BERKELEY, CA (UroToday.com) - Bladder carcinoma is the fourth most common cancer in men and the ninth most common cancer in women in the United States.
In 2010, approximately 70 000 new cases of bladder carcinoma (52 000 in men and 18 000 in women) and approximately 14 000 deaths were expected in the United States. More than 90% of bladder carcinomas are classified as urothelial carcinoma (UC) or transitional cell carcinoma (TCC), which arise from the urothelium. The primary risk factor for UC of the bladder (UCB) is cigarette smoking, which accounts for more than half of the cases.
UCB encompasses a heterogeneous group of diseases consisting primarily of a low-grade, noninvasive variant and a high-grade, invasive variant, which have different biological behaviors and appear to arise from different mechanisms. On one hand, low-grade noninvasive tumors frequently harbor gain-of-function mutations in oncogenes like the RAS, fibroblast growth factor receptor 3 (FGFR3), and PI3K genes. A small percentage of these tumors subsequently acquire additional chromosomal alterations (e.g. p53 mutations), which are associated with tumor progression. On the other hand, invasive tumors arise de novo or from carcinoma in situ (CIS) and the majority contain loss-of-function mutations in the tumor-suppressor genes p53, retinoblastoma protein (RB), or PTEN. Although not yet validated, we believe that in the near future, mutational analysis of UCB will aid physicians in staging, predicting metastasis, response, and recurrence, as well as identifying possible therapeutic agents.
When UCB is suspected (painless hematuria, unexplained recurrent irritable bladder symptoms), the standard diagnostic work up includes a cystoscopy and urine cytology. The limitations of cytology (poor sensitivity, especially for low-grade tumors) and the invasiveness of cystoscopy for detecting bladder carcinoma have generated interest in other noninvasive diagnostic tools for the detection of bladder carcinoma. Several of these tests, such as FISH, NMP22, and BTA-Stat, have been approved either for diagnosis or surveillance in patients with a history of bladder carcinoma, and multiple other tests are in development. Overall most of these tests have higher sensitivities than cytology but lower specificities. None of these tests demonstrate sufficient reliability to eliminate the need for cystoscopy or cytology and are used in conjunction. The staging system TNM (tumor, node, metastasis) is employed to separate patients into distinct prognostic groups: non-muscle invasive tumors (Ta, CIS, and T1 tumors), muscle-invasive tumors (T2, T3, T4), and metastatic disease (M1).
In non-muscle invasive tumors, treatment by cystoscopic resection and intravesical therapy is directed at reducing recurrences (which occur in 50-90% of cases) and preventing progression to a more advanced stage (10-30%) in high-risk cases. Bacillus Calmette-Guérin (BCG), a live attenuated form of Mycobacterium Bovis, is the most widely used intravesical agent, and appears to exert anti-tumor activity by enhancing the local immune response and certain cytokines. Novel intravesical and systemically administered agents are being evaluated for progressive disease following BCG therapy.
The recommended treatment for muscle-invasive tumors is a combination of radical cystectomy/lymph node dissection with perioperative chemotherapy to improve outcomes by reducing the risk of distant recurrences. Large randomized trials and a meta-analysis have proven a survival benefit for neoadjuvant cisplatin-based combination chemotherapy in muscle-invasive UCB. The most commonly used regimens are MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) and GC (gemcitabine and cisplatin). Although data with GC are extrapolated from studies with patients with advanced and metastatic cancer, it is the preferred regimen by many physicians due to its better side effect profile. There is no convincing data yet to support the use of adjuvant chemotherapy in muscle-invasive disease, given the incompletely accrued and under-powered trials performed so far. Bladder-sparing surgery combined with chemotherapy and radiotherapy can be offered to patients who refuse or are medically unfit for radical cystectomy. However, this modality has not been compared with radical cystectomy in a prospective trial and is not preferred for optimal patients who qualify for radical cystectomy. Outcomes in metastatic UC are dismal with current cisplatin- based combination chemotherapy (median survival ~15 months), although outcomes can vary considerably based on the presence of major prognostic factors (visceral disease, performance status). Progressive disease after frontline chemotherapy for metastatic UC is characterized by a short survival (median survival ~6-9 months) and there are no approved second-line agents in the United States. Therefore advanced UC patients should ideally be enrolled on trials evaluating novel agents.
There is extensive ongoing research for UC over the past decade. Novel agents are being evaluated for all stages of UC since currently available agents have only modest efficacy. A better understanding of oncogenic pathways that appear to be up-regulated in UCB may help develop molecular targets. A role for molecular markers predictive for benefit from chemotherapy is emerging, which may help develop tailored therapy and appropriate selection of patients. When appropriate, patients should be encouraged to participate in clinical trials to help improve the outcomes of this disease. Counseling patients on smoking cessation is very important as the risk of UCB decreases 40% after 4 years of stopping smoking.
Maria F. Tanaka, MD and Guru Sonpavde, MD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.