Non–muscle-invasive bladder cancer is a highly recurrent disease. The health care costs for non–muscle-invasive bladder cancer are a major burden for society. Bladder cancer treatment starts with a presumed complete transurethral resection of a bladder tumor. Despite international guidelines for perioperative and/or adjuvant intravesical instillation therapy in non–muscle-invasive bladder cancer, adequate worldwide application is lacking. In patients who do get adjuvant intravesical instillations, recurrences are still frequent. New therapies in non–muscle-invasive bladder cancer are unsatisfactory and still experimental.
Key points
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Bladder cancer is a frequent and expensive malignancy with high rates of recurrence.
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Good initial transurethral resection of the bladder tumor is crucial for adequate staging and prognosis.
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In low-risk and intermediate-risk non–muscle-invasive bladder cancer, 1 immediate instillation of chemotherapy is recommended.
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Adherence to international guidelines remains insufficient, resulting in high recurrence rates. New safe and effective therapies are needed.
Introduction
Bladder cancer (BC) is a frequent and costly disease: it is reported to be the most expensive cancer per patient, and it is the 11th most commonly diagnosed cancer and the 14th leading cause of cancer deaths worldwide. In the United States in 2012, there were an estimated 73,510 cases of BC, with 55,600 and 17,910 cases in men and women, respectively. Risk factors for BC include tobacco use (50%), exposure to aromatic amines and polycyclic aromatic hydrocarbons other than in tobacco (10%), and genetic predisposition and aging. The most common histologic subtype of BC is urothelial carcinoma, accounting for more than 90% of all bladder tumors. Approximately 75% of patients with BC present with non–muscle-invasive BC (NMIBC), ie, Ta (70%), T1 (20%), and carcinoma in situ (CIS; 10%). The remainder of patients present with tumors invading the detrusor muscle (stage T2), the perivesical tissue (T3), the organs surrounding the bladder (T4), or metastatic disease.
Introduction
Bladder cancer (BC) is a frequent and costly disease: it is reported to be the most expensive cancer per patient, and it is the 11th most commonly diagnosed cancer and the 14th leading cause of cancer deaths worldwide. In the United States in 2012, there were an estimated 73,510 cases of BC, with 55,600 and 17,910 cases in men and women, respectively. Risk factors for BC include tobacco use (50%), exposure to aromatic amines and polycyclic aromatic hydrocarbons other than in tobacco (10%), and genetic predisposition and aging. The most common histologic subtype of BC is urothelial carcinoma, accounting for more than 90% of all bladder tumors. Approximately 75% of patients with BC present with non–muscle-invasive BC (NMIBC), ie, Ta (70%), T1 (20%), and carcinoma in situ (CIS; 10%). The remainder of patients present with tumors invading the detrusor muscle (stage T2), the perivesical tissue (T3), the organs surrounding the bladder (T4), or metastatic disease.
Non–muscle-invasive bladder cancer
Stage Ta tumors have a papillary configuration, are confined to the urothelium, and do not penetrate into the lamina propria or detrusor muscle. Stage T1 tumors originate from the urothelium but penetrate the basement membrane separating the urothelium from the deeper layers. They invade into the lamina propria, but do not reach the detrusor muscle.
At present, 2 classifications are used for grading of papillary NMIBC (World Health Organization [WHO] 1973 and 2004; Box 1 ). 1973 WHO grade 1 carcinomas have been reassigned to papillary urothelial neoplasms of low malignant potential and low-grade carcinomas in the 2004 WHO classification. It is a subject of controversy that grade 2 carcinomas have been eliminated in the 2004 WHO classification and reassigned to either low-grade or high-grade carcinomas. The 2004 WHO classification contains a detailed histologic description of the various grades in order to minimize diagnostic variability among pathologists. However, so far, published comparisons do not clearly confirm better reproducibility for the WHO 2004 classification compared with the 1973 WHO classification.
1973 WHO grading
Urothelial papilloma
Grade 1: well differentiated
Grade 2: moderately differentiated
Grade 3: poorly differentiated
2004 WHO grading
Urothelial papilloma
Papillary urothelial neoplasm of low malignant potential
Low-grade papillary urothelial carcinoma
High-grade papillary urothelial carcinoma
Several studies have compared the two classifications concerning prognostic implications with conflicting results. Until the prognostic role of this classification has been validated by more prospective trials with sufficient follow-up, both classifications should be used, because it is indicated by the 2014 European Association of Urology (EAU) guideline on NMIBC as a grade A recommendation. Moreover, most clinical trials published so far have been performed using the 1973 WHO classification, meaning that recommendations from current guidelines are still based on this version.
CIS is a high-grade carcinoma confined to the urothelium, but with a flat nonpapillary configuration. Unlike a papillary tumor, CIS appears as reddened and velvety mucosa and is slightly elevated, although sometimes it is not visible. The diagnosis of CIS is based on the histology of biopsies from the bladder wall.
The standard initial therapy for Ta and T1 papillary bladder tumors is a visually complete transurethral resection (TURBT) including a part of the underlying muscle. This resection allows for the initial staging that is critical for further management decisions, and the TURBT is a first and important step in the treatment of the disease. A reresection is advised if there is any doubt about the completeness of the initial TURBT, or if there was no muscle in the specimen (with the exception of Ta grade 1 tumors and primary CIS). A restaging second TURBT within 2 to 6 weeks after the initial TURBT is necessary in all T1 and/or grade 3 tumors, except for tumors in patients with CIS alone.
Another means to improve the completeness of the initial TURBT is the use of fluorescence techniques (photodynamic diagnosis [PDD]) or narrow band imaging. Of these two techniques PDD is the best studied. The most recent review by Burger and colleagues clearly confirmed that PDD-guided cystoscopy significantly improves the detection of bladder tumors, leading to a significant and clinically meaningful reduction of recurrence at 9 to 12 months, but it has no impact on progression. The benefit is independent of the patient’s risk category, and is evident in patients with Ta, T1, CIS, primary, and recurrent cancer.
Because there is considerable risk for recurrence and/or progression of tumors after TURBT, perioperative and/or adjuvant intravesical instillation therapy is recommended. Risk stratification depends on clinical (number of tumors, tumor size, prior recurrence rate), and pathologic (T category, CIS, grade) factors. The European Organization for Research and Treatment of Cancer Genitourinary group has developed a scoring system and risk tables that predict separately the risks of recurrence and progression in individual patients at different intervals after TURBT. This scoring system and the corresponding risk tables have been used for several years to categorize patients and were the basis for risk-adapted treatment recommendations. However, in 2013 this scoring system was left and the risk group classification was simplified. The current EAU guideline recommends stratification of patients into 3 risk groups and provides practical treatment recommendations ( Table 1 ). The stratification is based on an overview of the International Bladder Cancer Group, which reviewed several international guidelines to give best practice recommendations for the management of patients with NMIBC. This recommendation resulted in a more uniform work-up to NMIBC management, and the EAU risk group classification is now similar to the American Urological Association (AUA) risk group stratification.
| Risk Category | Definition | Treatment Recommendation |
|---|---|---|
| Low | Primary, solitary, Ta, G1 (low grade), <3 cm, no CIS | One immediate instillation of chemotherapy |
| Intermediate | All cases not defined in the 2 adjacent categories | One immediate instillation of chemotherapy followed by further instillations, either chemotherapy for a maximum of 1 y or 1 y full-dose BCG |
| High |
| Full-dose BCG instillations for 1–3 y or cystectomy (in highest risk tumors) |
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