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Advanced Bladder Cancer: Chemotherapy and Immunotherapy of Metastasis

Review Literature: EAU guidelines superficial bladder cancer. EAU guidelines of muscle-invasive and metastatic bladder cancer. German S3 guidelines bladder carcinoma Harnblasenkarzinom.

• Bladder carcinoma: Definition, Epidemiology and Etiology
• Bladder carcinoma: Pathology and TNM tumor stages
• Bladder carcinoma: Symptoms and Diagnosis
• Bladder carcinoma: Surgical Treatment
• Bladder carcinoma: Chemotherapy and Immunotherapy of Metastases

First-line Therapy for Metastatic Bladder Cancer

First-line treatment options:

The combination of enfortumab vedotin plus pembrolizumab (EV+P) has been the preferred first-line therapy for all patients since 2024. In case of unavailability or contraindications, cisplatin-containing chemotherapy should be offered if the general condition and comorbidities allow this. According to the latest ESMO recommendations, platinum-containing chemotherapy should be combined with nivolumab, followed by maintenance therapy with nivolumab. Patients not suitable for cisplatin can be treated with a milder chemotherapy such as gemcitabine/carboplatin, after which adjuvant avelumab is recommended (Powles et al., 2024a). For the few patients unsuitable for combination therapy, there is the option of monotherapy with immune checkpoint inhibitors.

Enfortumab vedotin + pembrolizumab (EV+P):

Enfortumab vedotin is an antibody-drug conjugate: antibody against nectin-4 conjugated with monomethylauristatin E (MMAE). The covalent combination of cytotoxin and antibody with the aid of a linker enables targeted cytotoxic therapy. The immune checkpoint inhibitor pembrolizumab is a monoclonal antibody against the PD-1 receptor.

Results:

The combination EV+P was tested in a phase III trial (EV-302/KEYNOTE-A39) as first-line therapy against cisplatin-containing chemotherapy (Powles et al., 2024) with significantly better results: progression-free survival 12 vs. 6 months, overall survival 32 vs. 16 months, complete remission 29% vs. 13%, overall survival 32 vs. 16 months. Grade 3–5 adverse events were comparable, and the discontinuation rate due to adverse events was 35% vs. 19%.

Dosage of Enfortumab vedotin + pembrolizumab (EV+P):

One cycle of EV+P lasts 21 days. Enfortumab vedotin 1.25 mg/kg (maximum 125 mg) i.v. on days 1 and 8 until progression or severe side effects. Pembrolizumab 200 mg i.v. every three weeks on day one until progression or serious side effects, maximum 35 doses.

Side effects:

Grade 3–5 side effects are mainly skin reactions, polyneuropathy, hyperglycemia, and death (1%). See also section immune checkpoint inhibitors for side effects of immunotherapy.

Gemcitabine/cisplatin + nivolumab (GC+N):

Cisplatin-containing chemotherapy has been the standard treatment for metastatic urothelial carcinoma for 20 years, with median survival times of around 14 months. The combination of chemotherapy with the immune checkpoint inhibitor nivolumab improved the results.

Prerequisites for cisplatin:

Cisplatin-eligible patients have an ECOG performance status of 0–1, Karnofsky index above 70%, creatinine clearance above 50–60 ml/min, no hearing loss on audiometry (≥ grade 2), no peripheral neuropathy (≥ grade 2) and no heart failure NYHA III–IV.

Results:

The combination GC+N was tested in a phase III trial (CheckMate 901) as first-line therapy against GC (Heijden et al., 2023): Overall survival 22 vs. 19 months, complete remission 22% vs. 12%, grade 3–5 adverse events were 62% vs. 52%.

Dosage of Gemcitabine/cisplatin + nivolumab (GC+N):

Gemcitabine 1000 mg/m² on days 1 and 8, cisplatin 70 mg/m² on days 1 or 2, cycle duration 21 days (Parra et al., 2002), for chemotherapy schedule see section gemcitabine/cisplatin. If well tolerated, six cycles are administered if metastases are present. The dose of nivolumab is 360 mg i.v. every three weeks during chemotherapy and 480 mg i.v. every four weeks after chemotherapy as a maintenance therapy.

Side effects:

Especially mucositis, bone marrow suppression (leukopenia, leukopenic fever), alopecia, nausea, vomiting, and death (1%). See also sections cisplatin and gemcitabine for the general pharmacology. See also section immune checkpoint inhibitors for side effects of immunotherapy.

Gemcitabine/carboplatin + avelumab:

Chemotherapy with carboplatin is an option for patients who have contraindications to cisplatin (GFR between 30–50 ml/min, ECOG performance status > 1, see above) or to enfortumab vedotin. The prognosis is improved by the combination with avelumab (overall survival 21 vs. 14 months). Maintenance therapy is only approved for patients with a response to chemotherapy (CR, PR, or stable disease). The dosage of avelumab is 800 mg every two weeks intravenously and is administered until disease progression (Powles et al., 2020); maintenance therapy has been approved since 2021.

First-line monotherapy with immune checkpoint inhibitors:

Pembrolizumab and atezolizumab are approved as first-line therapy for platinum-ineligible patients with PD-L1 expression. With monotherapy, a complete remission can be achieved in 7–9%.

Cisplatin chemotherapy with MVAC:

MVAC is a historical chemotherapy combination of methotrexate (M), vinblastine (V), adriamycin (A) (=doxorubicin) and cisplatin (C), which was the standard before gemcitabine/cisplatin. MVAC has lost its significance due to the results of modern immune checkpoint inhibitors and antibody-drug conjugates.

Imaging during chemotherapy:

Restaging with CT or MRI every 2–3 months or cycles for timely diagnosis of progression with appropriate therapy adjustment.

Second-line Therapy of Metastatic Bladder Carcinoma

For second-line therapy of metastatic bladder carcinoma, the following therapeutic options exist:

Progression after enfortumab vedotin + pembrolizumab (EV+P):

If the patient is fit for platinum-containing chemotherapy, cisplatin or carboplatin combined with gemcitabine without immune checkpoint inhibitor is recommended. See below for further options for second-line chemotherapy.

Immunotherapy for advanced bladder cancer:

The agents mentioned below target the immune checkpoint "programmed cell death" signaling pathway, which enhances the cellular immune response against the tumor. Approval for second-line therapy was based on phase II data due to better tolerability compared to second-line chemotherapy and a relatively high rate of partial and complete remission in a disease with a very poor prognosis. Atezolizumab and pembrolizumab have been tested in phase III trials, and improved survival over second-line chemotherapy was recorded for pembrolizumab.

Atezolizumab:

Atezolizumab is a monoclonal antibody against PD-L1 (programmed cell death-ligand 1), which interferes with the interaction between PD-L1 and its PD-1 receptor. The dosage of atezolizumab is 1200 mg intravenously every three weeks. In patients with progression after cisplatin chemotherapy, the response rate was 15% and a 5% complete remission rate (Rosenberg et al., 2016). The higher the PD-L1 expression, the better the overall survival (11 vs. 9 vs. 8 months). In Europe, atezolizumab received approval in 2017, although the phase III trial failed to improve overall survival. However, atezolizumab was better tolerated than second-line chemotherapy with vinflunine, paclitaxel, or docetaxel (Powles et al., 2017). Atezolizumab has been approved for second-line therapy and as first-line therapy in cisplatin-ineligible patients.

Nivolumab:

Nivolumab is a monoclonal antibody directed against the PD-1 receptor. The dosage of nivolumab is 3 mg/kgKG every two weeks intravenously. Nivolumab showed a response rate of 20–26% as second-line therapy, and survival was 9–10 months (Sharma2016) (Sharma2017). Nivolumab was approved by the EMA for second-line therapy in 2017.

Pembrolizumab:

Pembrolizumab is a monoclonal antibody against the PD-1 receptor. The dosage of pembrolizumab is 200 mg every three weeks intravenously. Pembrolizumab improved response rate (21 vs. 11%) and survival time (10 vs. 7 months) in a phase III trial compared with second-line chemotherapy (Bellmunt et al., 2017). Pembrolizumab has been approved for second-line therapy and as first-line therapy in cisplatin-ineligible patients.

Prospects:

In the USA, the substances avelumab and durvalumab are already approved for second-line therapy.

Tyrosine kinase inhibitors:

Erdafitinib is an FGF receptor tyrosine kinase inhibitor with clinical activity in patients with proven FGF mutations following first-line chemotherapy (Loriot et al., 2019). Erdafitinib (Balversa) has been approved in the USA since 2019 and in Europe since 2024. Other comparable substances are currently undergoing clinical trials.

Antibody-drug conjugates:

Antibody-drug conjugates are covalent combinations of cytotoxin and antibodies using a linker; this enables targeted cytotoxic therapy.

Enfortumab vedotin:

Enfortumab vedotin is an antibody to Nectin-4 conjugated to monomethyl auristatin E (MMAE). Response rates of 45% were found in phase II studies of patients undergoing progression after first-line chemotherapy and second-line immunotherapy (Rosenberg et al., 2019). Enfortumab vedotin has been approved since 2019 in the United States and since 2022 in Europe for third-line therapy (after chemotherapy and immunotherapy).

Sacituzumab govitecan:

Sacituzumab govitecan is an antibody against Trop-2 (trophoblast cell surface antigen) conjugated to a metabolite of irinotecan (SN-38). Response rates of 27–70% were found in phase II studies of patients undergoing progression after first-line chemotherapy and second-line immunotherapy (Tagawa et al., 2021). Sacituzumab govitecan (Trodelvy) has been approved in the United States since 2021.

Second-line chemotherapy:

Second-line chemotherapy is an option when contraindications to immunotherapy are present.

Gemcitabine and cisplatin (GC):

If remission persists for more than six months after cisplatin-containing chemotherapy, re-challenge of cisplatin-containing chemotherapy is a reasonable option in case of progression.

Gemcitabine/paclitaxel:

Three-week regimen (gemcitabine 1000 mg/m² on days 1 and 8; paclitaxel 175 mg/m² on day 1) with a maximum of 6 cycles.

Vinflunine:

Vinflunine is a microtubule inhibitor, marginally improved survival (6.9 vs. 4.6 months) compared with palliative therapy (Bellmunt et al., 2009).

Palliative Therapy for Advanced Bladder Cancer

Hematuria:

Endoscopic hemostasis is possible using resection and coagulation. Therapy-refractory cases can be relieved with the instillation of silver nitrate, alumen, or formalin 1% [see section radiation cystitis]. Palliative radiation or, as an ultima ratio, palliative cystectomy with urinary diversion are other options (Weissbach et al., 2001).

Pain:

Pain medication. Bisphosphonates for painful bone metastases. Palliative radiation, surgical removal, or stabilization of painful lesions.

Hydronephrosis:

Watchful waiting; if creatinine is rising, consider transurethral ureteral splinting, percutaneous nephrostomy, or ureterocutaneostomy.

Follow-up Care

Follow-up of Superficial bladder carcinoma:

The EAU follow-up recommendations depend on the risk of recurrence and progression, see table EORTC risk classification 1 and EORTC risk classification 2.

Low risk of recurrence and progression:

Control cystoscopies at three months, then at six months, and then annually. Discontinuation of follow-up cystoscopy may be considered after five years.

Medium risk for recurrence and progression:

Individualized follow-up between low and high risk.

High risk for recurrence and progression:

Control cystoscopy and urine cytology every three months for two years, every four months in the third year, every six months in years 4–5, then annually. In addition, annual imaging of the upper urinary tract.

After cystectomy:

Laboratory tests (BB, creatinine, electrolytes, transaminases, gamma-GT), ultrasonography of kidneys and liver, CT scan of abdomen and chest every six months initially, then annually after five years. Semiannual venous blood gas analyses after continent urinary diversion, especially in chronic kidney disease. Annual control of vitamin B₁₂ concentration from the third year after continuous urinary diversion. Control of the remaining male urethra is indicated, especially after heterotopic urinary diversion, with annual irrigation cytology or cystoscopy.

Prognosis

Superficial bladder carcinoma:

EORTC risk classification: tumor size, number, recurrence rate, T stage, and grading can be used to determine the recurrence risk and progression risk of superficial bladder carcinoma, see table EORTC risk classification 1 and table EORTC risk classification 2.

Invasive bladder carcinoma:

10-year recurrence-free survival 80% (organ-confined, pN0), 61% (non-organ-confined, pN0), 45% (infiltration of adjacent organs, pN0), 34% for patient with pN1. The median time to recurrence is 12 months (4 months to 10 years) (Stein et al., 2001).

Lymph node metastases:

The median survival time for solitary lymph node metastasis after radical cystectomy is 30 months, and the five-year survival rate is 33%. Multiple lymph node metastases are significantly worse.

Distant metastases:

Without therapy, the median survival time is 6–9 months, with chemotherapy 14 months median survival time.

Small-cell carcinoma of the bladder:

Similar poor prognosis as small-cell bronchial carcinoma.

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  Deutsche Version: Chemotherapie und Immuntherapie des metastasierten Harnblasenkarzinoms