Non-muscle invasive bladder cancer (NMIBC) represents approximately 70% of all incident cases of bladder cancer. The financial burden of NMIBC continues to increase, underscoring the importance of efficient, evidence-based management of this disease. Consensus guidelines differ on risk definition and in management recommendations. This article reviews the incidence and financial impact of NMIBC and details the recommendations for diagnosis, treatment, and surveillance made by the American Urological Association, International Consultation on Bladder Cancer-European Association of Urology, and National Comprehensive Cancer Network. Established and developing adjunctive laboratory and imaging tests directed at diagnosis and management of NMIBC are also discussed.
Key points
- •
The financial burden of non-muscle invasive bladder cancer (NMIBC) continues to increase, underscoring the importance of efficient, evidence-based management of this disease. Management varies by risk (low, intermediate, or high).
- •
One of the treatment challenges rests in the heterogeneity within the umbrella diagnosis of NMIBC: mortality rates from low-risk disease are nonexistent, whereas those from high-risk disease approach 30% at 10 years. As such, there is concern for overtreatment of low-risk disease and undertreatment of high-risk disease.
- •
Following transurethral resection of bladder tumor (TURBT), consideration may be given to a single perioperative dose of intravesical chemotherapy. A European Organization for Research and Treatment of Cancer meta-analysis concluded that this practice was associated with a 12% reduction in tumor recurrence and a 39% reduction in the odds of recurrence. This finding was reportedly independent of the agent selected. An American Urological Association meta-analysis concluded there was a 17% absolute reduction in recurrence relative to TURBT alone across all risk groups. Evidence suggests, however, that the benefit of single-dose perioperative intravesical chemotherapy is limited for multiple or recurrent tumors or in cases of high-grade disease when bacillus Calmette-Guérin (BCG) therapy is planned.
- •
For those pursuing a bladder-sparing approach in pathologic Ta high-grade, Tis, and/or T1 disease, an induction course of intravesical BCG followed by maintenance BCG is a recommendation, with a meta-analysis suggesting a 5-year recurrence rate of 34% for those receiving TURBT and BCG maintenance.
- •
One of the foremost challenges to the urologist treating NMIBC is deciding when to abandon bladder-sparing therapies in favor of cystectomy. The morbidity of cystectomy is considerable, with short-term complication rates greater than 60%. However, it is also known that 40% to 50% of patients with Tis will fail BCG and nearly 25% will be pT2 or greater and 5.8% pN+ at cystectomy.
Introduction
In 2012, there were an estimated 73 510 new cases of bladder cancer diagnosed in the United States. Approximately 90% of bladder cancers are urothelial cell carcinoma (UC), with subtypes of squamous cell carcinoma and adenocarcinoma or other variants composing 5% and 2% or less of cases, respectively. Seventy percent of newly diagnosed bladder cancer is non-muscle invasive bladder cancer (NMIBC). Although historically known as superficial bladder cancer , this term has been replaced by the stratification of NMIBC into 3 risk categories: low, intermediate, and high. Although all major guidelines agree that risk stratification of NMIBC is appropriate, there is not consensus on the definitions of each risk category ( Table 1 ).
| Low Risk | Intermediate Risk | High Risk | |
|---|---|---|---|
| AUA 2007 | Small-volume Ta, low grade | Multifocal and/or large-volume Ta low grade | Ta high grade, T1, Tis |
| ICUD-EAU 2012 | Ta low grade | — | Ta high grade, T1, Tis |
| NCCN | Ta low grade | Ta high grade | T1 high grade, Tis |
One of the treatment challenges rests in the heterogeneity within the umbrella diagnosis of NMIBC: mortality rates from low-risk disease are nonexistent, whereas those from high-risk disease approach 30% at 10 years. As such, there is concern for overtreatment of low-risk disease and under treatment of high-risk disease. Improper management of NMIBC can be costly for patients and the health care system. Bladder cancer is estimated to be the ninth most expensive cancer in the United States, with total costs of approximately $3.98 billion in 2010, a number expected to increase to $4.9 billion by 2020. It is estimated that $39 293 of the $65 158 average lifetime cost of treatment is associated with surveillance and management of recurrence, underscoring the importance of efficiency and quality in delivery of care for NMIBC.
Evidence-based guidelines from the American Urological Association (AUA), the European Association of Urology (EAU), and the National Comprehensive Cancer Network (NCCN) have been established to simplify the diagnosis and treatment of this heterogeneous disease. This article reviews the consensus diagnostic and treatment algorithms for NMIBC, divided into 3 risk categories, and highlights the similarities and differences in recommendations across the AUA, EAU, and NCCN guidelines. The treatments discussed include (1) transurethral resection of bladder tumor (TURBT); (2) perioperative, postoperative, and maintenance intravesical therapy; and (3) cystectomy. When appropriate, rates of recurrence, progression, and mortality are addressed.
Introduction
In 2012, there were an estimated 73 510 new cases of bladder cancer diagnosed in the United States. Approximately 90% of bladder cancers are urothelial cell carcinoma (UC), with subtypes of squamous cell carcinoma and adenocarcinoma or other variants composing 5% and 2% or less of cases, respectively. Seventy percent of newly diagnosed bladder cancer is non-muscle invasive bladder cancer (NMIBC). Although historically known as superficial bladder cancer , this term has been replaced by the stratification of NMIBC into 3 risk categories: low, intermediate, and high. Although all major guidelines agree that risk stratification of NMIBC is appropriate, there is not consensus on the definitions of each risk category ( Table 1 ).
| Low Risk | Intermediate Risk | High Risk | |
|---|---|---|---|
| AUA 2007 | Small-volume Ta, low grade | Multifocal and/or large-volume Ta low grade | Ta high grade, T1, Tis |
| ICUD-EAU 2012 | Ta low grade | — | Ta high grade, T1, Tis |
| NCCN | Ta low grade | Ta high grade | T1 high grade, Tis |
One of the treatment challenges rests in the heterogeneity within the umbrella diagnosis of NMIBC: mortality rates from low-risk disease are nonexistent, whereas those from high-risk disease approach 30% at 10 years. As such, there is concern for overtreatment of low-risk disease and under treatment of high-risk disease. Improper management of NMIBC can be costly for patients and the health care system. Bladder cancer is estimated to be the ninth most expensive cancer in the United States, with total costs of approximately $3.98 billion in 2010, a number expected to increase to $4.9 billion by 2020. It is estimated that $39 293 of the $65 158 average lifetime cost of treatment is associated with surveillance and management of recurrence, underscoring the importance of efficiency and quality in delivery of care for NMIBC.
Evidence-based guidelines from the American Urological Association (AUA), the European Association of Urology (EAU), and the National Comprehensive Cancer Network (NCCN) have been established to simplify the diagnosis and treatment of this heterogeneous disease. This article reviews the consensus diagnostic and treatment algorithms for NMIBC, divided into 3 risk categories, and highlights the similarities and differences in recommendations across the AUA, EAU, and NCCN guidelines. The treatments discussed include (1) transurethral resection of bladder tumor (TURBT); (2) perioperative, postoperative, and maintenance intravesical therapy; and (3) cystectomy. When appropriate, rates of recurrence, progression, and mortality are addressed.
Diagnosis, detection, and surveillance tools
This section describes the presentation of bladder cancer as well as the tools available to the urologist in its diagnosis and surveillance. Its purpose is to outline both routine and investigational tools intended to improve the management of NMIBC. Any specific recommendations regarding the use of these agents are described in subsequent sections.
The diagnosis of bladder cancer is usually preceded by hematuria. Patients with macroscopic hematuria have reported rates of bladder cancer between 13.0% and 34.5%, with microscopic hematuria associated with bladder cancer at a rate of 0.5% to 10.5%. New-onset irritative voiding symptoms may also indicate underlying malignancy, with or without hematuria.
Although cystoscopy is the mainstay of bladder cancer diagnosis and surveillance, cytology and urinary markers are often used in an adjunctive role. Urinary cytology, which involves microscopic examination of voided or barbotaged urine, has a sensitivity of between 4% and 31% for the diagnosis of low-grade disease, with an overall sensitivity and specificity of 34% and 99%. Its sensitivity improves for high-grade disease, particularly carcinoma in situ (CIS); however, cytology may miss up to 60% of high-grade tumors.
Tumor marker assays have been developed in an effort to improve on cytology for the detection of bladder cancer with variable success. Commercially available tumor marker assays include bladder tumor antigen (BTA), ImmunoCyt, nuclear matrix protein 22 (NMP22), and UroVysion. BTA assays detect human complement factor H–related protein. Results can be impacted by hematuria from other causes. The overall sensitivity and specificity of the BTA stat test have been estimated at 57% to 83% and 60% to 92%, respectively. ImmunoCyt combines cytology and immunofluorescence from monoclonal antibodies against carcinoembryonic antigen and 2 bladder cancer–associated mucins. It has a reported sensitivity of 50% to 100% and a specificity of 69% to 79%. False positives are associated with benign prostatic hyperplasia and cystitis, and it is generally only recommended for monitoring rather than diagnosis. NMP22 detects nuclear matrix protein and is approved for use in bladder cancer surveillance as well as detection of cancer in at-risk patients. Sensitivity and specificity have been reported at 47% to 100% and 60% to 90%, respectively. Specificity is markedly decreased with coexistent inflammation or instrumentation, leading to a relatively high false-positive rate that has limited its utility in clinical practice.
UroVysion is a fluorescent in situ hybridization (FISH) assay that detects loss of 9p21 and aneuploidy of chromosomes 3, 7, and 17 and is approved for use in bladder cancer surveillance and detection. Sensitivity of FISH is reported at 74% overall and 100% for high-grade disease, outperforming cytology in a meta-analysis with an area under the receiver operating characteristic curve of 0.87 versus 0.63. FISH has been associated with the additional benefit of anticipatory positives; multiple studies report the development of cancer within 12 months in a high percentage of cases that seemed to be false positives based on initial cystoscopy. The weakness of FISH relative to cytology is its high rate of false positives, which can be improved by combining with cellular morphology. Nonetheless, the specificity when combined with morphology is only 65%. Similar to FISH, several markers designed to detect specific gene mutations common that are common in bladder cancer have shown promise but at this time are still investigational.
Photodynamic agents including 5-aminolevulinic (5-ALA) acid or hexaminolevulinate (HAL) are approved in 26 European countries for the detection of bladder cancer. Neoplastic cells preferentially uptake these agents and fluoresce in the red part of the spectrum under blue-violet light excitation. A meta-analysis by Kausch and colleagues concluded that combined with white-light cystoscopy, the use 5-ALA or HAL resulted in the detection of 20% more tumor-positive patients with NMIBC and 39% more with CIS. The odds of residual tumor being found were significantly less with photodynamic agents than with white-light cystoscopy alone (odds ratio 0.28; 95% confidence interval 0.15–0.52), and recurrence-free survival was significantly higher at 12 and 24 months. Photodynamic agents are not yet part of routine practice in the United States; however, several ongoing clinical trials will help define its role in bladder cancer diagnosis and surveillance in future practice ( www.clinicaltrials.gov ).
Upper tract imaging is indicated in the context of gross or microscopic hematuria not explained by obvious underlying causes, such as active infection, menstruation, or recent instrumentation. Historically, intravenous urography (IVU) was the imaging study of choice for its availability and cost. It is estimated to detect up to 60% of known bladder tumors and approximately two-thirds of upper tract lesions. IVU has, however, been almost entirely replaced by other imaging modalities for the evaluation of the upper tracts. Ultrasound avoids ionizing radiation, although its sensitivity is poor for the detection of renal pelvis tumors, and it does not evaluate the ureters. Its sensitivity for the detection of bladder tumors is highly variable, having been reported at 26.0% to 91.4%. Three-dimensional virtual and contrast-enhanced sonography may provide additional benefit for tumor detection within the bladder; however, the clinical utility of these modalities is unclear.
Computed tomography (CT) and CT urography (CTU) have become the American College of Radiology’s test of choice for the evaluation of the upper tracts in hematuria. In a study by Turney and colleagues, in 200 patients with hematuria with a cancer prevalence of 24% on cystoscopy, CTU had a sensitivity, specificity, and negative predictive value of 93%, 99%, and 98%, respectively. The sensitivity for the detection of bladder tumors seems to be best in patients with gross hematuria. CTU can fail to pick up smaller tumors (<5–10 mm) and has limited ability to distinguish cancer from mucosal changes related to recent cystoscopic procedures. Renal impairment can prevent the use of contrast in CTU, which limits its utility in this setting.
Gadolinium-enhanced magnetic resonance imaging (MRI) urography may be even better than CTU for tumor detection, with one head-to-head study reporting sensitivity of 93% versus 100% for CTU versus MRI urography and another suggesting superior ability to detect small (<10 mm) tumors. Diffusion-weighted MRI seems to have further advantages over standard MRI in the detection of lesions and in distinguishing benign from malignant disease. Although MRI does have the advantage of avoiding ionizing radiation, contrast administration is, as in CT, limited in those with poor renal function (estimated glomerular filtration rate <30 mL/min). Its relatively higher cost and lack of availability have also limited its use in clinical practice relative to CTU; however, given its advantages relative to CT in local staging, the use of MRI is increasing in some centers. Virtual cystoscopy with either CT or MRI, although an interesting concept, is associated with a higher cost and increased radiation exposure relative to conventional CT and has no role in routine workup of hematuria.
Low-risk disease
Low-risk disease is defined by the AUA’s guidelines as small, solitary, low-grade, primary disease. Differing slightly from the AUA, as evident from Table 2 , the International Consultation on Bladder Cancer–European Association of Urology’s (ICUD-EAU) guidelines and the NCCN’s Clinical Practice Guidelines in Oncology (NCCN’s guidelines) define low-risk disease as Ta low grade.
| Low-Risk | Intermediate-Risk | High-Risk | |
|---|---|---|---|
| AUA 2007 |
|
|
|
| ICUD-EAU 2012 |
| — |
|
| NCCN |
|
| Tis
|
Related posts:
Perioperative Chemotherapy
Office-based Bladder Tumor Fulguration and Surveillance
New Agents for Bacillus Calmette-Guérin–Refractory Bladder Cancer
The Conundrum of Prostatic Urethral Involvement
The Costs of Non-Muscle Invasive Bladder Cancer
New Imaging Techniques for Non-Muscle Invasive Bladder Cancer
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
