What is better for a patient with bladder cancer, high Charlson Comorbidity Index (CCI) and pT2 stage after Neoadjuvant Chemotherapy (NACT), radical cystectomy (RC) or systemic therapy?

Management of pT2 Bladder Cancer After NACT in Patients with High Charlson Comorbidity Index

For a patient with pT2 bladder cancer after neoadjuvant chemotherapy and high Charlson Comorbidity Index, proceed with radical cystectomy as soon as possible rather than additional systemic therapy, as pT2 disease represents residual muscle-invasive disease with significantly worse survival outcomes that require definitive local control. 1

Rationale for Radical Cystectomy Over Additional Systemic Therapy

Pathologic Stage Determines Prognosis After NACT

• Patients with residual ≥pT2 disease after neoadjuvant chemotherapy have dramatically inferior 5-year overall survival (38%) compared to those achieving <pT2 (87%), with a hazard ratio of 6.79 for all-cause death. 2
• The presence of residual muscle-invasive disease (≥pT2) after NACT indicates chemotherapy-resistant tumor biology that is unlikely to respond to additional systemic therapy. 2
• Five-year overall survival for patients with <pT2 residual disease versus ≥pT2 is 87% versus 38% (p<0.001), demonstrating that surgical extirpation remains the only curative option for residual muscle-invasive disease. 2

Timing of Surgery is Critical

• Radical cystectomy should be performed as soon as possible following completion of and recovery from neoadjuvant chemotherapy. 1
• Delaying radical cystectomy beyond 10 weeks after the last cycle of neoadjuvant chemotherapy is independently associated with increased overall mortality (p=0.027) and cancer-specific mortality (p=0.004). 3
• Patients with higher Charlson Comorbidity Index are more likely to experience prolonged time to cystectomy, but this delay must be minimized as it adversely affects survival outcomes. 3

High CCI Does Not Preclude Surgery

• While the ASA score and Charlson Comorbidity Index both predict perioperative mortality, the 90-day perioperative mortality after radical cystectomy is 7.9% overall, which is acceptable given the alternative of disease progression. 4
• The ASA score shows superior predictive ability for perioperative mortality compared to CCI (AUC 76.1 vs 73.8), and should be used for surgical risk stratification rather than as an absolute contraindication. 4
• Patients with significant comorbidities who cannot tolerate radical cystectomy should be considered for trimodal bladder-sparing therapy (maximal TURBT + chemotherapy + radiation), not additional systemic chemotherapy alone. 1

Why Additional Systemic Therapy is Not Recommended

No Evidence for Sequential Chemotherapy in This Setting

• Adjuvant chemotherapy is indicated only for patients with high-risk pathologic features (pT3/T4 or N+) who did not receive neoadjuvant chemotherapy. 1
• Patients with pT2 disease and no nodal involvement or lymphovascular invasion after cystectomy are considered lower risk and are not recommended to receive adjuvant chemotherapy. 1
• There is no established role for additional systemic therapy in patients who have already received neoadjuvant chemotherapy and have residual pT2 disease—the standard is to proceed directly to surgery. 1

Carboplatin is Not an Alternative

• Carboplatin-based regimens should not be prescribed for clinically resectable bladder cancer, and patients ineligible for cisplatin-based therapy should proceed directly to definitive locoregional therapy (surgery or radiation). 1
• There are no data to support perioperative chemotherapy for patients who are not cisplatin-eligible. 1

Treatment Algorithm for This Clinical Scenario

Step 1: Assess Surgical Candidacy

• Evaluate using ASA score rather than CCI alone for perioperative risk assessment. 4
• Obtain multidisciplinary input including anesthesia, medical oncology, and urology. 1

Step 2: If Surgical Candidate

• Proceed with radical cystectomy with bilateral pelvic lymphadenectomy within 10 weeks of last chemotherapy cycle. 1, 3
• Minimum lymph node dissection should include common iliac, external iliac, internal iliac, and obturator nodes. 5
• Target removal of at least 19 lymph nodes, as each additional node removed trends toward improved survival (HR 0.97 per node, p=0.056). 2

Step 3: If Not a Surgical Candidate Due to Comorbidities

• Consider trimodal bladder-sparing therapy with maximal TURBT, concurrent chemoradiation (45-50.4 Gy), and close surveillance. 1
• This approach is appropriate for patients who desire bladder preservation or have significant comorbid conditions precluding major surgery. 1
• Trimodal therapy achieves 5-year overall survival of 50-60% in appropriately selected patients with complete TURBT, unifocal tumors <6cm, and absence of hydronephrosis. 1

Step 4: Post-Cystectomy Management

• No adjuvant chemotherapy is indicated for isolated pT2N0 disease without lymphovascular invasion. 1
• If final pathology reveals pT3/T4 or node-positive disease, then adjuvant cisplatin-based chemotherapy should be offered. 1

Common Pitfalls to Avoid

• Do not delay surgery beyond 10 weeks from last chemotherapy cycle while attempting additional systemic therapy, as this significantly worsens survival. 3
• Do not substitute carboplatin for cisplatin in any perioperative setting, as it has not demonstrated survival benefit. 1
• Do not give adjuvant chemotherapy for pT2N0 disease after neoadjuvant chemotherapy and cystectomy, as this population is considered lower risk. 1
• Do not use CCI alone to exclude patients from surgery—use comprehensive assessment including ASA score and multidisciplinary evaluation. 4
• Do not offer systemic therapy alone as definitive treatment for residual muscle-invasive disease, as this is not curative. 1, 2