What are the management options for urothelial carcinoma?

Management of Urothelial Carcinoma

For advanced/metastatic urothelial carcinoma, enfortumab vedotin plus pembrolizumab is now the preferred first-line treatment over platinum-based chemotherapy, regardless of platinum eligibility, based on superior overall survival and progression-free survival outcomes. 1

Non-Muscle-Invasive Bladder Cancer (Ta, T1, Tis)

Low-Grade Ta Tumors

• Complete transurethral resection of bladder tumor (TURBT) followed by a single immediate intravesical chemotherapy instillation (typically mitomycin C) is the standard approach. 2
• Avoid immediate intravesical treatment if TURBT was extensive or bladder perforation is suspected. 2
• Follow-up cystoscopy at 3 months initially, then at increasing intervals. 2

High-Grade Ta Tumors

• Perform repeat TURBT if no muscle was present in the initial specimen, as 49% of patients without muscularis propria will be understaged. 2
• After complete resection, administer intravesical BCG (preferred over mitomycin C) based on four meta-analyses demonstrating superior prevention of recurrences. 2
• Surveillance includes cystoscopy and urinary cytology every 3-6 months for 2 years, then at increasing intervals. 2
• Upper tract imaging every 1-2 years is required for high-grade tumors. 2

T1 Disease (Subepithelial Invasion)

• Repeat TURBT within 2-6 weeks is mandatory for high-risk disease, particularly if complete resection is uncertain, no muscle in specimen, lymphovascular invasion present, or inadequate staging suspected. 2
• For particularly high-risk T1 disease (multifocal lesions, vascular invasion, or recurrence after BCG), consider early cystectomy rather than repeat TURBT due to high progression risk. 2

Carcinoma In Situ (Tis)

• Complete endoscopic resection followed by 6-week induction course of intravesical BCG. 2
• Reevaluate at 12 weeks after therapy initiation. 2
• For persistent/recurrent disease at 12 weeks, administer a second course of BCG or mitomycin (maximum 2 consecutive induction courses). 2
• If residual disease persists after second BCG course at second 12-week follow-up, proceed to cystectomy. 2

Muscle-Invasive Bladder Cancer (T2-T4a)

Primary Treatment Approach

• Radical cystectomy with bilateral pelvic lymphadenectomy (including common, internal iliac, external iliac, and obturator nodes at minimum) remains the gold standard. 1
• Segmental (partial) cystectomy is reserved only for solitary lesions in locations amenable to resection with adequate margins and no carcinoma in situ. 1

Neoadjuvant Chemotherapy

• Administer cisplatin-based neoadjuvant chemotherapy before cystectomy for T2-T4a tumors without nodal involvement, as this increases median survival and reduces residual disease rates. 2
• This approach is particularly important as it allows treatment while renal function is preserved. 3

Surgical Considerations

• Perform cystoprostatectomy in men or cystectomy with hysterectomy in women. 2
• Extended pelvic lymph node dissection is integral to surgical management and may improve survival. 2
• Factors precluding lymphadenectomy include severe scarring from prior treatments, advanced age, or severe comorbidities. 2

Post-Cystectomy Surveillance

• Every 3-6 months for 2 years: urine cytology, creatinine, electrolytes, and imaging of chest, abdomen, and pelvis. 1, 2
• Urethral wash cytology every 6-12 months, particularly if Tis was found in bladder or prostatic urethra. 1
• Monitor vitamin B12 annually if continent diversion was created. 1, 2

Upper Tract Urothelial Carcinoma (UTUC)

Risk Stratification and Treatment Selection

Low-risk UTUC (small, low-grade tumors):

• Kidney-sparing surgery is the preferred approach, as survival is similar to radical nephroureterectomy (RNU) without the morbidity of kidney function loss. 1
• Endoscopic ablation via ureteroscopy for low-risk pelvicaliceal tumors. 1
• Second-look ureteroscopy within 8 weeks after initial endoscopic treatment is mandatory to assess for residual or recurrent disease (present in up to 50% of patients). 1
• Percutaneous management can be considered for low-risk UTUC in the renal pelvis or lower caliceal system inaccessible via flexible ureteroscopy. 1
• Distal ureterectomy with ureteroneocystostomy for distal ureteral tumors (ipsilateral upper tract recurrence 0-18% vs. 25-85% with endoscopic approaches). 1

High-risk UTUC (larger, high-grade lesions):

• Radical nephroureterectomy with bladder cuff excision and regional lymphadenectomy is the standard treatment. 1, 4
• For distal ureteral tumors, distal ureterectomy with ureteral reimplantation is preferred if clinically feasible. 1

Adjuvant Therapy for UTUC

• No adjuvant therapy for lesions pT1 or less; serial follow-up of urothelial tracts is recommended. 1
• For more extensive disease (pT2 or higher), consider systemic adjuvant chemotherapy depending on patient tolerance and comorbidities. 1

Advanced/Metastatic Urothelial Carcinoma

First-Line Treatment

Cisplatin-eligible patients:

• Enfortumab vedotin plus pembrolizumab is preferred over platinum-based chemotherapy (median OS 31.5 vs. 16.1 months; HR 0.47). 1
• Alternative: Nivolumab plus gemcitabine-cisplatin for up to 6 cycles, followed by maintenance nivolumab (median OS 21.7 vs. 18.9 months; HR 0.78). 1

Cisplatin-ineligible patients:

• Enfortumab vedotin plus pembrolizumab remains the preferred option. 1

Maintenance Therapy

• For patients achieving clinical benefit with first-line platinum-based chemotherapy without disease progression, maintenance avelumab improves PFS and OS. 1

Second-Line and Beyond

After disease progression:

• Pembrolizumab (Level I, Grade A evidence). 1
• Erdafitinib for tumors with FGFR DNA fusions and mutations (Level I, Grade A evidence). 1
• Enfortumab vedotin (Level I, Grade A evidence). 1
• Sacituzumab govitecan (Level III, Grade B evidence). 1

Important Toxicity Considerations

• Grade 3 treatment-related adverse events occur in 55.9% with enfortumab vedotin-pembrolizumab vs. 69.5% with platinum-based chemotherapy. 1
• Most common grade ≥3 adverse events with enfortumab vedotin: skin reactions (15.5%), peripheral neuropathy (6.8%), hyperglycemia (6.1%). 1
• Peripheral neuropathy (grade 1-2) occurs in 56.4% of patients on enfortumab vedotin-pembrolizumab. 1
• Treatment discontinuation due to adverse events: 35.0% with enfortumab vedotin-pembrolizumab vs. 18.5% with chemotherapy. 1

Nonurothelial Carcinomas of the Bladder

Pure Squamous Cell Carcinoma

• Cystectomy, radiotherapy, or agents commonly used for squamous cell carcinoma at other sites (5-FU, taxanes, methotrexate). 1

Adenocarcinoma

• Radical or segmental cystectomy. 1
• Conventional chemotherapy (e.g., MVAC) for urothelial carcinoma is not effective. 1

Small Cell Component

• Neoadjuvant chemotherapy using small-cell lung cancer regimens followed by local treatment (cystectomy or radiotherapy). 1

Urachal Carcinoma

• Requires complete urachal resection with en-bloc resection of urachal ligament and umbilicus. 1
• Conventional chemotherapy for urothelial carcinoma is not effective. 1

Prostatic Urothelial Carcinoma

Limited to Prostatic Urethra (No Acinar/Stromal Invasion)

• BCG and transurethral resection of prostate (TURP) with follow-up similar to superficial bladder disease. 1

Ductal Acini or Stromal Invasion

• Cystoprostatectomy with or without urethrectomy is required for stromal invasion. 1
• Neoadjuvant chemotherapy may be considered for stromal invasion based on extrapolation from bladder cancer data. 1
• Alternative for ductal acini invasion only: TURP and BCG. 1
• Recurrences after TURP and BCG are treated with cystoprostatectomy with or without urethrectomy. 1