EMDA has demonstrated clinical efficacy either alone, sequentially after intravesical BCG, or prior to transurethral resection of bladder tumor (TURBT) [157,161-163].
●Mitomycin reverse thermal gel – In a phase III trial of 282 patients with new or recurrent low-grade intermediate-risk NMIBC, mitomycin reverse thermal gel demonstrated similar three-month tumor-free complete response compared with TURBT (65 versus 64 percent) [164].
POSTTREATMENT SURVEILLANCE —
All patients with non-muscle invasive bladder cancer (NMIBC) require careful surveillance to assess for disease recurrence. The intensity of such follow-up is adapted to the risk of disease recurrence. Second primary urothelial carcinoma can develop anywhere along the epithelium of the genitourinary tract, including the renal pelvis, ureters, and prostatic urethra, as well as the bladder. (See "Urethral cancer" and "Malignancies of the renal pelvis and ureter".)
Surveillance schedule — We offer the following surveillance schedule, which is generally consistent with clinical guidelines from various professional organizations [35,165]. Key components of surveillance include periodic cystoscopy, urine cytology, and imaging of the upper urinary tract.
All patients should undergo their first surveillance cystoscopy three months after transurethral resection of bladder tumor (TURBT), which is also noted in the surveillance schedules below. Following a negative initial postsurgical assessment, surveillance is tailored depending on risk.
●Low-risk tumors – Cystoscopy at 3 and 12 months, then annually [60]. Subsequent surveillance cystoscopies are ordered at the discretion of the urologist. For patients with low-risk tumors who do not develop recurrent disease, surveillance cystoscopy is often discontinued after five years. Urine cytology or imaging of the upper urinary tract is obtained at the time of diagnosis but is not required for surveillance.
●Intermediate-risk tumors – Urine cytology and cystoscopy at months 3, 6, and 12 for year one, every six months for year two, then annually. Clinical guidelines vary on the approach to imaging the upper urinary tract. Although some guidelines suggest imaging only as clinically indicated [35], others image the upper urinary tract every two years for at least five years. (See 'Upper urinary tract imaging studies' below.)
●High-risk tumors – Urine cytology and cystoscopy every three months for years one and two, followed by every six months for years three and four, and then annually starting at year five for at least 10 years, although most guidelines offer lifelong surveillance. Imaging of the upper urinary tract at one year and then every one to two years thereafter for at least 10 years. (See 'Upper urinary tract imaging studies' below.)
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 carcinoma of the bladder", section on 'Smoking cessation'.)
Urinary biomarkers are not routinely used as part of surveillance for recurrent NMIBC, as none have sufficient diagnostic reliability to eliminate the need for cystoscopy. Further details are discussed separately. (See "Urine biomarkers for the detection of urothelial (transitional cell) carcinoma of the bladder", section on 'Urine biomarkers'.)
Upper urinary tract imaging studies — In patients treated for primary NMIBC, the incidence of renal pelvis and ureteral tumors in the upper urinary tract ranges from 1 to 4 percent [166-170]. The median time to diagnosis of these upper urinary tract tumors varies from three to seven years [166,167,170].
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 Bacille Calmette-Guérin (BCG) treatment, and occupational exposure [167,168,170-172]. (See "Malignancies of the renal pelvis and ureter", section on 'Diagnosis'.)
Options to image the upper urinary tract include computed tomography (CT) urography, retrograde pyelography, or magnetic resonance imaging (MRI) urogram. The use of these studies is based on the risk for development of an upper tract tumor.
●There are no data to support routine upper tract imaging for patients with low-risk tumors [36].
●For patients with no obvious intravesical tumor and positive urinary cytology, we offer random bladder (or targeted bladder biopsies using blue-light cystoscopy) and prostatic urethral biopsies [173], as well as careful periodic evaluation of the upper tracts [174]. CT urography is the preferred imaging modality in this situation, which can be combined with ureteroscopy for any suspicious lesions as well as urinary tract cytology from each separate side to assess if the upper urinary tract is the source of the positive tumor cells in the urinary cytology.
●For patients with high-risk disease and high-grade intermediate-risk disease who have completed transurethral resection of all visible bladder tumor (TURBT) and have a negative urine cytology, we image the upper urinary tract every one to two years to exclude involvement with metachronous lesions [35,175,176]. This should be continued at least 10 years for patients with high-risk disease. We do not routinely obtain imaging surveillance for intermediate risk tumors that are low-grade.
Monitoring of the prostatic urethra — Second primary tumors in the prostatic urethra and ducts have been observed after an initial diagnosis of NMIBC [177]. While most relapses in the urethra occur in the first five years after treatment completion, approximately one-third of all relapses occur later (between 5 and 15 years after treatment completion).
Asymptomatic urethral recurrences are usually diagnosed during surveillance cystoscopy as a visual abnormality or due to a planned urethral biopsy. The most common symptom of a locally advanced urethral tumor is urinary tract obstruction. Patients suspected of urethral cancer require cystourethroscopy and further pelvic imaging as necessary, as urethral involvement is a significant predictive factor for muscle invasive cancer [178]. Further details on urethral cancer are discussed separately. (See "Urethral cancer".)
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
●Diagnostic evaluation – For patients with suspected non-muscle invasive bladder cancer (NMIBC; Tis, Ta, and T1 disease (figure 1 and table 1)), the diagnostic evaluation includes an examination under anesthesia, a complete transurethral resection of bladder tumor (TURBT), and staging imaging studies. (See 'Diagnosis' above.)
●Indications for restaging TURBT – For patients with a confirmed diagnosis of NMIBC after initial TURBT, a restaging TURBT should be performed four to six weeks after the initial resection for the following indications (see 'Indications for restaging TURBT' above):
•Incomplete resection with the initial TURBT
•T1 tumor
•Select cases of high-grade Ta disease (eg, large and/or multiple tumors)
●Risk stratification – Patients with a histologically confirmed diagnosis of NMIBC who complete TURBT are stratified for risk of recurrence and progression (low, intermediate, high, and very-high) based on clinical and tumor-specific factors. (See 'Management' above.)
●Treatment – The approach to additional intravesical adjuvant therapy is based on risk stratification for disease recurrence. (See 'Risk stratification' above.)
•Low-risk disease – For patients with suspected low-risk disease or a European Organisation for Research and Treatment of Cancer (EORTC) recurrence score of <5, we suggest a postoperative single intravesical instillation of chemotherapy rather than no treatment or other regimens (Grade 2B), followed by surveillance. Among the available regimens, we suggest gemcitabine (Grade 2C), with mitomycin, epirubicin, and pirarubicin as acceptable alternatives. (See 'Low-risk disease' above and 'Prediction models' above.)
•Intermediate-risk disease – For patients with intermediate-risk disease, we suggest intravesical chemotherapy with gemcitabine, followed by one year of maintenance therapy to reduce the risk of disease recurrence, rather than other agents or treatment approaches (Grade 2C). (See 'Intermediate-risk disease' above.)
-Other options for intravesical chemotherapy include epirubicin and mitomycin. However, intravesical mitomycin is less preferred since it is significantly more toxic than gemcitabine. (See 'Intravesical epirubicin' above and 'Intravesical mitomycin' above.)
-Although intravesical Bacille Calmette-Guérin (BCG) is an effective alternative, it is also less preferred since disease progression is infrequent in intermediate-risk disease, it is more toxic, and availability is limited due to an ongoing BCG shortage. (See 'Intravesical BCG (intermediate-risk disease)' above.)
•High-risk disease – For most patients with high-risk disease, we suggest treatment with intravesical BCG rather than intravesical chemotherapy (Grade 2C). BCG is administered as an induction course, followed by a three-year course of maintenance therapy. (See 'High-risk disease' above.)
•Very high-risk disease – For most patients with very high-risk disease, we suggest immediate radical cystectomy rather than intravesical therapy (Grade 2C). Intravesical therapy is an alternative for those with high-grade T1 tumors and concomitant focal carcinoma in situ (CIS), and trimodality therapy (TMT; maximal TURBT followed by chemoradiation) is an alternative for those with a well-functioning bladder who have T1 disease, lymphovascular invasion (LVI), and no CIS. (See 'Very high-risk disease' above.)
●Posttreatment surveillance – All patients with NMIBC require careful surveillance. The intensity of such follow-up is adapted to the risk of disease recurrence. Key components of 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 NMIBC is discussed separately. (See "Treatment of recurrent or persistent non-muscle invasive urothelial carcinoma of the bladder".)
ACKNOWLEDGMENT —
The UpToDate editorial staff acknowledges Michael O'Donnell, MD, who contributed to earlier versions of this topic review.
