Author(s): Marc A Dall'Era [*] 1 , Liang Cheng 2 , Chong-Xian Pan 3 4
bladder urothelial carcinoma; chemotherapy; cisplatin; personalized chemotherapy; targeted therapy
Carcinoma of the bladder of all histologic subtypes remains a major global health issue. The 2004 WHO World Cancer Report estimates that bladder cancer is the ninth most commonly diagnosed malignancy worldwide, accounting for 330,000 new cases annually [1,2] . Bladder cancer incidence varies dramatically from country to country, with the highest rates in North America and Europe where urothelial carcinoma (UC) represents the most common histologic form encountered, and cigarette smoking continues to be the strongest risk factor of development of the disease  . It is estimated that, in the USA, there will be 73,510 new cases of bladder cancer in 2012  , with 14,880 deaths attributable to this disease. Bladder cancer mortality is less varied geographically, yet is highest in developed countries. Despite advances in diagnosis, treatment and molecular characterization of bladder tumors, the outcomes from bladder cancer treatment have not significantly improved over the last two decades.
Bladder cancer can be clinically dichotomized by stage as either muscle invasive or non-muscle-invasive based on involvement of the detrusor muscle. Approximately 20% of tumors are muscle invasive at presentation, requiring aggressive and often systemic therapies. Clinical experience also clearly describes two general phenotypic variants of UC of the urinary bladder largely based on tumor grade, which is a well-established predictor of disease progression and bladder cancer-specific mortality  . High-grade bladder tumors harbor significant risks for recurrence, local invasion and metastasis, and are primarily responsible for the high degree of mortality associated with UC. This review will focus on the contemporary management of high-grade muscle-invasive UC of the bladder.
To review the current literature on treatment options and outcomes for muscle-invasive localized UC.
We searched MEDLINE, EMBASE, the Cochrane Central Registry of Controlled Trials, the Cochrane Methodology Registry, and the Cochrane Database of Systematic Reviews. All searches were performed with the assistance of a certified medical librarian. The search terms included bladder cancer, urinary bladder neoplasms, urothelial carcinoma, transitional cell carcinoma, muscle invasive, not nonmuscle invasive, advanced, and myoinvasive. No language restrictions were imposed. The reference lists from retrieved articles were examined to identify additional relevant studies. The abstracts from all retrieved citations were reviewed to determine their eligibility for inclusion in this paper and full-length articles were then reviewed for final selection. For the results section of this paper, preference was given to studies describing results from randomized data and meta-analyses. Clinical trials and population-based observational studies comparing treatment strategies for primarily high-grade muscle-invasive bladder cancer were sought. Studies focusing on superficial UC, regardless of grade, including primarily carcinoma in situ were excluded. To meet inclusion criteria, studies had to provide a comprehensive description of the demographic and disease characteristics of the patients at the time of diagnosis, including data on clinical or pathologic stage and tumor grade.
Radical cystectomy has long been considered the 'standard of care' for muscle-invasive UC. Radical cystectomy typically...