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INTRODUCTION — Bladder cancer is the most common malignancy involving the urinary system. Urothelial (transitional cell) carcinoma is the predominant histologic type in the United States and Europe, where it accounts for 90 percent of all bladder cancers. In other areas of the world, non-urothelial carcinomas are more frequent. Much less commonly, urothelial cancers can arise in the renal pelvis, ureter, or urethra. (See "Malignancies of the renal pelvis and ureter" and "Urethral cancer" and "Epidemiology and risk factors of urothelial (transitional cell) carcinoma of the bladder", section on 'Epidemiology'.)
Approximately 25 percent of patients will have muscle-invasive disease and either present with or later develop metastases. Systemic chemotherapy is the standard approach for the initial treatment of patients with inoperable locally advanced or metastatic urothelial malignancies. Although initial response rates are high, the median survival with multiagent chemotherapy is approximately 15 months [1,2]. While this is superior to the estimated six-month survival with metastatic disease prior to the development of modern chemotherapy regimens, the five-year survival rate is approximately 15 percent with contemporary regimens [2,3]. Second-line chemotherapy has had only a limited role, but checkpoint inhibitor immunotherapy offers an additional option for patients progressing after their initial systemic therapy.
The approach to systemic treatment for metastatic urothelial carcinoma arising in the renal pelvis or ureter is based upon results from trials composed primarily of patients with urothelial carcinoma of the bladder.
Systemic therapy for metastatic urothelial cancer is reviewed here. The use of neoadjuvant or adjuvant chemotherapy in conjunction with cystectomy and as part of a multimodality approach to preserve the bladder is discussed separately. (See "Neoadjuvant treatment options for muscle-invasive urothelial bladder cancer" and "Adjuvant chemotherapy for muscle invasive urothelial carcinoma of the bladder".)
PROGNOSTIC FACTORS — A number of clinical and molecular characteristics are correlated with survival. An appreciation of these prognostic factors is important for the interpretation of clinical trial results and for determining which patients may benefit from therapy. (See 'Defining medical fitness' below.)
Clinical factors — A poor performance status and the presence of visceral (ie, pulmonary, liver, bone) metastases correlate with shortened survival in clinical trials. This was illustrated by an Intergroup trial that compared cisplatin alone with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) in patients with metastatic disease [4,5].
●The presence of bone or liver metastases and a poor performance status were most predictive of poor response and survival. The presence of these unfavorable features was associated with a median survival of four months, compared with 18 months in those patients without these features .
Several subsequent reports confirmed the relationship between shortened survival and poor performance status or the presence of visceral metastases [2,6-9]. Similar to the first-line setting, the presence of liver metastases, a poor performance status, and a low hemoglobin level appear to predict a worse outcome in the second-line setting . Shorter time from prior chemotherapy may enhance prognostic classification independent of the factors above, particularly in the setting of second-line therapy for advanced urothelial cancer .
Molecular factors — Molecular abnormalities are also being studied as prognostic/predictive factors, with the goal of using the molecular characteristics of an individual tumor to help select treatment and to predict outcome. However, none of these factors has been validated, and they should not be used to make clinical decisions.
●The role of mutations in the p53 gene has been extensively studied but remains uncertain. Multiple studies have suggested that such mutations are associated with resistance to MVAC chemotherapy and a poor prognosis [12-16]. In contrast, at least one report found that tumors with p53 mutations have a worse tumor-specific prognosis but with potentially increased sensitivity to the MVAC or equivalent regimen, at least in the adjuvant setting . In an analysis of another trial, the presence of p53 mutations was neither predictive nor prognostic .
●The ERCC1 gene is involved in DNA repair and may mediate resistance to alkylating-agent chemotherapy. In a study of 57 patients with advanced bladder cancer who were treated with a cisplatin-based regimen, the median survival was significantly longer in patients with low ERCC1 levels (25 versus 15 months in those with high ERCC1 expression) .
●Other potential markers of chemotherapy resistance include the multidrug resistance p-glycoprotein, multidrug resistance-associated protein, glutathione, and metallothioneins [20-24].
There is hope that molecular characterization by The Cancer Genome Atlas (TCGA) consortium will help to better inform the genomic alterations in urothelial cancers, which can be exploited for novel therapies . (See 'Targeted therapy' below.)
FIRST-LINE THERAPY — A cisplatin-based combination chemotherapy regimen is the preferred initial therapy for patients with metastatic urothelial cancer of the bladder and urinary tract who are cisplatin candidates (algorithm 1). Importantly, a small proportion of patients with distant metastases in the nodes or lung may be cured by combination chemotherapy.
As described below, cisplatin-based combination chemotherapy results in superior survival when compared with single-agent cisplatin. However, cisplatin-related toxicity is a concern for many patients. In addition, not all patients with urothelial cancer are appropriate candidates for cisplatin therapy.
Defining medical fitness — All patients who are candidates for chemotherapy should undergo evaluation of renal function. For patients with impaired renal function, reversible causes (eg, urinary tract obstruction secondary to a tumor mass) should be identified and treated prior to initiation of cisplatin-based therapy.
An assessment that incorporates physiologic and biologic considerations can stratify patients into medically "fit" and "frail" populations, which are used to determine treatment options. The treatment options based on ability to tolerate cisplatin are discussed below.
We agree with the use of criteria published by a consensus working group that defined medically frail patients in whom the decision to treat with a cisplatin-based regimen should be balanced with consideration of the increased risks of toxicity :
●Creatinine clearance less than 60 mL/min
●Hearing loss (measured at audiometry) of 25 dB at two contiguous frequencies
●Grade 2 or greater peripheral neuropathy (ie, sensory alteration or paresthesia, including tingling, but not interfering with activities of daily living)
●New York Heart Association class III or greater heart failure (table 3)
For medically fit patients (who do not have any of the criteria described above), we recommend initial treatment using cisplatin-based combination chemotherapy. (See 'Cisplatin-based regimens' below.)
For patients who are unable to receive cisplatin due to medical frailty or comorbidities, options include a carboplatin-based regimen (carboplatin plus gemcitabine, or carboplatin, gemcitabine, and paclitaxel) or a non-platinum-based combination (eg, paclitaxel plus gemcitabine). A decision regarding treatment should take into account the patient's performance status and the clinician's medical judgment as to the patient's ability to tolerate chemotherapy:
●For patients with a good performance status (ie, ECOG performance status <2) who are otherwise candidates for combination chemotherapy, we suggest a carboplatin-based regimen (eg, carboplatin plus gemcitabine). However, a non-platinum-based combination (eg, paclitaxel plus gemcitabine) would be a reasonable alternative. (See 'Carboplatin-based regimens' below and 'Non-platinum regimens' below.)
●For patients with a poor performance status who are not candidates for combination chemotherapy, single-agent chemotherapy is a reasonable option. The choice of a specific treatment is based on patient and provider preference. (See 'Non-platinum regimens' below and 'Single-agent chemotherapy' below.)
Cisplatin-based regimens — Regimens used in the treatment of metastatic urothelial carcinoma include the following:
●PGC – Paclitaxel (80 mg/m2 before gemcitabine and cisplatin on days 1 and 8), gemcitabine (1000 mg/m2 on days 1 and 8), and cisplatin (70 mg/m2 on day 1), repeated every 21 days for a maximum of six cycles.
The data to support these recommendations are reviewed below.
MVAC — MVAC is a standard first-line option based on the results of randomized clinical trials demonstrating improved survival outcomes [4,28]. This was demonstrated in a multicenter trial of 269 patients with advanced urothelial carcinoma who were randomly assigned to treatment with either MVAC or single-agent cisplatin . Compared with cisplatin, MVAC resulted in:
●A significant improvement in the overall response rate (ORR; 39 versus 12 percent)
●A significant increase in median progression-free survival (PFS; 10 versus 4 months)
●A significant improvement in median overall survival (OS; 13 versus 8 months)
Increasing the dose intensity of MVAC by administering treatment every two weeks with granulocyte-colony stimulating factor (G-CSF) support has also been evaluated in an effort to improve long-term survival [29,30]. Although dose-intense treatment probably does not result in a clinically meaningful difference in OS, increased experience has suggested a reduction in toxicity. There is no consensus, and thus, both standard MVAC and dose-intense MVAC are used frequently in clinical practice. The National Comprehensive Cancer Network (NCCN) recommends dose-dense MVAC, but this recommendation remains controversial .
Toxicity is a major concern with MVAC therapy, particularly since many patients with bladder cancer are older adults or have multiple comorbidities. Myelosuppression, neutropenic fever, sepsis, mucositis, and nausea and vomiting are common. As an example, 54 percent of patients in one earlier series were hospitalized due to toxicity . Furthermore, toxicity-related deaths have been reported in most trials evaluating MVAC for advanced urothelial cancer [4,33]. The use of hematopoietic growth factor support may ameliorate some of these toxicities, especially myelosuppression and mucositis [34,35].
GC — The combination of gemcitabine plus cisplatin (GC) has similar efficacy and less toxicity compared with MVAC. This was demonstrated in a phase III trial in which 405 patients were randomly assigned to either GC or MVAC . Compared with MVAC, GC resulted in:
●Similar ORR (49 versus 46 percent).
●Similar time to progression (seven months in each arm).
●Similar OS (14 versus 15 months). At five years, there was also a similar five-year survival rate (13 and 15 percent) .
●Similar quality of life, though patients experienced less weight loss, a better performance status, and less fatigue.
●Less serious (grade 3/4) toxicity, including neutropenia (71 versus 82 percent), neutropenic sepsis (2 versus 14 percent), and mucositis (1 versus 22 percent) .
This trial was designed to assess if GC is superior and was not powered to demonstrate equivalency between the two regimens, but given the similar efficacy and lesser toxicity, many consider GC rather than MVAC to be the standard first-line regimen for patients with advanced urothelial carcinoma of the bladder.
Alternate dosing schedules with the GC regimen have used a three-week instead of four-week schedule [36-38]. Although these different GC schedules have not been compared in randomized phase III trials, the results appear to be similar. Of note, one trial comparing dose-dense GC versus dose-dense MVAC demonstrated no apparent benefit to dose intensification .
PGC (paclitaxel plus GC) — The triplet combination of paclitaxel, gemcitabine, and cisplatin (PGC) is another option for patients with metastatic urothelial carcinoma. This was demonstrated in the European Organization for the Research and Treatment of Cancer (EORTC) study 30987, which enrolled 626 patients with advanced urothelial carcinoma (81 percent with primary bladder cancer) and randomly assigned them to treatment with GC or PGC for a maximum of six cycles . Final results after a median follow-up of 4.6 years have been reported . Compared with GC, PGC resulted in:
●An increase in the ORR (56 versus 44 percent, p = 0.003).
●A trend towards an improvement in PFS (median 8.3 versus 7.6 months, hazard ratio [HR] for progression 0.87, 95% CI 0.74-1.03).
●A trend towards longer OS (median 16 versus 13 months, HR for death 0.85, 95% CI 0.72-1.02). When the analysis was restricted to patients who met all eligibility criteria (92 percent of the randomized population), PGC was associated with a significant increase in OS (median 16 versus 13 months, HR 0.82, 95% CI 0.68-0.98). In addition, PGC was associated with a significant improvement in OS among patients with primary bladder cancer compared with GC (median 16 versus 12 months, HR 0.80, 95% CI 0.66-0.97).
●An increased incidence of serious (grade 3/4) toxicity, including neutropenia (65 versus 51 percent), fatigue (15 versus 11 percent), and infections (18 versus 14 percent), but a lower incidence of serious (grade 3/4) thrombocytopenia (35 versus 52 percent).
These results suggest that PGC is a treatment option for patients with metastatic urothelial carcinoma and suggest it should be used for those with the bladder as primary origin.
Carboplatin-based regimens — For patients who are otherwise candidates for combination chemotherapy but are unable to receive cisplatin, we suggest the combination of gemcitabine and carboplatin. The benefit of carboplatin-based therapy was demonstrated in EORTC trial 30986.
In the EORTC 30986 study, 238 chemotherapy-naïve patients with impaired renal function (glomerular filtration rate <60 but >30 mL/min) and/or a poor performance status (ECOG ≥2) were randomly assigned to treatment with carboplatin and gemcitabine, or methotrexate, carboplatin, and vinblastine (MCAVI) . Compared with MCAVI, treatment with carboplatin plus gemcitabine resulted in:
●A higher ORR (41 versus 30 percent, respectively) that did not reach statistical significance.
●No difference in median OS (nine versus eight months, HR for death 0.94, 95% CI 0.72-1.22).
●No difference in median PFS (six versus four months, HR for progression 1.04, 95% CI 0.80-1.35).
●Less serious (grade 3/4) toxicity overall (9 versus 21 percent), including neutropenia (52 versus 63 percent) and febrile neutropenia (5 versus 15 percent). However, it was associated with a higher rate of serious thrombocytopenia (47 versus 18 percent).
The final results of this trial suggest that the combination of gemcitabine and carboplatin is as effective as MCAVI, with a better toxicity profile, and support its use in patients with impaired renal function or a poor performance status (ECOG ≥2) who are otherwise candidates for combination chemotherapy.
However, it is important to ascertain the basis for renal dysfunction prior to selecting a regimen. When simple and reversible causes, such as urinary obstruction by a primary tumor, are the basis for reduced renal function, they should be corrected first; this may allow the use of standard MVAC or GC regimens.
Several other randomized trials have compared carboplatin-based chemotherapy regimens with cisplatin-based combinations [43-45]. However, neither efficacy nor toxicity could be evaluated due to the small number of patients enrolled.
Non-platinum regimens — Regimens that combine gemcitabine with a taxane (either paclitaxel or docetaxel) rather than platinum have been evaluated with encouraging results. Paclitaxel plus gemcitabine appears to be more active than docetaxel plus gemcitabine in patients with advanced urothelial cancer:
●The combination of paclitaxel plus gemcitabine results in objective response rates of 54 to 70 percent and median survival of 13 to 16 months [46-49]. Toxicity with this combination is primarily hematologic, although severe pulmonary toxicity was reported in five patients treated with paclitaxel on a weekly schedule in one series .
Single-agent chemotherapy — A number of chemotherapy drugs have single-agent activity in patients with metastatic urothelial carcinoma, either in the first-line setting or in previously treated patients. These include platinum compounds (cisplatin, carboplatin), gemcitabine, vinca alkaloids (vinblastine, vinflunine), anthracyclines (doxorubicin, epirubicin), methotrexate, taxanes (paclitaxel, docetaxel), and ifosfamide [52-60]. Responses to single-agent chemotherapy are generally of short duration, and no consistent improvement in survival has been demonstrated. However, the activity with various single agents led to the development of combination regimens, most of which are cisplatin-based and discussed above. (See 'Cisplatin-based regimens' above.)
Immunotherapy — Up to 50 percent of patients with advanced urothelial carcinoma are not candidates for cisplatin-based chemotherapy because of age or comorbidity (eg, impaired renal function, neuropathy, heart failure). Although comparative phase III data are not available for first-line immunotherapy in this setting, a phase II study supports its use and tolerability [61,62].
The toxicity of these agents in the first-line setting is similar to that seen when used after cisplatin-based chemotherapy or in other indications. (See 'Second-line immunotherapy' below and "Toxicities associated with checkpoint inhibitor immunotherapy".)
Additional clinical trials and longer clinical follow-up with the programmed cell death-1 protein (PD-1)/PD-1 ligand (PD-L1) checkpoint inhibitors will be required to define their role in treating locally advanced and metastatic urothelial carcinoma in the first-line setting and also to define their potential for neoadjuvant and/or adjuvant therapy.
Pembrolizumab — In the phase II KEYNOTE-052 study, 370 patients with advanced urothelial carcinoma who were not eligible for a cisplatin-based regimen were treated with pembrolizumab (200 mg every three weeks for up to two years) . The average age of the study population was 74 years, and 29 percent of patients were aged ≥80 years. Liver metastases were present in 21 percent, and 42 percent were performance status 2; 50 percent of patients were included because of renal impairment.
At a median follow-up of 9.5 months, the objective response rate, the primary endpoint of the study, was 29 percent for the entire cohort, including 7 percent complete responses and 22 percent partial responses. The median duration of response had not been reached at the time of analysis. Response rates were consistent across all major subgroups. The objective response rate was higher in patients with PD-L1 expression >10 percent, but responses also were observed in those with PD-L1 expression <10 percent.
Atezolizumab — In a multicenter, single-arm phase II study, atezolizumab (total dose 1200 mg every three weeks) was used as first-line therapy in 119 patients with advanced or metastatic urothelial carcinoma of the bladder or upper urinary tract who were not eligible for treatment with a cisplatin-based regimen .
At a median follow-up of 17 months, objective responses were observed in 27 patients (23 percent), including 11 (9 percent) with a complete response. Median duration of response had not been reached, and 19 of 27 continued to respond at the time of analysis. The median OS for the entire cohort was 16 months. Atezolizumab was granted conditional approval by the US Food and Drug Administration (FDA) in April 2017 as the initial therapy for patients who are not candidates for platinum-based chemotherapy.
Rationale — Research into immunotherapy has led to important advances in the treatment of melanoma, non-small cell lung cancer, and other malignancies using checkpoint inhibition, particularly with antibodies directed against the programmed cell death-1 protein (PD-1) or its ligand (PD-L1). Five antibodies (pembrolizumab, nivolumab, atezolizumab, durvalumab, and avelumab) targeting this pathway have been approved by the US Food and Drug Administration (FDA) for patients who have progressed during or after platinum-based therapy (algorithm 1). (See "Principles of cancer immunotherapy".)
Pembrolizumab — Pembrolizumab prolongs overall survival in patients with metastatic urothelial carcinoma who have progressed during or after platinum-based chemotherapy.
In the phase III Keynote-045 trial, 542 patients who had recurred after or progressed on a platinum-containing regimen were randomly assigned to pembrolizumab (200 mg every three weeks for 24 months) or investigator's choice chemotherapy (paclitaxel, docetaxel, or vinflunine) . Patients were enrolled regardless of the level of PD-L1 expression. The co-primary endpoints of the trial were overall survival and progression-free survival. Data from the primary endpoint of the trial were updated at the 2017 annual meeting of the American Society of Clinical Oncology (ASCO) :
●Overall survival was significantly increased with pembrolizumab compared with chemotherapy (median 10.3 versus 7.4 months, hazard ratio 0.70, 95% CI 0.57-0.86). The 12-month overall survival rates were 44.4 versus 36.1 percent, and the 18-month overall survival rates were 36.1 and 20.5 percent, respectively.
●There was no statistically significant difference in progression-free survival (median 2.1 versus 3.3 months, hazard ratio 0.96, 95% CI 0.79-1.16). The estimated one-year progression-free survival rates were 17.6 versus 7.9 percent, and the 18-month progression-free survival rates were 16.8 versus 3.5 percent, respectively.
●The response rate was higher with pembrolizumab than with chemotherapy (21.1 versus 11.0 percent), and the estimated rate of response duration of 12 months or longer was also higher with pembrolizumab (68 versus 35 percent).
●Serious treatment-related adverse events were significantly less frequent with pembrolizumab (15.0 versus 43.9 percent). Adverse events in patients treated with pembrolizumab were consistent with those observed in other malignancies treated with pembrolizumab. (See "Toxicities associated with checkpoint inhibitor immunotherapy".)
Atezolizumab — Atezolizumab is a PD-L1 inhibitor that is indicated for the treatment of advanced urothelial carcinoma that has progressed during or after previous platinum-based chemotherapy, either for metastatic disease or for progressive disease less than 12 months after adjuvant or neoadjuvant chemotherapy. Atezolizumab (1200 mg intravenously every three weeks) was approved by the FDA in May 2016.
An expanded phase I study provided initial evidence of the safety and efficacy of atezolizumab . These results were expanded in a phase II study including two different cohorts. The results of cohort 2, in which 310 patients with metastatic urothelial cancer were treated with atezolizumab, have been reported . All patients in this cohort had progressed during or after prior platinum-based chemotherapy.
●Objective responses, as assessed by independent review, were observed in 45 cases (15 percent). At a median follow-up of 12 months, 38 of 45 (84 percent) responses were ongoing.
●Response data were analyzed based upon expression of PD-L1. Although the response rates were higher in those with more expression of PD-L1 on infiltrating immune cells, objective responses were sometimes observed even in those with no expression of PD-L1.
●The most common adverse event was fatigue, which was observed in 50 cases (16 percent); this was severe (grade 3/4) in five cases.
●Severe immune-mediated adverse events occurred in 15 cases (5 percent); these included pneumonitis, abnormal liver function tests, rash, and dyspnea. There were no treatment-related deaths. (See "Toxicities associated with checkpoint inhibitor immunotherapy".)
Results of a phase III trial (NCT02302807) that is currently ongoing comparing atezolizumab with second-line chemotherapy will be required to confirm the role of atezolizumab to treat urothelial carcinoma.
Nivolumab — Nivolumab is a PD-1 inhibitor that is indicated for the treatment of advanced urothelial carcinoma that has progressed during or after previous platinum-based chemotherapy either for metastatic disease or for progressive disease less than 12 months after adjuvant or neoadjuvant chemotherapy. Nivolumab (240 mg intravenously every two weeks) was approved by the FDA in February 2017 .
In the larger of the two published phase II studies, 270 patients were treated with nivolumab (3 mg per kilogram every two weeks) . The overall objective response rate was 19.6 percent, and responses were seen at all levels of PD-L1 expression, with no differences between more or less than 5 percent positivity. At seven months follow-up, overall survival for the entire cohort was 8.7 months; for those with PD-L1 expression <1 and ≥1 percent, median overall survival durations were 6.0 and 11.3 months, respectively.
Avelumab — Avelumab, a PD-L1 inhibitor, was approved in May 2017 for the treatment of advanced urothelial carcinoma that progressed during or after platinum-based chemotherapy. The conditional approval was based upon a phase I expansion cohort of 44 patients who were followed for a median of 16.5 months .
●The objective response rate was 18 percent based upon independent review. There were three patients with a partial response and five patients with a complete response. The median overall survival was 13.7 months, and the one-year overall survival rate was 54 percent.
●The most frequent treatment-related adverse events were fatigue or weakness (31.8 percent), infusion-related reactions (20.5 percent), and nausea (11.4 percent).
Durvalumab — Durvalumab is a PD-L1 inhibitor that is indicated for the treatment of advanced urothelial carcinoma that has progressed during or after previous platinum-based chemotherapy, either for metastatic disease or for progressive disease less than 12 months after adjuvant or neoadjuvant chemotherapy [71,72]. Durvalumab (10 mg/kg intravenously every two weeks) was approved by the FDA in May 2017.
●Objective responses were observed in 34 patients (17.8 percent), including 7 complete responses and 27 partial responses. The response rate was higher in high PD-L1 expression tumors compared with low or negative PD-L1 expression (28 versus 5 percent). At a median follow-up of 5.8 months, the median duration of response had not been reached. The one-year overall survival rate was 55 percent.
●Grade 3/4 treatment-related adverse events were seen in 7 percent of patients. There were two immune-mediated adverse events leading to death (autoimmune hepatitis, pneumonitis).
SECOND-LINE CHEMOTHERAPY — Although a significant number of patients have an objective response to first-line therapy, most eventually progress. Second-line chemotherapy may be indicated for those who are not candidates for immunotherapy and for those who progress during or after immunotherapy (algorithm 1).
A number of contemporary chemotherapy agents have clinical activity after patients have progressed despite methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) or gemcitabine plus cisplatin (GC). However, none of these agents has been approved for use in patients with metastatic urothelial carcinoma nor have their activities been validated in phase III clinical trials.
These agents include pemetrexed, vinflunine (not approved in the United States) , paclitaxel [54,75], docetaxel , gemcitabine , ifosfamide [53,76], and oxaliplatin . Reported response rates with single agents in the larger series have generally been 20 percent or less. Although these drugs have also been combined with either each other or other agents, no one regimen is considered to be the standard second-line therapy [77-82].
A review of results from eight phase II studies suggested that salvage therapy with combination chemotherapy regimens resulted in improved overall survival compared with single-agent therapy . However, these observations require validation in prospective randomized trials.
Patients with advanced bladder cancer who have failed an initial chemotherapy regimen should be encouraged to participate in clinical trials whenever possible.
Vinflunine — Vinflunine is approved in Europe for second-line treatment of urothelial cancer based upon one trial that showed a benefit to treatment when compared with best supportive care. However, vinflunine is not approved in the United States.
In the phase III trial, 370 previously treated patients were randomly assigned to either vinflunine or best supportive care . Compared with best supportive care, treatment with vinflunine resulted in a 9 percent objective response rate and an increase in survival (6.9 versus 4.6 months, hazard ratio 0.88, 95% CI 0.69-1.12). Imbalances in prognostic factors may have accounted for the lack of statistical significance in the primary analysis, with 10 percent more patients in the best supportive care arm than in the vinflunine arm having a better performance status (performance status was 0 in 38.5 versus 28.5 percent, respectively).
Ramucirumab — Ramucirumab is an antibody that binds the vascular endothelial growth factor (VEGF) receptor-2 (VEGFR-2), blocking all VEGF ligands from binding to VEGFR-2 and leading to more complete target inhibition of the VEGF pathway.
In the phase III RANGE trial, patients with advanced or metastatic urothelial carcinoma were randomly assigned to docetaxel plus ramucirumab or docetaxel plus placebo . All patients had progression during or after platinum-based therapy.
Progression-free survival with the combination was prolonged compared with docetaxel alone (median 4.1 versus 2.8 months, HR 0.76, 95% CI 0.61-094); in addition, the objective response rate was increased with the combination (24.5 versus 14.0 percent).
An assessment of the role of ramucirumab in combination with docetaxel will require longer follow-up and an analysis of overall survival, as well as information on its activity in patients who have received checkpoint inhibitor immunotherapy. Ramucirumab is not currently approved for patients with advanced urothelial carcinoma.
Pemetrexed — Antifolates are known to be active in advanced bladder cancer, with a number of regimens incorporating methotrexate, including MVAC. Pemetrexed, a multitargeted antifolate, has shown activity in previously treated patients [85,86]. As an example, in a Hoosier Oncology Group study, 47 previously treated patients received single-agent pemetrexed . The objective response rate was 28 percent, including three complete responses (6 percent). The median overall survival was 10 months.
Nabpaclitaxel — Nanoparticle, albumin-bound paclitaxel (nabpaclitaxel) has demonstrated significant activity as second-line therapy in patients with metastatic urothelial cancer. As an example, in a phase II study of nabpaclitaxel involving 48 patients, the overall response rate was 28 percent .
TARGETED THERAPY — Molecular analysis has identified genetic and epigenetic alterations in high-grade urothelial carcinomas, and up to 60 percent of these alterations can be targeted by drugs already approved for use in other indications or in clinical trials . Examples include:
●Mutations in the receptor tyrosine kinases (RTKs) RAS/RAF, PI3K, AKT, and mammalian target of rapamycin (mTOR) pathways 
●Regulators of G1-S cell cycle progression, such as TP53 and RB1
●FGFR3 mutations and translocations
●Amplifications in FGFR1, CCND1, and MDM2
●Aberrations of the chromatin remodeling genes (eg, UTX, MLL-MLL3, CREBBP-EP300, NCOR1, ARID1A, and CHD6)
Agents that target these pathways are being actively evaluated in a number of studies. Although they do not have an established role, single-patient benefit has been reported .
NON-UROTHELIAL BLADDER CANCER — Urothelial carcinomas constitute the majority of bladder cancers in the United States, while squamous cell carcinomas and adenocarcinomas comprise a small fraction of bladder cancers. The management of non-urothelial bladder cancer, including chemotherapy for the treatment of advanced disease, is discussed separately. (See "Non-urothelial bladder cancer".)
SUMMARY AND RECOMMENDATIONS
●Advances in the management of advanced urothelial (transitional cell) carcinoma using cisplatin-based combination chemotherapy have led to a substantial increase in survival. Despite this progress, metastatic disease is associated with a limited life expectancy, and cures are infrequent.
●The overall approach to the treatment of metastatic urothelial carcinoma is summarized in the algorithm (algorithm 1).
●For patients with good performance status, adequate renal function, and metastatic or inoperable locally advanced urothelial cancer, we recommend initial treatment using cisplatin-based combination chemotherapy (Grade 1A). Reasonable options include methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), dose-dense MVAC, gemcitabine plus cisplatin (GC), and paclitaxel, gemcitabine, and cisplatin (PGC). The choice between them is individualized based on patient and provider preferences. (See 'First-line therapy' above.)
•For patients with impaired renal function, reversible causes (eg, urinary tract obstruction secondary to a tumor mass) should be identified and treated prior to initiation of cisplatin-based therapy. (See 'Defining medical fitness' above.)
●For patients with advanced urothelial cancer who are not cisplatin candidates, treatment should take into account the patient's performance status and ability to tolerate systemic therapy (see 'Defining medical fitness' above). Options include both chemotherapy and immunotherapy:
•For patients with a good performance status (World Health Organization [WHO]/Eastern Cooperative Oncology Group [ECOG] performance status <2) who are otherwise candidates for a combination regimen, options include carboplatin-based regimens or a non-platinum-based combination (eg, paclitaxel plus gemcitabine). (See 'Carboplatin-based regimens' above and 'Non-platinum regimens' above.)
•Single-agent chemotherapy is a reasonable alternative, or treatment with best supportive care is a reasonable option. The choice between them should be based on clinical factors such as the patient's performance status and his or her values and preferences. (See 'Second-line chemotherapy' above.)
•Checkpoint inhibition immunotherapy with an agent targeting the programmed cell death-1 protein (PD-1) or its ligand (PD-L1) is an option for patients with access to one of these agents. Enrollment in a formal clinical trial assessing the role of immunotherapy is recommended whenever possible.
●For patients who relapse following treatment with a platinum-based regimen, we recommend checkpoint inhibition with an agent targeting the programmed cell death-1 protein (PD-1) or PD-L1 (Grade 1B). There are no clinical trials that compare atezolizumab, nivolumab, durvalumab, avelumab, and pembrolizumab. Whenever possible, patients should be enrolled in formal clinical trials. (See 'Second-line immunotherapy' above.)
Multiple chemotherapy agents also have modest activity, including gemcitabine, vinflunine, ifosfamide, paclitaxel, docetaxel, and pemetrexed. These agents may be indicated when a checkpoint inhibitor or clinical trial is not feasible. (See 'Second-line chemotherapy' above.)
ACKNOWLEDGMENT — The authors and editors would like to recognize Dr. Gary MacVicar, who contributed to previous versions of this topic review.
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