Only a small fraction of patients with stage IV bladder cancer can be cured, and for many patients, the emphasis is on palliation of symptoms. The potential for cure is restricted to patients with stage IV disease with involvement of pelvic organs by direct extension or metastases to regional lymph nodes.
Standard Treatment Options for Stage IV Bladder Cancer
Standard treatment options for patients with T4b, N0, M0 disease
Treatment options for patients with T4b, N0, M0 disease include the following:
- Chemotherapy alone.
- Radical cystectomy.
- Radical cystectomy followed by chemotherapy.
- Radical cystectomy alone.
- External-beam radiation therapy (EBRT) with or without concomitant chemotherapy.
- Urinary diversion or cystectomy for palliation.
Chemotherapy alone
Cisplatin-based combination chemotherapy regimens are the standard of care for stage IV bladder cancer. The only chemotherapy regimens that have been shown to result in longer survival in randomized controlled trials are methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC); high-dose MVAC; and cisplatin, methotrexate, and vinblastine (CMV). Gemcitabine plus cisplatin (GC) was compared with MVAC in a randomized controlled trial and no difference in response rate or survival was reported. Of note, patients with good performance status and lymph node-only disease have a low but significant rate of achieving a durable complete remission with MVAC or GC. For example, in the large, randomized controlled trial that compared MVAC with GC, the 5-year overall survival (OS) rate in patients with lymph node-only disease was 20.9%.
Single-agent cisplatin and multiagent regimens that do not include cisplatin have never been shown to improve survival in a randomized controlled trial. For patients who are not candidates for cisplatin-based multiagent chemotherapy regimens, there is no regimen that has been shown to prolong survival; however, many regimens have demonstrated radiologically measurable responses.
These include carboplatin plus paclitaxel, carboplatin plus gemcitabine, paclitaxel plus gemcitabine, single-agent gemcitabine, and single-agent paclitaxel. Regimens of carboplatin, methotrexate, and vinblastine; carboplatin, epirubicin, methotrexate, and vinblastine; and paclitaxel, gemcitabine, and carboplatin have been studied but are not widely used.
Evidence (chemotherapy alone):
- Results from a randomized controlled trial that compared MVAC with docetaxel plus cisplatin in 220 patients reported that MVAC was associated with longer OS (median survival, 14.2 months vs. 9.3 months; P = .026).
- A randomized trial that compared MVAC with cisplatin, cyclophosphamide, and doxorubicin demonstrated improved response and median survival rates (48 weeks vs. 36 weeks; P = .003) with the MVAC regimen.
- Results from a randomized trial that compared MVAC with single-agent cisplatin in advanced bladder cancer also showed a significant advantage with MVAC in both response rate and median survival (12.5 months vs. 8.2 months; P = .002).
- A multicenter randomized controlled trial compared CMV with methotrexate plus vinblastine without cisplatin in 214 patients. The relative risk of dying was 0.68 (95% confidence interval , 0.51–0.90; P = .0065) in favor of CMV. The median survival was 7 months with CMV and 4.5 months with methotrexate plus vinblastine.
- The European Organisation for Research and Treatment of Cancer (EORTC) conducted another randomized trial that studied 263 patients with advanced bladder cancer and evaluated the efficacy of a high-dose intensity MVAC regimen administered every 2 weeks with granulocyte colony-stimulating factor (G-CSF) versus a classic MVAC regimen administered every 4 weeks.
- Although there was no significant difference in OS at a median follow-up of 3.2 years (hazard ratio , 0.80; 95% CI, 0.60–1.06; P = .122), an update at a median follow-up of 7.3 years reported that the high-dose intensity MVAC regimen was associated with improved OS (HR, 0.76; 95% CI, 0.58–0.99; P = .042), with a 5-year survival rate of 22% compared with 14% in patients treated with the classic MVAC regimen.
- The high-dose intensity MVAC regimen was also associated with higher response rates (72% vs. 58%; P = .016), improved median progression-free survival (PFS) (9.5 months vs. 8.1 months; P = .017), and decreased neutropenic fever (10% vs. 26%; P < .001), although only 19% of patients treated with a classic MVAC regimen ever received G-CSF. An imbalance in baseline prognostic factors (i.e., visceral metastases were found in 37 patients randomly assigned to the high-dose MVAC regimen and 47 patients assigned to the classic MVAC regimen) may account, in part, for these results.
- Gemcitabine plus cisplatin.
- In a multicenter, randomized, phase III trial that compared GC with the MVAC regimen in 405 patients with advanced or metastatic bladder cancer, GC yielded response rates, time-to-progression, and OS (HR, 1.04; 95% CI, 0.82–1.32; P = .75) similar to MVAC, but GC had a better safety profile and was better tolerated than MVAC.
- Although this study was not designed to show the equivalence of the two regimens, the similar efficacy and reduced toxic effects of GC make it a reasonable alternative in patients who may not tolerate the MVAC regimen.
Radical cystectomy
Patients with stage IV disease with involvement of pelvic organs by direct extension or metastases to regional lymph nodes may undergo radical cystectomy with pelvic lymph node dissection. The extent of lymph node dissection during cystectomy is controversial because there are no data from prospective trials demonstrating improved outcomes with lymph node dissection. Because T4b tumors cannot generally be completely resected and because lymph node metastases usually signal distant micrometastases, patients with locally advanced bladder cancer are usually given chemotherapy before surgery with the goal of facilitating resection and eliminating micrometastatic disease. Although there are data supporting preoperative chemotherapy for clinical stage II and stage III disease, patients with stage IV disease were excluded from most clinical trials investigating the role or preoperative chemotherapy.
External-beam radiation therapy (EBRT) with or without concomitant chemotherapy
Definitive radiation therapy with or without concurrent chemotherapy, evaluated mainly in patients with locally advanced (T2–T4) disease, appears to have minimal curative potential in patients with regional lymph node metastases. Patients with evidence of lymph node metastases have generally been excluded from phase III trials of radiation therapy.
Urinary diversion or cystectomy for palliation
Urinary diversion may be indicated, not only for palliation of urinary symptoms but also for preservation of renal function in candidates for chemotherapy.
Standard treatment options for patients with any T, any N, M1 disease
Standard treatment options for patients with any T, any N, M1 disease include the following:
- Chemotherapy alone or as an adjunct to local treatment.
- Immunotherapy.
- EBRT for palliation.
- Urinary diversion or cystectomy for palliation.
Chemotherapy alone or as an adjunct to local treatment
Cisplatin-based combination chemotherapy regimens are the standard of care for first-line therapy for stage IV bladder cancer in patients who can tolerate it. The only chemotherapy regimens that have been shown to result in longer survival in randomized controlled trials are MVAC, dose-dense MVAC, and CMV. GC was compared with MVAC in a randomized controlled trial and neither regimen was associated with a statistically significant difference in response rate or survival. The two regimens are generally considered equivalent, but they have never been compared in a noninferiority trial. Of note, patients with good performance status and lymph node-only disease have a low but significant rate of achieving a durable complete remission with MVAC or GC. In the large, randomized, controlled trial comparing MVAC with GC, for example, 5-year OS in patients with lymph node-only disease was 20.9%. Dose-dense MVAC and standard-dose MVAC were compared in a randomized controlled trial, and dose-dense MVAC was associated with longer survival.
Single-agent cisplatin and multiagent regimens that do not include cisplatin have never been shown to improve survival in a randomized controlled trial. For patients who are not candidates for cisplatin-based multiagent chemotherapy regimens, there is no regimen that has been shown to prolong survival; however, many regimens have demonstrated radiologically measurable responses.
These include carboplatin plus paclitaxel, carboplatin plus gemcitabine, paclitaxel plus gemcitabine, single-agent gemcitabine, and single-agent paclitaxel. The regimens of carboplatin, methotrexate, and vinblastine; carboplatin, epirubicin, methotrexate, and vinblastine; and paclitaxel, gemcitabine, and carboplatin have been studied but are not widely used.
Ongoing studies are evaluating new chemotherapy combinations.
Evidence (chemotherapy):
- A prospective randomized trial that compared MVAC with cisplatin, cyclophosphamide, and doxorubicin demonstrated improved response rate and longer median survival (48 weeks vs. 36 weeks; P = .003) with the MVAC regimen.
- Results from a randomized trial that compared MVAC with single-agent cisplatin in advanced bladder cancer also showed a significant advantage with MVAC in both response rate and median survival (12.5 months vs. 8.2 months; P = .002).
- A multicenter, randomized, controlled trial compared CMV with methotrexate plus vinblastine without cisplatin in 214 patients. The relative risk of dying was 0.68 (95% CI, 0.51–0.90; P = .0065) in favor of CMV. The median survival was 7 months with CMV compared with 4.5 months for methotrexate plus vinblastine.
- The EORTC conducted another randomized trial that studied 263 patients with advanced bladder cancer and evaluated the efficacy of a high-dose intensity MVAC regimen given every 2 weeks with G-CSF compared with a classic MVAC regimen given every 4 weeks.
- Although there was no significant difference in OS at a median follow-up of 3.2 years (HR, 0.80; 95% CI, 0.60–1.06; P = .122), an update at a median follow-up of 7.3 years reported that the high-dose intensity MVAC regimen was associated with improved OS (HR, 0.76; 95% CI, 0.58–0.99; P = .042), with a 5-year survival rate of 22%, compared with 14% in patients treated with the classic MVAC regimen.
- The high-dose intensity MVAC regimen was also associated with higher response rates (72% vs. 58%; P = .016), improved median PFS (9.5 months vs. 8.1 months; P = .017), and decreased neutropenic fever (10% vs. 26%, P < .001), although only 19% of patients treated with a classic MVAC regimen ever received G-CSF. An imbalance in baseline prognostic factors (i.e., visceral metastases were found in 37 patients randomly assigned to the high-dose MVAC regimen and 47 patients assigned to the classic MVAC regimen) may account, in part, for these results.
- Gemcitabine plus cisplatin:
- In a multicenter randomized phase III trial that compared GC with the MVAC regimen in 405 patients with advanced or metastatic bladder cancer, GC yielded response rates, time-to-progression, and OS (HR, 1.04; 95% CI, 0.82–1.32; P = .75) similar to MVAC, but GC had a better safety profile and was better tolerated than MVAC.
- Although this study was not designed to show the equivalence of the two regimens, the similar efficacy and reduced toxic effects of GC make it a reasonable alternative in patients who may not tolerate the MVAC regimen.
- Other chemotherapy regimens that have shown activity in metastatic bladder cancer include single-agent paclitaxel, single-agent gemcitabine, single-agent pemetrexed, carboplatin combined with either gemcitabine or paclitaxel, and gemcitabine combined with paclitaxel. There are no phase III trials demonstrating a survival or quality-of-life benefit from second-line chemotherapy.
Ongoing studies are evaluating new chemotherapy combinations.
Immunotherapy
Immunotherapy has emerged as a treatment alternative for patients with stage IV bladder cancer. Immune checkpoint inhibitors that have anti−programmed death-1 (PD-1) or anti−programmed death-ligand 1 (PD-L1) activity have been shown in clinical trials to have activity against urothelial carcinoma in patients who have previously been treated with or who are ineligible for platinum-based chemotherapy. There are currently several different agents approved; however, pembrolizumab is the agent with the highest level of evidence and the greatest data in terms of survival.
Pembrolizumab
Pembrolizumab is a humanized monoclonal antibody that binds to PD-1. In patients previously treated with platinum-based chemotherapy, pembrolizumab has been shown to prolong OS compared with second-line chemotherapy. As a result, pembrolizumab has been approved by the U.S. Food and Drug Administration (FDA) for patients with locally advanced or metastatic urothelial carcinoma who fall into one of the following three categories:
- Cisplatin-ineligible and have tumors that express PD-L1 (combined positive score of at least 10%).
- Cisplatin- and carboplatin-ineligible.
- Progression of disease after treatment with platinum-based chemotherapy.
It is important to note that in 2018, the FDA issued an alert about preliminary data from two ongoing first-line therapy trials comparing pembrolizumab or atezolizumab with cisplatin- or carboplatin-based therapy. The data showed that immunotherapy was associated with shorter survival in patients with low expression of PD-L1. As a result, the labels were amended to restrict use of both agents to the three categories above.
Evidence (pembrolizumab):
- In an open-label, international, randomized, controlled phase III trial (NCT02256436) of pembrolizumab (200 mg intravenously every 21 days) versus second-line chemotherapy (investigator’s choice of paclitaxel, docetaxel, or vinflunine) in patients whose disease had progressed after treatment with platinum-based chemotherapy, median OS was longer with pembrolizumab (10.3 months vs. 7.4 months; HR, 0.73; 95% CI, 0.59–0.91).
- In patients with a PD-L1 CPS of at least 10%, median OS was 8.0 months with pembrolizumab compared with 5.2 months of chemotherapy (HR, 0.57; 95% CI, 0.37–0.88).
- The PFS rate at 12 months was 16.8% (95% CI, 12.3%–22.0%) in the pembrolizumab arm and 6.2% (95% CI, 3.3%–10.2%) in the chemotherapy arm.
- The objective response rate was 21.1% in the pembrolizumab arm and 11.4% in the chemotherapy arm. Among those who responded, the median duration of response was longer than 18 months with pembrolizumab compared with a response of 4.3 months with chemotherapy.
- Pembrolizumab was associated with a lower rate of treatment-related adverse events than was chemotherapy (60.9% vs. 90.2%) and a lower rate of high-grade adverse events (15.0% vs. 49.4%). The most common adverse events with pembrolizumab were pruritus, fatigue, nausea, diarrhea, and decreased appetite.
- In a single-arm, phase II trial (NCT02335424) of pembrolizumab in 370 treatment-naïve, cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma, the overall response rate was 29%. In patients with a PD-L1 CPS of at least 10%, the overall response rate was 51%.
- Median duration of response had not been reached. Eighty-two percent of responses lasted at least 6 months.
- Ten percent of patients had a serious treatment-related adverse event, and one patient died of treatment-related adverse events. The most common high-grade adverse events were fatigue (2%), elevated alkaline phosphatase (1%), colitis (1%), and muscle weakness (1%).
Atezolizumab
Atezolizumab is a humanized monoclonal antibody that binds to PD-L1 and prevents it from binding to its receptors, PD-1 or B7-1. Clinical trials have reported that atezolizumab acts against urothelial carcinoma, but it has not shown prolonged OS or improved quality of life. The only randomized controlled trial testing atezolizumab reported no significant difference in OS compared with second-line chemotherapy.
Atezolizumab has been approved by the FDA for patients with locally advanced or metastatic urothelial carcinoma who fall into one of the following three categories:
- Cisplatin-ineligible and have tumors that express PD-L1 (at least 5% of the tumor area covered by tumor-infiltrating immune cells that stain for PD-L1).
- Cisplatin- and carboplatin-ineligible.
- Progression of disease after treatment with platinum-based chemotherapy.
It is important to note that in 2018, the FDA issued an alert about preliminary data from two ongoing first-line therapy trials comparing pembrolizumab or atezolizumab with cisplatin- or carboplatin-based therapy. The data showed that immunotherapy was associated with shorter survival in patients with low expression of PD-L1. As a result, the labels were amended to restrict use of both agents to the three categories above.
Evidence (atezolizumab):
- The IMvigor211 trial (NCT02302807) is a randomized, controlled trial that compared atezolizumab with second-line chemotherapy (docetaxel, paclitaxel, or vinflunine) in 931 patients with locally advanced or metastatic urothelial carcinoma who were previously treated with platinum-containing chemotherapy. The trial design specified that OS would be primarily assessed in patients with tumors in which at least 5% of cells stained for PD-L1.
- Median OS was 11.1 months for atezolizumab versus 10.6 months for chemotherapy in patients with at least 5% of tumor cells staining for PD-L1 (P = .41).
- Response rates were also similar: 23% with atezolizumab and 22% with chemotherapy.
- Patients receiving atezolizumab had a lower rate of high-grade toxicity (20% vs. 43%) and a lower rate of treatment discontinuation resulting from adverse events (7% vs. 18%).
- In a multicenter, single-arm trial (NCT0108652) of atezolizumab (1,200 mg IV every 21 days) in 315 cisplatin-ineligible patients or patients who were previously treated with platinum-based chemotherapy and who had inoperable locally advanced or metastatic urothelial carcinoma, the following results were reported:
- The overall response rate was 15%.
- With a median follow-up of 11.7 months, 38 of 45 responders (84%) had an ongoing response.
- The response rate was 27% in those with PD-L1 expression of at least 5%, 10% in those with PD-L1 expression of 1% to 5%, and 8% in those with PD-L1 expression of less than 1%.
- Grade 3 to 4 adverse events were reported in 16% of patients, and high-grade, immune-related adverse events were reported in 5% of patients.
- Similarly, a study (NCT02108652) of 123 previously untreated patients with cisplatin-ineligible, locally advanced metastatic urothelial carcinoma who were treated with atezolizumab reported that at a median follow-up of 17.2 months, the objective response rate was 23%, and 9% had complete responses.
- Of the 27 responses, 19 were ongoing at the time of data analysis. Median OS was 15.9 months.
- High-grade adverse events were reported in 16% of patients, 8% of patients discontinued treatment because of the adverse events, and there was one treatment-related death.
Nivolumab
Nivolumab is a fully human immunoglobulin G4 PD-1 immune checkpoint inhibitor antibody that blocks interaction between PD-L1 and PD-L2 with PD-1. There are no published controlled trials and thus no data regarding whether nivolumab results in longer survival or improved quality of life.
Evidence (nivolumab):
- In a multicenter trial (NCT01928394) of 86 patients with metastatic urothelial carcinoma whose disease progressed after platinum-based chemotherapy, patients were treated with nivolumab (3 mg/kg IV every 2 weeks).
- With a minimum follow-up of 9 months and a median follow-up of 15 months, 24% had an objective response, and 22% had grade 3 or 4 adverse events.
- The most common adverse events were elevated lipase or amylase, fatigue, rash, dyspnea, lymphopenia, and neutropenia.
- Another multicenter study (NCT02387996) of 270 patients with locally advanced or metastatic urothelial carcinoma that had progressed after treatment with platinum-based chemotherapy reported an objective response rate of 20%.
- When evaluated by PD-L1 expression, the objective response rate was 28% in those with PD-L1 expression of 5% or greater; 24% in those with PD-L1 expression of 1% or greater; and 16% in those with PD-L1 expression of less than 1%.
- Grade 3 to 4 adverse events were reported in 18% of patients.
- There were three treatment-related deaths.
Avelumab
Avelumab is a monoclonal anti–PD-L1 antibody that has shown activity against urothelial carcinoma. A randomized controlled trial reported an OS benefit from maintenance avelumab when given after platinum-based chemotherapy in patients whose cancer did not progress during chemotherapy.
Evidence (avelumab):
- A phase III study (NCT02603432) evaluated maintenance avelumab (10 mg/kg IV every 14 days) in patients with metastatic urothelial carcinoma who had not progressed during treatment with first-line chemotherapy with gemcitabine combined with either cisplatin or carboplatin. After four to six cycles of chemotherapy, 700 patients were randomly assigned to receive either best supportive care (control arm) or best supportive care plus maintenance avelumab (avelumab arm).
- The 1-year OS rate was 71.3% in the avelumab arm compared with 58.4% in the control arm (HR, 0.69; 95% CI, 0.56–0.86).
- The OS benefit was limited to patients whose tumors were PD-L1 positive. The OS in patients with PD-L1–negative tumors was not significantly different between the two arms.
- Patients with PD-L1–positive tumors had a 1-year OS rate of 79.1% in the avelumab arm and 60.4% in the control arm (HR, 0.56; 95% CI, 0.40–0.79).
- In the overall study population, the median PFS was 3.7 months for patients in the avelumab arm and 2.0 months for patients in the control arm (HR, 0.62; 95% CI, 0.52–0.75). In patients with PD-L1–positive tumors, the median PFS was 5.7 months with avelumab and 2.1 months with best supportive care alone (HR, 0.56; 95% CI, 0.43–0.73).
- Grade 3 or higher adverse events were reported for 47.4% of patients in the avelumab arm and 25.2% of patients in the control arm. Most adverse events with avelumab were immune related, and 9% of patients who received avelumab were treated with high-dose glucocorticoids for these events.
- A study (NCT01772004) of avelumab (10 mg/kg IV every 14 days) in 249 patients with metastatic urothelial carcinoma who had progressed after treatment with platinum-based chemotherapy reported the following results:
- Among the 161 patients with at least 6 months of follow-up, the overall response rate was 17%, and response was ongoing in 23 of 28 responders with a median follow-up of 7.3 months. Six percent of the patients had a complete response.
- The overall response rate was 25.0% in patients with at least 5% of tumor cells staining for PD-L1 and 14.7% for those with less than 5% PD-L1 positivity.
- Median PFS was 6.3 weeks; 23% of the patients were progression free at 24 weeks.
- A treatment-related adverse event was reported in 66.7% of patients, including 8.4% of patients with high-grade adverse events. There was one treatment-related death from pneumonitis. High-grade immune-related adverse events were reported in 2.4% of patients.
Durvalumab
Durvalumab is an anti–PD-L1 monoclonal antibody that has shown activity against urothelial carcinoma. There are no published controlled trials and no data demonstrating either longer survival or improved quality of life with this agent.
Evidence (durvalumab):
- The efficacy of durvalumab (10 mg/kg IV every 14 days) was assessed in a study (NCT01693562) of 191 patients with locally advanced or metastatic urothelial carcinoma whose disease had progressed while they were on chemotherapy or who were either ineligible for or unwilling to be treated with chemotherapy.
- With a median follow-up of 5.78 months, the overall response rate was 17.8%.
- The response rate was 27.6% in patients with high expression of PD-L1 compared with 5.1% in patients with low or no PD-L1 expression.
- High-grade adverse events were reported in 6.8% of patients, including 2.1% with high-grade immune-mediated adverse events.
EBRT for palliation
Definitive radiation therapy with or without concurrent chemotherapy, evaluated mainly in patients with locally advanced (T2–T4) disease, appears to have minimal curative potential in patients with regional lymph node metastases.
Urinary diversion or cystectomy for palliation
Urinary diversion may be indicated, not only for palliation of urinary symptoms, but also for preservation of renal function in candidates for chemotherapy.
Treatment Options Under Clinical Evaluation for Patients With Any T, Any N, M1 Disease
Prognosis is poor in patients with stage IV disease and consideration of entry into a clinical trial is appropriate.
Other chemotherapy regimens appear to be active in the treatment of metastatic disease. Chemotherapy agents that have shown activity in metastatic bladder cancer include paclitaxel, docetaxel, ifosfamide, gallium nitrate, and pemetrexed.