What is the management of high-grade invasive urothelial carcinoma?

Management of High-Grade Invasive Urothelial Carcinoma

Radical cystectomy with bilateral pelvic lymphadenectomy preceded by neoadjuvant cisplatin-based combination chemotherapy is the standard of care for muscle-invasive (cT2-T4a) high-grade urothelial carcinoma. 1, 2

Neoadjuvant Chemotherapy (Preferred Approach)

Neoadjuvant chemotherapy must be administered before radical cystectomy for all cisplatin-eligible patients with cT2-T3 disease, as this provides superior evidence compared to adjuvant therapy. 1, 3, 2

Recommended Regimens:

• DDMVAC (dose-dense methotrexate, vinblastine, doxorubicin, cisplatin) with growth factor support for 3-4 cycles is the preferred regimen (Category 1 evidence). 3
• Gemcitabine-cisplatin for 4 cycles is a reasonable alternative (Category 1 evidence). 3
• Durvalumab added to gemcitabine-cisplatin (perioperative treatment) represents the new standard of care for cisplatin-eligible patients, with 2-year event-free survival of 67.8% vs 59.8% without durvalumab (HR 0.68, p<0.001) and overall survival of 82.2% vs 75.2% (HR 0.75, p=0.01). 2

Survival Benefit:

Two large randomized trials and meta-analysis demonstrate a 5% absolute survival benefit at 5 years with neoadjuvant chemotherapy. 1, 3, 2

Radical Cystectomy

Cystectomy must be performed within 3 months of diagnosis if no neoadjuvant therapy is given, as delays beyond this timeframe negatively impact outcomes. 1, 3

Surgical Technique:

In males: Remove bladder, prostate, seminal vesicles, proximal vas deferens, and proximal urethra (cystoprostatectomy). 1

In females: Remove bladder; consider organ-sparing (uterus, ovaries, fallopian tubes) based on disease location and characteristics, though anterior vaginal wall removal may be necessary for adequate margins. 1

Mandatory Pelvic Lymphadenectomy:

Bilateral pelvic lymph node dissection is an integral component and must include at minimum: common iliac, internal iliac, external iliac, and obturator nodes (standard lymphadenectomy). 1

Extended lymphadenectomy yields superior outcomes: More extensive dissection including common iliac or lower para-aortic/para-caval nodes increases positive node detection, improves survival, and reduces pelvic recurrence rates. 1, 4 Over 35% of positive lymph nodes are found in nonregional distribution, supporting extended dissection even in low-stage or post-neoadjuvant settings. 4

Alternative Surgical Approaches (Highly Selected Cases)

Partial Cystectomy:

Reserved for <5% of cases with cT2 disease meeting ALL criteria: 1

• Solitary lesion amenable to segmental resection with adequate margins
• No carcinoma in situ on random biopsies
• Must receive neoadjuvant cisplatin-based chemotherapy
• Requires bilateral pelvic lymphadenectomy

Bladder Preservation:

Maximal TURBT with concurrent chemoradiotherapy is reserved for patients meeting ALL criteria: 1

• Smaller solitary tumors
• Negative lymph nodes
• No carcinoma in situ
• No tumor-related hydronephrosis
• Good pre-treatment bladder function

This approach is primarily for patients medically unfit for surgery or those refusing cystectomy. 1, 2

Adjuvant Therapy (When Neoadjuvant Not Given)

Adjuvant Chemotherapy:

Consider adjuvant cisplatin-based chemotherapy for patients with high-risk pathologic features (≥pT3, pT4, or N+) after cystectomy who did not receive neoadjuvant therapy, though evidence is insufficient for routine use. 1, 3

Adjuvant Immunotherapy:

Adjuvant nivolumab should be administered to patients with high-risk features after cystectomy (with or without neoadjuvant chemotherapy): 1

• Eligible patients: ypT2-ypT4 or N+ after neoadjuvant chemotherapy, OR pT3-pT4a or N+ without neoadjuvant chemotherapy
• Dosing: Nivolumab every 2 weeks for 1 year
• Initiate within 90 days of cystectomy for maximum benefit (though benefit persists beyond 90 days)

Metastatic Disease (Stage IV)

Pembrolizumab combined with enfortumab vedotin is indicated for locally advanced or metastatic urothelial cancer, demonstrating: 5

• Median overall survival: 31.5 months vs 16.1 months with chemotherapy (HR 0.47, p<0.0001)
• Median progression-free survival: 12.5 months vs 6.3 months (HR 0.45, p<0.0001)
• Objective response rate: 68% vs 44% (p<0.0001)

Alternative platinum-based regimens for metastatic disease: 1

• Methotrexate-vinblastine-doxorubicin-cisplatin (MVAC)
• Gemcitabine-cisplatin

For cisplatin-ineligible patients, carboplatin-based regimens, single-agent taxane, or gemcitabine may be used for palliation. 1

Post-Treatment Surveillance

Follow-up protocol after radical cystectomy: 3

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

For bladder preservation patients: 1, 2

• Cystoscopy and urine cytology every 3 months during first 2 years
• Every 6 months thereafter

Critical Pitfalls to Avoid

Do not delay cystectomy beyond 3 months from diagnosis if no therapy is given, as this worsens outcomes. 1, 3

Do not omit neoadjuvant chemotherapy in cisplatin-eligible patients, as it provides superior evidence compared to adjuvant approaches. 3, 2

Do not perform inadequate lymphadenectomy: Extended dissection detects more positive nodes even in low-stage disease and post-neoadjuvant settings. 1, 4

Do not assume low pathologic stage excludes nodal metastases: Positive lymph nodes occur in pT2 and below disease, detected only with extended lymphadenectomy. 4