What is the optimal adjuvant treatment for a cisplatin‑eligible patient with urothelial carcinoma after radical cystectomy with pathology pT2N2 (muscle‑invasive disease with multiple regional lymph node metastases)?

Optimal Adjuvant Treatment for pT2N2 Cisplatin-Eligible Urothelial Carcinoma Post-Cystectomy

For a cisplatin-eligible patient with pT2N2 urothelial carcinoma after radical cystectomy, adjuvant nivolumab 240 mg IV every 2 weeks (or 480 mg IV every 4 weeks) for up to 1 year is the optimal treatment, initiated within 90 days of surgery. 1

Primary Recommendation: Adjuvant Nivolumab

Nivolumab is the only checkpoint inhibitor with FDA approval and Level A evidence for this indication, demonstrating superior disease-free survival compared to observation in the CheckMate 274 trial. 1, 2

• The CheckMate 274 trial showed median disease-free survival of 21.9 months versus 11.0 months with placebo (HR 0.71,95% CI 0.58-0.86) in the intention-to-treat population. 2
• Overall survival benefit was also demonstrated: median OS of 75.0 months with nivolumab versus 50.1 months with placebo (HR 0.83,95% CI 0.67-1.02). 2
• The benefit is substantially greater in patients with PD-L1 ≥1% tumor expression, with median DFS of 55.5 months versus 8.4 months with placebo (HR 0.58,95% CI 0.42-0.79). 2
• Treatment should be initiated within 90 days of cystectomy for maximum benefit, though some benefit persists even after 90 days. 1

Alternative: Adjuvant Platinum-Based Chemotherapy

If nivolumab is not accessible or the patient prefers chemotherapy, administer a minimum of 3-4 cycles of cisplatin-based combination chemotherapy using either gemcitabine plus cisplatin or dose-dense MVAC (ddMVAC). 3, 1, 4

• Meta-analysis of 9 trials (N=945 patients) demonstrated a 23% risk reduction for death (HR 0.77,95% CI 0.59-0.99, P=0.049) and improved disease-free survival (HR 0.66,95% CI 0.45-0.91, P=0.014) with adjuvant chemotherapy. 3, 4, 2
• Patients with node-positive disease (like this pT2N2 case) derive even greater benefit from adjuvant therapy. 3, 4, 2
• The NCCN designates adjuvant chemotherapy as a Category 2A recommendation for patients with high-risk pathology (pT3, pT4, or node-positive disease) who did not receive neoadjuvant therapy. 3, 4

Specific Chemotherapy Regimens

Gemcitabine plus cisplatin: 3, 4

• Both 21-day and 28-day schedules are acceptable, with better dose compliance potentially achieved using the 21-day schedule. 3
• This regimen has Category 1 evidence showing equivalence to conventional MVAC in advanced disease with less toxicity. 3

Dose-dense MVAC (ddMVAC) with growth factor support: 3, 4

• Preferred over standard MVAC based on Category 1 evidence showing better tolerability and greater effectiveness than conventional MVAC. 3
• Traditional dose and schedule for MVAC is no longer recommended. 3

Critical Caveats

Carboplatin is NOT an Acceptable Substitute

Carboplatin should never be substituted for cisplatin in the perioperative setting, as it has not demonstrated a survival benefit. 3, 4

Renal Function Assessment

• Verify cisplatin eligibility by calculating actual creatinine clearance using the Cockcroft-Gault equation or 24-hour urine collection, as serum creatinine significantly underestimates renal impairment, especially in elderly patients. 4
• The threshold for full-dose cisplatin-based chemotherapy is CrCl ≥60 mL/min. 4
• For patients with borderline renal function, split-dose cisplatin administration (such as 35 mg/m² on days 1 and 2 or days 1 and 8) may be considered, though relative efficacy remains undefined. 3

Node-Positive Disease Carries High Recurrence Risk

Node-positive disease (N2 in this case) carries approximately 70% systemic recurrence risk without additional treatment, emphasizing the critical need for adjuvant therapy. 1

Adjuvant Radiation Therapy Consideration

For patients who cannot receive systemic therapy (either immunotherapy or chemotherapy), consider adjuvant radiation therapy (45-50.4 Gy) given the high pelvic failure rates of 40-45% at 5 years in patients with pT3/pT4 disease or positive lymph nodes. 3, 4

• One randomized study of 236 patients with pT3a-pT4a bladder cancer demonstrated improvement in 5-year disease-free survival and local control compared with surgery alone. 3
• A more recent randomized phase II trial showed significant improvement in local control for chemoradiation (3-year local control of 96% vs 69%), though improvement in DFS and OS was not significant. 3

Treatment Algorithm

1. Confirm cisplatin eligibility: Assess renal function (CrCl ≥60 mL/min), hearing, neuropathy, and performance status. 4, 2

2. First-line recommendation: Adjuvant nivolumab 240 mg IV every 2 weeks or 480 mg IV every 4 weeks for up to 1 year, initiated within 90 days of cystectomy. 1

3. If nivolumab is not accessible: Administer 3-4 cycles of gemcitabine plus cisplatin or ddMVAC. 3, 1, 4

4. If cisplatin-ineligible: Obtain PD-L1 testing and consider nivolumab if PD-L1 ≥1%, particularly if the patient declined or is unfit for platinum-based chemotherapy. 2

5. If neither systemic therapy option is feasible: Consider adjuvant radiation therapy. 3, 4

Important Contraindications

Do not substitute durvalumab for nivolumab in the adjuvant setting, as durvalumab lacks supporting evidence for this indication. 1