The most common metastatic sites are bone, liver, and lung. Non-local regional recurrences after radical cystectomy for localized disease reflect micrometastatic disease present at diagnosis.
Per the 2019 Consensus Statement, locally advanced bladder cancer is defined as cT4b and/or cN1–3. cT4b disease (invading the pelvic wall, abdominal wall, or adjacent bowel/rectum) is considered unresectable unless significant downstaging is achieved. cN1–2 is nodal involvement in the true pelvis, and cN3 is common-iliac involvement. These patients should be discussed in a multidisciplinary forum and can be cured with multimodality treatment — a further argument for a curative approach is that some cN1–3 patients proceeding directly to surgery are found to be pN0 (false-positive clinical staging).
Treatment summary: first-line is 4–6 cycles of gemcitabine + cisplatin; if cisplatin is contraindicated, gemcitabine + carboplatin; if not suitable for combination, single-agent gemcitabine, paclitaxel, or docetaxel (no immunotherapy). Second-line is pembrolizumab.
First-Line Systemic Therapy
- Preferred: 4–6 cycles of platinum-based chemotherapy. CUA contraindications to cisplatin (5; almost identical to the NAC list but with an eGFR cutoff of ≤60 rather than ≤50): eGFR ≤60 mL/min/1.73m², heart failure (NYHA >II), ≥grade 2 hearing loss, ≥grade 2 neuropathy, ECOG ≥2. In select cases eGFR 45–60 and/or ECOG 2 may be extended, using split-dose cisplatin.
- Cisplatin-eligible — preferred regimen GC (phase III vs MVAC: similar efficacy, less toxicity). Dose-dense MVAC with growth-factor support in select aggressive cases (EORTC 30924: 5-year OS 21.8% DD-MVAC vs 13.5% standard MVAC). No completed trials support first-line immunotherapy in cisplatin-eligible patients.
- Cisplatin-ineligible — preferred regimen gemcitabine/carboplatin (carboplatin is inferior — lower response rates, trend to inferior survival — but active). If not suitable for combination, single-agent gemcitabine, paclitaxel, or docetaxel (response 25–47%, short duration, median OS 8–12 months).
- First-line immunotherapy — pembrolizumab and atezolizumab have efficacy in cisplatin-ineligible advanced UC. KEYNOTE-361 (~1,000 patients, pembrolizumab + chemo vs pembrolizumab vs chemo): no significant PFS or OS benefit of adding pembrolizumab or of pembrolizumab alone vs chemotherapy. 2019 CUA: not routinely recommended first-line for cisplatin-ineligible patients. FDA (August 2021): pembrolizumab approved for previously untreated locally advanced/metastatic UC ineligible for any platinum chemotherapy.
Second-Line Systemic Therapy
Although 40–70% of metastatic patients respond initially, most progress (median survival 14 months, 5-year OS 5–20%); those who fail first-line have a dismal prognosis. For progression during/after platinum-based chemotherapy, pembrolizumab is preferred (if available); second-line evidence is more robust than first-line. KEYNOTE-045 (n=542, pembrolizumab vs paclitaxel/docetaxel/vinflunine): median OS 10.3 vs 7.4 months, grade 3–5 toxicity 15% vs 49%. Other agents studied: atezolizumab (IMvigor 211), nivolumab (CheckMate 275), avelumab (JAVELIN), durvalumab. PD-L1 IHC should not be used to select second-line patients, and no single biomarker predicts response. Where pembrolizumab is unavailable or the patient is ineligible, single-agent paclitaxel or docetaxel is preferred. Platinum re-treatment is reasonable after a prolonged (>6–12 month) initial response. Cancers of the ureter, renal pelvis, and proximal urethra (5–10% of UC) are treated with similar systemic therapy.
Consolidation, Oligometastatic & Local Treatment
- Consolidation after systemic therapy — RC + PLND or radical radiotherapy (± concurrent chemotherapy), depending on response and MDT input. Radiotherapy is favoured over surgery in two situations: persistent N3 disease after chemotherapy (high relapse risk, less invasive option) and cT4b disease failing to downstage (surgery usually not feasible).
- Oligometastatic disease — routine metastasectomy or ablative radiotherapy is not recommended, though it may be appropriate in selected cases within a multidisciplinary context.
- Metastatic disease — routine localized treatment to the primary (RC or high-dose radiotherapy ± chemotherapy) is not recommended, but may be appropriate in selected cases; individualize after systemic treatment.