What is the recommended treatment approach for bladder cancer, including non‑muscle‑invasive, muscle‑invasive, and metastatic disease?

Treatment of Bladder Cancer

Non-Muscle-Invasive Bladder Cancer (NMIBC)

Complete transurethral resection of bladder tumor (TURBT) is the initial treatment for all bladder cancers, followed by risk-stratified intravesical therapy. 1

Initial Management

• Perform complete TURBT with adequate muscle sampling (muscularis propria) to correctly identify clinical stage and grade 1
• Conduct bimanual examination under anesthesia at time of TURBT to assess for extravesical extension 1
• Obtain upper tract imaging (CT urography preferred) to exclude synchronous upper tract tumors, which occur in 2.5% of patients 1

Risk-Stratified Intravesical Therapy

• For high-grade Ta and T1 tumors: administer intravesical BCG with maintenance therapy, which is superior to TURBT alone or chemotherapy in preventing recurrences 1
• Consider second TURBT for high-risk tumors before or after intravesical therapy 1
• For very high-risk features (multiple grade 3 T1 tumors with carcinoma in situ, or increased depth of invasion): proceed directly to radical cystectomy 1
• For BCG-unresponsive disease: radical cystectomy is recommended due to high progression risk 1

Common Pitfall

BCG therapy is significantly underused—only 22% of eligible patients receive it despite demonstrated 23% mortality reduction 1

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Muscle-Invasive Bladder Cancer (MIBC)

For cisplatin-eligible patients with muscle-invasive bladder cancer (T2-T4aN0), the new standard of care is durvalumab added to neoadjuvant gemcitabine-cisplatin for 4 cycles, followed by radical cystectomy with extended pelvic lymph node dissection. 2, 3

Neoadjuvant Immunotherapy-Chemotherapy (Preferred Approach)

• Durvalumab perioperative treatment added to neoadjuvant gemcitabine-cisplatin demonstrates superior outcomes: 2-year event-free survival of 67.8% versus 59.8% without durvalumab (HR 0.68, p<0.001) and 2-year overall survival of 82.2% versus 75.2% (HR 0.75, p=0.01) 2, 3
• This represents a significant improvement over historical neoadjuvant chemotherapy alone, which showed only 5% absolute survival benefit at 5 years 2, 4
• Cisplatin eligibility criteria: adequate renal function (GFR >60 mL/min), ECOG performance status 0-1, no significant cardiac dysfunction, neuropathy, or hearing loss 1

Radical Cystectomy

• Perform radical cystectomy with bilateral extended pelvic lymph node dissection (common iliac, internal iliac, external iliac, and obturator nodes as minimum) 1, 3
• Complete surgery within 90 days of diagnosis or completion of neoadjuvant therapy—delays beyond 3 months negatively impact outcomes 3, 4
• Extended lymphadenectomy is potentially curative even with micrometastases to few nodes and correlates with improved progression-free and overall survival 1

For Cisplatin-Ineligible Patients

• Do NOT use carboplatin-based neoadjuvant chemotherapy—proceed directly to definitive locoregional therapy 1
• Consider bladder-preservation approaches (see below) 1, 3

Adjuvant Therapy for High-Risk Disease

• For patients with residual disease, node-positive disease, pT3/pT4a disease, or lymphovascular invasion after cystectomy: offer adjuvant nivolumab within 90 days of surgery 3
• For cisplatin-eligible patients with non-organ confined disease (pT3/T4 and/or N+) who did not receive neoadjuvant chemotherapy: offer adjuvant cisplatin-based chemotherapy (DDMVAC with growth factor support for 3-4 cycles preferred, or gemcitabine-cisplatin for 4 cycles) 1, 3, 4
• Critical distinction: neoadjuvant chemotherapy is strongly preferred over adjuvant therapy based on superior level of evidence 4

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Bladder-Preservation Approaches

Trimodal therapy (maximal TURBT followed by concurrent chemoradiotherapy) is a reasonable alternative for patients preferring bladder preservation or medically unfit for surgery, achieving comparable survival to radical cystectomy in patients ≥65 years (median OS 27.3 months versus 23.2 months for cystectomy alone, p=0.39). 3, 5

Patient Selection Criteria

• Solitary tumor amenable to complete TURBT 5
• No hydronephrosis (independent predictor of poor outcomes and extravesical disease) 1
• Adequate bladder function 5

Partial Cystectomy

• Consider only in <5% of cases when tumor location allows removal of adequate soft tissue margin and ≥2 cm uninvolved urothelium without compromising continence or significantly reducing bladder capacity 2

Surveillance Requirements

• Mandatory cistoscopy and cytology every 3 months during first 2 years, then every 6 months 2, 3
• Immediate salvage cystectomy for recurrence 2

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Metastatic/Advanced Disease

For metastatic urothelial carcinoma, platinum-based combination chemotherapy is standard first-line treatment, with median overall survival of approximately 13 months. 1

First-Line Systemic Therapy

• Cisplatin-eligible patients: gemcitabine-cisplatin or DDMVAC (dose-dense methotrexate-vinblastine-doxorubicin-cisplatin with growth factor support) 1, 2
• Cisplatin-ineligible patients with high PD-L1 expression: atezolizumab or pembrolizumab as first-line options based on phase II studies 1
• Carboplatin-based regimens for cisplatin-ineligible patients without high PD-L1 expression 1

Prognostic Factors

• Karnofsky performance status <80% and/or presence of visceral metastases predict worse outcomes 1
• Zero risk factors: median survival 33 months 1
• One risk factor: median survival 13.4-13.6 months 1
• Two risk factors: median survival 9.3 months 1

Second-Line Therapy

• Immune checkpoint inhibitors (anti-PD-1/PD-L1 agents) are now incorporated into second-line treatment after platinum failure 1, 6

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Surveillance After Definitive Treatment

Post-Cystectomy

• Urinary cytology, creatinine, and electrolytes every 3-6 months for 2 years, then as clinically indicated 3, 4
• Chest, abdomen, and pelvis imaging every 3-12 months for 2 years based on recurrence risk 3, 4

Post-Bladder Preservation

• Cystoscopy and urinary cytology every 3 months during first 2 years, every 6 months subsequently 2, 3
• Cross-sectional imaging as per post-cystectomy protocol 3

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Critical Practice Points

Multidisciplinary Approach

• Engage multidisciplinary team (urology, medical oncology, radiation oncology, pathology) before determining treatment plan 1
• Experienced genitourinary pathologist should review all cases with variant histology or equivocal muscle invasion (micropapillary, nested, plasmacytoid, neuroendocrine, sarcomatoid, extensive squamous/glandular differentiation) 1

Pre-Treatment Counseling

• Counsel patients regarding treatment complications and quality of life implications: continence, sexual function, fertility, bowel dysfunction, metabolic problems 1

Timing Considerations

• Perform imaging (CT/MRI abdomen/pelvis) BEFORE TURBT when invasive tumor suspected to avoid interference from post-TURBT inflammation 1
• Do not delay cystectomy—perform as soon as possible after recovery from neoadjuvant therapy 1