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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 Chemotherapy of Metastatic Bladder Cancer
First-line treatment options:
Patients should be offered cisplatin-containing chemotherapy if general condition and comorbidities permit (MVAC, high-dose MVAC, or gemcitabine/cisplatin). Cisplatin-eligible patients should 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.
Cisplatin ineligible patients can be treated with either a milder chemotherapy such as gemcitabine/carboplatin, alternatively the checkpoint inhibitor pembrolizumab can be used if the tumor material has a positive PD-L1 status (see below under second-line therapy). There are no randomized trial between first-line chemotherapy or immunotherapy; approval was based on trials for second-line therapy (see below).
MVAC chemotherapy for bladder cancer:
Combination of methotrexate (M), vinblastine (V), adriamycin (A) (=doxorubicin), and cisplatin (C). Adriamycin is often replaced with epirubicin (MVEC) to reduce cardiotoxicity.
With MVAC, 13–35% of patients achieve complete remission (CR), partial response or stable disease is possible in most patients (up to 90%). Despite chemotherapy, median survival is only 14 months in metastatic urothelial carcinoma, with approximately 10% alive after three years. In the absence of visceral metastases (only lymph node metastases) and a Karnofsky index above 79%, a median survival time around 30 months and five-year survival rate of 33% can be expected.
Dosage of MVAC:
One cycle of MVAC lasts 28 days. If well tolerated, six cycles are given for proven metastases. After cystectomy with high probability of recurrence (T3–4 N1–3), four cycles are given as adjuvant therapy. For neoadjuvant therapy, 2–4 cycles are given, and further postoperative chemotherapy is decided upon histology and response. Discontinuation of therapy is necessary in cases of toxicity or progressive disease with chemotherapy.
- Methotrexate: 30 mg/m2, days 1, 15, 22.
- Vinblastine: 3 mg/m2, day 2, 15, 22.
- Adriamycin (=doxorubicin): 30 mg/m2 or epirubicin 45 mg/m2, day 2
- Cisplatin: 70 mg/m2, day 2.
High-dose MVAC regimen:
Above mentioned doses from day 1 and 2 and a cycle duration of 14 days, for which the concomitant administration of G-CSF is obligatory. Oncological results are slightly better than with conventional MVAC, with fewer dose delays and less toxicity (Sternberg et al., 2001).
Side effects of MVAC:
Mainly mucositis, bone marrow depression (leukopenia, leukopenic fever), alopecia, nausea, vomiting, death. See also section MVAC and Cisplatin for general pharmacology.
Gemcitabine and cisplatin (GC):
The combination of gemcitabine and cisplatin (GC) offers comparable oncological results in randomized trials to MVAC (survival time, CR, OR) but with fewer side effects (Maase et al., 2005). If well tolerated, six cycles are given for proven metastases. After cystectomy with high probability of recurrence (T3–4 N1–3), four cycles are given as adjuvant therapy. For neoadjuvant therapy, 2–4 cycles are given, and further postoperative chemotherapy is decided upon histology and response. Discontinuation of therapy is necessary in cases of toxicity or progressive disease with chemotherapy. See also section cisplatin and gemcitabine for general pharmacology.
Results and side effects:
See above, comparable to MVAC.
Gemcitabine 1000 mg/m2 on day 1 and 8, cisplatin 70 mg/m2 on day 1 or 2, cycle duration 21 days (Parra et al., 2002), chemotherapy schedule see section gemcitabine and cisplatin combination.
Imaging during chemotherapy:
Restaging with CT or MRI every 2–3 months or cycles for timely diagnosis of progression with appropriate therapy adjustment.
Avelumab maintenance therapy after platinum-based chemotherapy:
The monoclonal antibody against PD-L1 as maintenance therapy after chemotherapy improves the prognosis (OS 21 vs. 14 months). Maintenance therapy is approved in Europe since 2021 for patients who showed a response or stable disease with chemotherapy. The dosage of avelumab is 800 mg intravenously every two weeks and is administered until the disease progresses (Powles et al., 2020).
Second-line Therapy of Metastatic Bladder Carcinoma
For second-line therapy of metastatic bladder carcinoma, the following therapeutic options exist for patients in good general condition:
Immunotherapy for advanced bladder cancer:
The agents mentioned below target the immune checkpoint "programmed cell death" signaling pathway, this leads to the enhancement of 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 now been tested in phase III trials, and pembrolizumab has been shown to have a survival benefit over second-line chemotherapy.
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 5% complete remission rate (Rosenberg et al., 2016). The higher the PD-L1 expression, the better was 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 is approved for second-line therapy and as first-line therapy in cisplatin-ineligible patients. For first-line therapy, approval is limited to patients with a PD-L1 expression of ≥5%.
Nivolumab is a monoclonal antibody directed against the PD-1 receptor. The dosage of nivolumab is 3 mg/kgKG every 2 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 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 is approved for second-line therapy and as first-line therapy in cisplatin-ineligible patients. For first-line therapy, approval is limited to patients with a CPS ≥10. The CPS (combined positive score) is an immunoassay used to determine PD-L1 expression of solid tumors.
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). Phase III studies are not available; Erdafitinib (Balversa) is approved in the USA since 2019.
Antibody-drug conjugates are covalent combinations of cytotoxin and antibody using a linker, this enables targeted cytotoxic therapy.
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 is approved since 2019 in the United States and since 2022 in Europe for third-line therapie (after chemotherapy and immunotherapy). The combination of enfortumab vedotin with pembrolizumab showed even higher response rates and is in a phase III trial as first-line therapy.
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) is approved in the United States since 2021.
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.
Three week regimen (gemcitabine 1000 mg/m2 on day 1 and 8; paclitaxel 175 mg/m2 on day 1) with a maximum of 6 cycles.
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
Endoscopic hemostasis by resection and coagulation. Therapy-refractory cases can be relieved with instillation of silver nitrate, alumen, or formalin 1% [see section radiation cystitis]. Palliative radiation or, as ultima ratio, palliative cystectomy with urinary diversion are other options (Weissbach et al., 2001).
Pain medication. Bisphosphonates for painful bone metastases. Palliative radiation, surgical removal or stabilization of painful lesions.
Watchful waiting, transurethral ureteral splinting, percutaneous nephrostomy, ureterocutaneostomy.
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 table 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.
Laboratory tests (BB, creatinine, electrolytes, transaminases, gamma-GT), ultrasonography of kidneys and liver, CT Abdomen and Thorax every six months initially, then annually after 5 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 in case of heterotopic urinary diversion, annual irrigation cytology or cystoscopy is recommended.
Superfical 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. Median time to recurrence is 12 months (4 months to 10 years) (Stein et al., 2001).
Lymph node metastases:
For solitary lymph node metastasis after radical cystectomy median survival time 30 months and five-year survival rate 33%, otherwise significantly worse.
Without therapy median survival time 6–9 months, with chemotherapy 14 months median survival time.
Small cell carcinoma of the bladder:
Similar poor prognosis as small cell bronchial carcinoma.
|Bladder cancer: diagnosis||Index||Bladder cancer TURB|
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Deutsche Version: Operative Therapie des Harnblasenkarzinoms: TURB und Zystektomie