What are the treatment options for a patient with N1 lymph node involvement after radical cystectomy who has already received Neoadjuvant Chemotherapy (NACT)?

Treatment Options for N1 Lymph Node Involvement After Neoadjuvant Chemotherapy and Radical Cystectomy

For patients with N1 lymph node involvement after receiving neoadjuvant chemotherapy and radical cystectomy, adjuvant nivolumab immunotherapy is the recommended treatment based on the CheckMate274 trial, which demonstrated significantly improved disease-free survival in this exact patient population. 1

Primary Recommendation: Adjuvant Immunotherapy

• Adjuvant nivolumab should be administered every 2 weeks for 1 year to patients with ypT2-ypT4 or N+ disease who received neoadjuvant cisplatin-based chemotherapy prior to cystectomy. 1

• Treatment should ideally be initiated within 90 days of cystectomy for maximum benefit, though retrospective analysis shows some benefit even when started after 90 days. 1

• This represents a paradigm shift from traditional approaches, as the CheckMate274 trial (published 2021) specifically included patients who had already received neoadjuvant chemotherapy and still had high-risk features at cystectomy. 1

Alternative Option: Adjuvant Chemotherapy (Lower Priority)

While adjuvant nivolumab is now the preferred approach, adjuvant cisplatin-based chemotherapy remains an option, particularly if immunotherapy is contraindicated or unavailable:

• Minimum of 3 cycles of cisplatin-based combination chemotherapy (ddMVAC, gemcitabine/cisplatin, or CMV) can be considered. 1, 2

• However, the evidence for additional chemotherapy after neoadjuvant chemotherapy is weak. A National Cancer Database study of 705 patients with pT3/4 and/or pN+ disease after neoadjuvant chemotherapy showed no survival advantage with adjuvant chemotherapy (median survival 23 vs 20 months, p=0.52). 3

• Additional chemotherapy after neoadjuvant chemotherapy does not appear beneficial in most cases, as patients who progress through neoadjuvant therapy are unlikely to respond to more of the same treatment approach. 3

Adjuvant Radiotherapy Consideration

Adjuvant pelvic radiotherapy should be strongly considered for N1 disease, especially with additional high-risk features:

• Recommended dose: 45-50.4 Gy to the cystectomy bed and pelvic lymph nodes, with potential boost to 54-60 Gy for areas of extranodal extension if normal tissue constraints allow. 1, 2

• Radiation should NOT be given concurrently with chemotherapy in the adjuvant setting; if both are used, sandwich the radiation between chemotherapy cycles. 2

• This addresses the 40-45% pelvic failure rate at 5 years seen in node-positive patients. 1

Critical Clinical Algorithm

1. Verify adequate lymphadenectomy was performed (minimum 19 lymph nodes removed including common iliac, external iliac, internal iliac, and obturator nodes). 4

2. Assess patient eligibility for adjuvant nivolumab (performance status, absence of autoimmune contraindications). 1

3. Initiate nivolumab within 90 days of cystectomy if eligible. 1

4. If nivolumab is contraindicated, consider adjuvant radiotherapy (45-50.4 Gy) rather than additional chemotherapy, given the lack of benefit shown for chemotherapy after neoadjuvant treatment. 1, 2, 3

5. Do NOT routinely add adjuvant chemotherapy if the patient already received neoadjuvant chemotherapy, as this has not shown survival benefit. 3

Important Caveats and Pitfalls

• The UK practice survey revealed that 45% of clinicians would not give any adjuvant treatment after neoadjuvant chemotherapy and cystectomy in node-positive patients, highlighting the controversy and lack of consensus before the CheckMate274 trial. 5

• Patients with lymph node density <20% may have better outcomes with adjuvant treatment compared to those with higher nodal burden. 6

• Approximately 70% of node-positive patients will develop systemic recurrence despite treatment, with most occurring within 2-3 years. 1

• Performance status and response to neoadjuvant chemotherapy are key factors in determining whether any adjuvant therapy is appropriate. 5

• Carboplatin should never be substituted for cisplatin in the perioperative setting as it has not demonstrated survival benefit. 1