A meta-analysis of randomized trials comparing cisplatin-versus carboplatin-based therapy in UC revealed that cisplatin-based chemotherapy was associated with a significant improvement in the likelihood of achieving an objective response [RR = 1.33 (95 % CI: 1.04, 1.71), p = 0.025] or a complete response [RR = 3.54 (95 % CI: 1.48, 8.49), p = 0.004] [26]. However, UC is largely a disease of the elderly [27] and due to age-associated (and disease-associated) impairment in renal function and performance status, approximately 30–50 % of patients are ineligible for cisplatin-based chemotherapy [28]. As a result, a disconnect has emerged between the “efficacy” of treatment as demonstrated by randomized trials, and the “effectiveness” of treatment when applied to the general population of patients with UC. Investigators, long appreciating this disconnect, have designed trials specifically for patients “unfit” for cisplatin-based chemotherapy [29–34].

There have been two randomized phase III trials initiated in the cisplatin-ineligible population. EORTC 30986 was a randomized phase II/III trial of GC versus methotrexate, vinblastine, plus carboplatin (M-CAVI) in “unfit” patients (WHO performance status of 2 and/or creatinine clearance 30–60 ml/min) with metastatic UC [32]. Both treatment arms enrolled 119 patients and the criteria for cisplatin-ineligibility were equally distributed among the arms. There was no significant difference in the progression-free survival (GC 5.8 months, M-CAVI 4.2 months; HR 1.04, 95 % CI: 0.8, 1.35; p = 0.78) or the overall survival (GC 9.3 months, M-CAVI 8.1 months; HR 0.94, 95 % CI: 0.72, 1.22; p = 0.64) between the treatment arms. The M-CAVI arm was associated with a higher incidence of neutropenic fever, grade 3 mucositis, and treatment-related deaths. This trial solidified the role of gemcitabine plus carboplatin as a standard treatment for this patient population and provided a benchmark for clinical outcomes in “unfit” patients.

The only other phase III trial to be initiated, to date, in “unfit” patients with metastatic UC was the VINCENT (Vinflunine in Cisplatin-ineligible Patients Trial) trial, a randomized trial of vinflunine plus gemcitabine versus placebo plus gemcitabine. Eligibility for the VINCENT trial was based on either renal impairment (creatinine clearance ≤60 mL/min) or New York Heart Association Classification Stage III-IV congestive heart failure. Patients were required to have an ECOG performance status of 0-2. This trial was designed to accrue 450 patients; however, the trial was prematurely closed to accrual based on a decision by the sponsor.

Trials in the “unfit” patient population have been hampered by heterogeneous eligibility criteria resulting in confusion regarding the precise population being targeted for drug development. In an effort to develop a consensus definition of patients with metastatic UC “unfit” for cisplatin-based chemotherapy, a Working Group was assembled. Based on a survey of 120 international academic and community-based genitourinary oncologists, a proposed definition of “unfit” patients with metastatic UC was formulated with the goal of establishing uniform eligibility criteria for future clinical trials [35]. According to this definition, patients meeting at least one of the following criteria were considered “unfit”: ECOG performance status of 2, creatinine clearance less than 60 mL/min, grade ≥2 hearing loss, grade ≥2 neuropathy, and/or New York Heart Association Class III heart failure [36].

Multiple small phase II trials exploring a variety of agents as second-line therapy for metastatic UC have been performed. Overall, the most active of these agents have demonstrated response rates of approximately 10–30 % (Table 36.2). Many of these trials have been performed at single-institutions, have been small, and have employed heterogeneous eligibility criteria.

There has been one completed phase III trial in the second-line setting, which randomized 370 patients with progressive UC after first-line platinum-based chemotherapy to vinflunine versus best supportive care [58]. The main grade 3-4 adverse events on the vinflunine arm included neutropenia (50 %), febrile neutropenia (6 %), anemia (19 %), fatigue (19 %), and constipation (16 %). In the intent-to-treat population, there was a numerical improvement in median survival (6.9 months for vinflunine versus 4.6 months for best supportive care) which did not reach statistical significance (hazard ratio [HR] = 0.88; 95 % CI, 0.69–1.12; P = .287). When only the eligible population was included in the analysis (n = 357), the median overall survival was significantly longer for vinflunine than for best supportive care. Based on these results, in 2009, The Committee for Medicinal Products for Human Use of the European Medicines Agency granted marketing authorization for vinflunine for the treatment of patients with advanced UC progressing on a prior platinum-containing regimen. Vinflunine is the first drug specifically approved for the second-line setting in metastatic UC. Vinflunine has not been submitted for regulatory approval in the United States.

Approximately 10 % of cancers arising from the urothelial tract are of non-transitional cell histologies including squamous cell carcinomas, adenocarcinomas, and small cell carcinomas [59]. Given the rarity of these subtypes, much of the data regarding management of these malignancies is derived from single center retrospective series. However, there have been a few prospective trials attempting to define active chemotherapeutic regimens in these rare patient subsets.

A phase II trial evaluated a combination regimen of paclitaxel, ifosfamide, and cisplatin in patients with non-transitional cell histologies [60]. A total of 20 patients were enrolled including the following histologic subtypes: adenocarcinoma (n = 11), squamous cell carcinoma (n = 8), and small cell carcinoma (n = 1). Overall, 7 (35 %) of 20 patients (95 % CI: 15, 59 %) achieved an objective response (3 partial and 4 complete). This is a small cohort, and includes a mix of different histologies, but does demonstrate that combination chemotherapy has some activity in advanced adenocarcinomas and squamous cell carcinomas of bladder origin.

Investigators at MD Anderson Cancer Center performed a phase II study of an alternating doublet chemotherapy regimen (ifosfamide/doxorubicin and etoposide/cisplatin) in patients with small cell carcinoma of the bladder [61]. Of the 12 patients with surgically unresectable disease, eight had a complete clinical response, whereas three patients experienced a partial response. Despite this impressive activity, most patients with experienced relapse, with a median OS time of 13.3 months. Notably, brain metastases occurred in 8/16 patients presenting with bulky primary tumors or advanced disease, highlighting a potential role for prophylactic cranial irradiation.

Several studies have highlighted the importance of post-chemotherapy surgery in the setting of minimal residual disease after achieving a “near” complete response to chemotherapy [62–64]. In a retrospective study of 203 patients treated on five trials with MVAC, 50 patients underwent post-chemotherapy surgery for suspected or known residual disease [62]. In 17 patients, no viable tumor was found at post-chemotherapy surgery. Three patients had unresectable disease. In the remaining 30 patients, residual metastatic UC was completely resected resulting in a complete response to chemotherapy plus surgery. Of these 30 patients, 10 (33 %) remained alive at 5 years, similar to results attained by patients achieving a complete response to chemotherapy alone (41 %). Optimal candidates for post-chemotherapy surgical consolidation were those patients with pre-chemotherapy disease limited to the primary site or lymph nodes.

Although the initial treatment for most patients with metastatic UC is systemic chemotherapy, a subset of patient will develop progressive symptoms related to a specific metastatic deposit. Radiation therapy plays a prominent role in palliating metastatic UC [65]. The precise radiation dose and technique needs to be individualized to the patient and pattern of metastatic disease. Radiation should be, whenever possible, delivered in a modest or short period of time [66].

Because UC is a chemosensitive neoplasm, yet only a fraction of patients respond to a particular chemotherapeutic regimen, there has been much interest in developing tools to allow more rational use of existing drugs. One approach has involved evaluating the levels of DNA-repair genes, or their protein products, in tumors, based on the concept that tumors with higher levels of DNA-repair genes may be more resistant to therapy. Excision repair cross complementing 1 (ERCC-1) is a critical regulator in nucleotide excision repair and its expression has been correlated with outcomes to cisplatin-based chemotherapy in a variety of solid tumors [67–72]. RRM1, the regulatory subunit of ribonucleotide reductase, has been implicated in tumor response to gemcitabine [73]. A retrospective study analyzed levels of the DNA-repair genes ERCC1, RRM1, BRCA1, and caveolin-1, in tumor tissue from 57 patients with bladder cancer treated with cisplatin-based combination chemotherapy [74]. The median survival in this cohort was higher in patients with low ERCC1 levels (25.4 vs. 15.4 months; p = 0.03). However, development of ERCC1 as a widely available predictive biomarker has been hampered by difficulties with analytic validation [75].

Given the genomic complexity of solid tumors, relying on a single gene or protein as a predictive biomarker for response to cytotoxic chemotherapy is unlikely to yield substantial improvements in patient selection. Alternatively, profiling expression of multiple genes may better capture the heterogeneity of responses to therapy. Indeed, gene “signatures” of response to platinum-based chemotherapy have been generated and correlated with clinical outcomes in patients with bladder cancer [76–78]. While this approach is promising, the predictive signature is limited to the particular treatment regimen evaluated in the study in which the signature was generated. As a result, new signatures must be developed for each new treatment regimen entering clinical use, and the gene signatures cannot be used to aid in the development of novel drugs that have not yet been explored in human studies.

In an effort to overcome many of these limitations, Theodorescu and colleagues developed a novel bioinformatics approach known as Coexpression Extrapolation or COXEN [79]. COXEN utilizes the publicly available gene-expression profiling data and drug sensitivity data from the NCI-60 cell line panel as a “Rosetta Stone” to predict chemosensitivity of gene-expression profiled bladder cancer samples using a computational algorithm. The COXEN approach can be utilized to predict responses to multi-agent regimens, by combining data regarding single agents, and has also been utilized successfully to identify novel agents with activity in UC. A study is currently being planned to prospectively evaluate the COXEN approach for selection of chemotherapy for patients with UC.

Personalized cancer care via profiling tumors for potentially “actionable” genomic mutations is perhaps best exemplified by the emerging treatment approach to advanced non-small cell lung cancer where identification of aberrations in EGFR and ALK have changed the treatment paradigm [80, 81]. Several groups have evaluated UC samples for specific somatic mutations in known oncogenes and tumor suppressor genes. However, given the distinct pathways of pathogenesis of UC, and corresponding clinical phenotypes, knowledge of the genomic profiles of non-invasive versus invasive tumors is necessary to identify targets relevant for therapeutic strategies in these particular clinical states. In the most comprehensive analysis published to date, Sjodahl et al. performed mutation analyses of 16 genes (FGFR3, PIK3CA, PIK3R1, PTEN, AKT1, KRAS, HRAS, NRAS, BRAF, ARAF, RAF1, TSC1, TSC2, APC, CTNNB1, and TP53) in 145 cases of UC [82]. This study identified that FGFR3 and PIK3CA mutations were most commonly identified in non-invasive low grade tumors. Furthermore, the potential importance of APC signaling was identified as 6 % of the investigated tumors either demonstrated inactivating APC or activating CTNNB1 mutations. The mTOR regulatory tuberous sclerosis complex genes (TSC2 and TSC2) were found to be mutated at a combined frequency of approximately 15 %. Future efforts will focus on pairing these aberrations with appropriate therapeutic agents.