Perioperative Muscle-Invasive Bladder Cancer

Authored by Natalia Gandur, published on 2026-08-13 17:28:44.0

Confirm Cystectomy-Intent MIBC

Confirm established bladder-primary MIBC, cT2–T4a, cN0–N1, M0, with curative-intent radical cystectomy and pelvic lymph-node dissection planned. Confirm that the patient is entering a perioperative, cystectomy-intent MIBC pathway. Required clinical context: - Histologically established bladder cancer with muscle-invasive disease. - Clinical stage cT2–T4a, cN0–N1, M0. - No distant metastatic disease. - Candidate for curative-intent radical cystectomy with pelvic lymph-node dissection. - Adequate staging to exclude disease requiring a locally advanced or metastatic pathway. Detailed treatment-specific eligibility, organ-function assessment, laboratory requirements, and toxicity screening are addressed at subsequent treatment-selection nodes.
- Predominantly urothelial histology?
  
  Determine whether urothelial carcinoma is the predominant histology and the patient should remain within this perioperative urothelial MIBC pathway. Answer YES when urothelial carcinoma is the predominant histology. For evidence-fit with KEYNOTE-B15/EV-304, predominant urothelial histology was defined as ≥50% urothelial carcinoma. Urothelial carcinoma with partial squamous, glandular, or other divergent differentiation can remain within the urothelial pathway, while recognizing that clinically significant variant histology may warrant multidisciplinary or expert review. Answer NO when the tumor is predominantly or purely non-urothelial, including: - Pure squamous cell carcinoma. - Pure adenocarcinoma. - Pure neuroendocrine/small-cell carcinoma. - Other predominant non-urothelial histologies requiring histology-specific management. Clinically meaningful neuroendocrine/small-cell differentiation should prompt expert review rather than automatic application of standard urothelial perioperative regimens.
  - No — Other / histology-specific
    - Open: Histology-Specific Bladder Cancer Pathway
      
      Exit this urothelial MIBC pathway when predominant histology requires a dedicated treatment strategy. Use a histology-specific or expert pathway for predominant non-urothelial disease. Examples include: - Pure squamous cell carcinoma. - Pure adenocarcinoma. - Pure neuroendocrine/small-cell carcinoma. - Other predominant non-urothelial histologies. Management should be individualized according to histology, stage, resectability, and multidisciplinary review rather than extrapolated automatically from urothelial perioperative trials.
  - Yes — Predominantly urothelial
    - Cisplatin suitable?
      
      Assess whether cisplatin-based perioperative therapy is clinically feasible based on organ function, performance status, comorbidities, and treatment-related toxicity risk. Assess cisplatin suitability using the clinical factors that meaningfully affect treatment feasibility: - ECOG performance status. - Renal function, including GFR or creatinine clearance. - Hearing impairment. - Peripheral neuropathy. - Cardiac function and clinically significant comorbidity. Common consensus criteria used in urothelial cancer identify cisplatin ineligibility when one or more major limiting factors are present, including impaired performance status, reduced renal function, grade ≥2 hearing loss, grade ≥2 peripheral neuropathy, or NYHA class III heart failure. Do not apply a GFR threshold of 60 mL/min as an automatic exclusion in this perioperative pathway. In NIAGARA, patients with eGFR ≥40 mL/min were eligible, with split-dose cisplatin permitted for eGFR 40–60 mL/min. Answer YES when cisplatin-based perioperative treatment is clinically feasible. Answer NO when organ function, functional status, comorbidity, or toxicity risk makes cisplatin-based treatment inappropriate.
      - Cisplatin-suitable
        
        Select perioperative strategy
        
        For cisplatin-suitable MIBC, select an evidence-supported perioperative strategy based on efficacy, toxicity, patient fit, surgical timing, access, and patient preference. Discuss the available evidence-supported perioperative strategies: - Perioperative enfortumab vedotin + pembrolizumab. - Perioperative durvalumab + gemcitabine/cisplatin. - Neoadjuvant cisplatin-based combination chemotherapy followed by radical cystectomy. Selection should integrate: - Clinical fitness and organ function. - Treatment-specific toxicity considerations. - Surgical timing and ability to complete curative-intent treatment. - Patient priorities and preferences. - Treatment availability and logistics. Do not assume a universal hierarchy between perioperative EV + pembrolizumab and durvalumab + gemcitabine/cisplatin. These strategies were established in separate phase III trials and have not been directly compared with each other. Clinical trial participation should remain visible as a separate free-standing option.
        
        Perioperative durvalumab + gemcitabine/cisplatin
        
        Administer neoadjuvant durvalumab + gemcitabine/cisplatin, followed by radical cystectomy and protocol-defined adjuvant durvalumab. Use this perioperative strategy in an appropriate cisplatin-suitable, immunotherapy-eligible patient with cystectomy-intent MIBC. The NIAGARA strategy consists of: - Neoadjuvant durvalumab combined with gemcitabine/cisplatin. - Radical cystectomy with pelvic lymph-node dissection. - Adjuvant durvalumab after adequate postoperative recovery. NIAGARA demonstrated significant improvements in event-free survival and overall survival compared with neoadjuvant gemcitabine/cisplatin followed by cystectomy alone. Patient selection should account for cisplatin suitability, immune-checkpoint inhibitor suitability, organ function, treatment-related toxicity risk, and the ability to proceed to definitive surgery without avoidable delay. Dose & toxicity management: - Durvalumab is not dose-reduced. Withhold or permanently discontinue according to the severity of immune-mediated toxicity. - Modify or delay gemcitabine/cisplatin according to hematologic toxicity, renal function, and regimen-specific criteria. - In selected patients with eGFR 40–60 mL/min, split-dose cisplatin may be used as in NIAGARA. - Monitor closely for cytopenias, renal dysfunction, electrolyte abnormalities, hearing loss, neuropathy, and immune-mediated adverse events. - Treatment-related toxicity should be managed promptly to avoid unnecessary delay of definitive cystectomy.
        
        Restaging and Surgical Reassessment
        
        After neoadjuvant or perioperative treatment, reassess disease status and confirm that curative-intent radical cystectomy remains feasible. Reassess the patient after completion of the planned neoadjuvant phase and before radical cystectomy. Review: - Interval clinical and radiographic disease status. - Evidence of local or distant progression. - Recovery from treatment-related toxicity. - Performance status and organ function relevant to surgery. - Continued surgical candidacy and curative intent. If disease remains resectable and the patient remains an appropriate surgical candidate, proceed toward radical cystectomy without avoidable delay. If interval progression may preclude curative cystectomy, transition to the subsequent progression decision node and multidisciplinary reassessment. Do not use radiographic response alone to omit planned radical cystectomy in an otherwise appropriate cystectomy-intent patient.
        
        Has progression precluded curative cystectomy?
        
        Determine whether interval disease progression still permits definitive radical cystectomy with curative intent. Assess restaging findings after neoadjuvant or perioperative treatment. Answer YES when interval progression means curative-intent cystectomy is no longer appropriate, including: - New distant metastatic disease. - Locoregional progression that is no longer surgically resectable with curative intent. - Clinical deterioration that fundamentally changes the treatment goal. Answer NO when disease remains amenable to curative-intent radical cystectomy and the patient remains an appropriate surgical candidate. Apparent clinical or radiographic response alone should not be used to omit planned definitive local therapy outside an appropriate bladder-preservation strategy or clinical trial.
        
        Yes- Progression precludes cystectomy
        
        Open: Locally Advanced / Metastatic Urothelial Carcinoma Pathway
        
        Exit the cystectomy-intent pathway when progression prevents curative surgery and transition to advanced-disease management. If interval progression precludes curative radical cystectomy: - Confirm the extent and pattern of progression. - Reassess treatment intent in a multidisciplinary setting. - Transition to the appropriate locally advanced or metastatic urothelial carcinoma pathway. - Base subsequent systemic treatment on prior perioperative exposure, current disease extent, clinical status, and treatment-specific eligibility. Do not continue along the curative cystectomy pathway once definitive surgery is no longer clinically appropriate.
        
        No- Cystectomy remains feasible
        
        Radical cystectomy + pelvic lymph-node dissection
        
        Proceed with definitive radical cystectomy and pelvic lymph-node dissection when curative-intent surgery remains clinically appropriate. Proceed to definitive radical cystectomy with pelvic lymph-node dissection after completion of the planned neoadjuvant phase and confirmation that disease remains surgically manageable. Key principles: - Avoid unnecessary delay once the patient is ready for definitive surgery. - Confirm adequate recovery from neoadjuvant treatment and continued surgical fitness. - Perform pelvic lymph-node dissection as part of definitive surgical management. - Do not omit cystectomy solely because of an apparent clinical or radiographic response to neoadjuvant therapy. Postoperative systemic management depends on the perioperative strategy already received, recovery from surgery, and whether a protocol-defined adjuvant component is planned.
        
        Is a protocol-defined adjuvant component planned?
        
        Determine whether the perioperative regimen selected before cystectomy includes a planned post-cystectomy systemic-treatment phase. Answer YES when the selected perioperative strategy includes a protocol-defined adjuvant phase after radical cystectomy. This includes: - Perioperative enfortumab vedotin + pembrolizumab. - Perioperative durvalumab + gemcitabine/cisplatin followed by adjuvant durvalumab. Answer NO when no regimen-defined adjuvant phase was established before surgery, including: - Neoadjuvant cisplatin-based chemotherapy alone. - Upfront radical cystectomy without a perioperative systemic regimen. This decision identifies whether to complete the previously selected perioperative strategy or transition to postoperative risk-based management.
        
        Planned adjuvant phase
        
        Complete planned adjuvant component
        
        After adequate postoperative recovery, resume and complete the adjuvant phase defined by the perioperative regimen unless recurrence or unacceptable toxicity intervenes. Continue the postoperative component of the perioperative strategy selected before cystectomy. For perioperative enfortumab vedotin + pembrolizumab: - Resume the regimen-defined adjuvant EV + pembrolizumab phase after adequate surgical recovery. - Continue pembrolizumab according to the applicable perioperative schedule. - Use the schedule corresponding to the patient’s original cisplatin-eligible or cisplatin-ineligible treatment pathway. For perioperative durvalumab + gemcitabine/cisplatin: - Continue single-agent durvalumab after cystectomy. - Durvalumab is administered every 4 weeks for up to 8 postoperative cycles. Do not dose-reduce pembrolizumab or durvalumab for immune-mediated toxicity; withhold or discontinue according to toxicity severity. EV may be interrupted or dose-reduced for treatment-related toxicity. Discontinue or modify treatment for recurrence, unacceptable toxicity, or other clinical circumstances that make continuation inappropriate.
        
        Surveillance / Follow-Up and Postoperative Management Handoff
        
        Transition to risk-adapted oncologic surveillance, functional follow-up, and survivorship care after completion of perioperative treatment. After completion of planned perioperative therapy: - Monitor for local, nodal, and distant recurrence.- Continue functional follow-up after urinary diversion.- Monitor renal function and treatment-related late toxicity.- Address urinary, metabolic, sexual, rehabilitation, and survivorship needs.- Individualize surveillance intensity according to pathologic risk, patient fitness, and competing health risks. EAU provides a practice-based post-cystectomy surveillance framework rather than a single proven standardized schedule; CT imaging every 6 months through year 3 followed by annual imaging is one suggested approach.
        
        No planned adjuvant phase
        
        Open: Post-Cystectomy Risk & ctDNA MRD Pathway
        
        Transition to postoperative risk-based management when no regimen-defined adjuvant phase was established before cystectomy. Use the dedicated postoperative pathway to integrate: - Prior neoadjuvant systemic therapy. - Final pathologic stage and nodal status. - Surgical recovery and organ function. - Eligibility for adjuvant cisplatin-based chemotherapy when no neoadjuvant systemic therapy was given. - High-risk adjuvant immunotherapy considerations. - Serial ctDNA MRD assessment and ctDNA-guided adjuvant therapy. - Surveillance or clinical-trial options. Current FDA approval permits adjuvant atezolizumab after cystectomy for adults with MIBC who have ctDNA MRD detected by an FDA-authorized test. Do not assume routine sequential checkpoint-inhibitor therapy after prior perioperative pembrolizumab or durvalumab; this remains an evidence-gap requiring individualized expert review.
        
        Cisplatin-based neoadjuvant chemotherapy
        
        Administer an evidence-based cisplatin-containing combination regimen before radical cystectomy in an appropriate cisplatin-suitable patient. Neoadjuvant cisplatin-based combination chemotherapy remains an evidence-supported option for cystectomy-intent MIBC. Common established regimens include: - Dose-dense MVAC (ddMVAC). - Gemcitabine/cisplatin. The VESPER phase III trial supports ddMVAC as a highly active neoadjuvant option; in the neoadjuvant subgroup, 5-year overall survival favored ddMVAC over gemcitabine/cisplatin. Select the chemotherapy regimen according to patient fitness, renal function, comorbidities, toxicity profile, treatment logistics, and local practice. Do not substitute carboplatin-containing chemotherapy for cisplatin as neoadjuvant therapy solely because a patient is cisplatin-ineligible. Proceed to definitive surgery after completion of neoadjuvant treatment provided curative-intent cystectomy remains feasible. Dose & toxicity management: - Use regimen-specific treatment delays and dose modifications for clinically significant hematologic or non-hematologic toxicity. - Reassess cisplatin feasibility with evolving renal dysfunction, hearing loss, neuropathy, or declining performance status. - Split-dose cisplatin may be considered in selected patients with borderline renal function when clinically appropriate. - Maintain appropriate growth-factor support when using dose-dense MVAC. - Do not substitute carboplatin for cisplatin as neoadjuvant therapy solely because cisplatin becomes unsuitable; reassess the treatment strategy instead.
        
        Restaging and Surgical Reassessment
        
        After neoadjuvant or perioperative treatment, reassess disease status and confirm that curative-intent radical cystectomy remains feasible. Reassess the patient after completion of the planned neoadjuvant phase and before radical cystectomy. Review: - Interval clinical and radiographic disease status. - Evidence of local or distant progression. - Recovery from treatment-related toxicity. - Performance status and organ function relevant to surgery. - Continued surgical candidacy and curative intent. If disease remains resectable and the patient remains an appropriate surgical candidate, proceed toward radical cystectomy without avoidable delay. If interval progression may preclude curative cystectomy, transition to the subsequent progression decision node and multidisciplinary reassessment. Do not use radiographic response alone to omit planned radical cystectomy in an otherwise appropriate cystectomy-intent patient.
        
        Has progression precluded curative cystectomy?
        
        Determine whether interval disease progression still permits definitive radical cystectomy with curative intent. Assess restaging findings after neoadjuvant or perioperative treatment. Answer YES when interval progression means curative-intent cystectomy is no longer appropriate, including: - New distant metastatic disease. - Locoregional progression that is no longer surgically resectable with curative intent. - Clinical deterioration that fundamentally changes the treatment goal. Answer NO when disease remains amenable to curative-intent radical cystectomy and the patient remains an appropriate surgical candidate. Apparent clinical or radiographic response alone should not be used to omit planned definitive local therapy outside an appropriate bladder-preservation strategy or clinical trial.
        
        Yes- Progression precludes cystectomy
        
        Open: Locally Advanced / Metastatic Urothelial Carcinoma Pathway
        
        Exit the cystectomy-intent pathway when progression prevents curative surgery and transition to advanced-disease management. If interval progression precludes curative radical cystectomy: - Confirm the extent and pattern of progression. - Reassess treatment intent in a multidisciplinary setting. - Transition to the appropriate locally advanced or metastatic urothelial carcinoma pathway. - Base subsequent systemic treatment on prior perioperative exposure, current disease extent, clinical status, and treatment-specific eligibility. Do not continue along the curative cystectomy pathway once definitive surgery is no longer clinically appropriate.
        
        No- Cystectomy remains feasible
        
        Radical cystectomy + pelvic lymph-node dissection
        
        Proceed with definitive radical cystectomy and pelvic lymph-node dissection when curative-intent surgery remains clinically appropriate. Proceed to definitive radical cystectomy with pelvic lymph-node dissection after completion of the planned neoadjuvant phase and confirmation that disease remains surgically manageable. Key principles: - Avoid unnecessary delay once the patient is ready for definitive surgery. - Confirm adequate recovery from neoadjuvant treatment and continued surgical fitness. - Perform pelvic lymph-node dissection as part of definitive surgical management. - Do not omit cystectomy solely because of an apparent clinical or radiographic response to neoadjuvant therapy. Postoperative systemic management depends on the perioperative strategy already received, recovery from surgery, and whether a protocol-defined adjuvant component is planned.
        
        Is a protocol-defined adjuvant component planned?
        
        Determine whether the perioperative regimen selected before cystectomy includes a planned post-cystectomy systemic-treatment phase. Answer YES when the selected perioperative strategy includes a protocol-defined adjuvant phase after radical cystectomy. This includes: - Perioperative enfortumab vedotin + pembrolizumab. - Perioperative durvalumab + gemcitabine/cisplatin followed by adjuvant durvalumab. Answer NO when no regimen-defined adjuvant phase was established before surgery, including: - Neoadjuvant cisplatin-based chemotherapy alone. - Upfront radical cystectomy without a perioperative systemic regimen. This decision identifies whether to complete the previously selected perioperative strategy or transition to postoperative risk-based management.
        
        Planned adjuvant phase
        
        Complete planned adjuvant component
        
        After adequate postoperative recovery, resume and complete the adjuvant phase defined by the perioperative regimen unless recurrence or unacceptable toxicity intervenes. Continue the postoperative component of the perioperative strategy selected before cystectomy. For perioperative enfortumab vedotin + pembrolizumab: - Resume the regimen-defined adjuvant EV + pembrolizumab phase after adequate surgical recovery. - Continue pembrolizumab according to the applicable perioperative schedule. - Use the schedule corresponding to the patient’s original cisplatin-eligible or cisplatin-ineligible treatment pathway. For perioperative durvalumab + gemcitabine/cisplatin: - Continue single-agent durvalumab after cystectomy. - Durvalumab is administered every 4 weeks for up to 8 postoperative cycles. Do not dose-reduce pembrolizumab or durvalumab for immune-mediated toxicity; withhold or discontinue according to toxicity severity. EV may be interrupted or dose-reduced for treatment-related toxicity. Discontinue or modify treatment for recurrence, unacceptable toxicity, or other clinical circumstances that make continuation inappropriate.
        
        Surveillance / Follow-Up and Postoperative Management Handoff
        
        Transition to risk-adapted oncologic surveillance, functional follow-up, and survivorship care after completion of perioperative treatment. After completion of planned perioperative therapy: - Monitor for local, nodal, and distant recurrence.- Continue functional follow-up after urinary diversion.- Monitor renal function and treatment-related late toxicity.- Address urinary, metabolic, sexual, rehabilitation, and survivorship needs.- Individualize surveillance intensity according to pathologic risk, patient fitness, and competing health risks. EAU provides a practice-based post-cystectomy surveillance framework rather than a single proven standardized schedule; CT imaging every 6 months through year 3 followed by annual imaging is one suggested approach.
        
        No planned adjuvant phase
        
        Open: Post-Cystectomy Risk & ctDNA MRD Pathway
        
        Transition to postoperative risk-based management when no regimen-defined adjuvant phase was established before cystectomy. Use the dedicated postoperative pathway to integrate: - Prior neoadjuvant systemic therapy. - Final pathologic stage and nodal status. - Surgical recovery and organ function. - Eligibility for adjuvant cisplatin-based chemotherapy when no neoadjuvant systemic therapy was given. - High-risk adjuvant immunotherapy considerations. - Serial ctDNA MRD assessment and ctDNA-guided adjuvant therapy. - Surveillance or clinical-trial options. Current FDA approval permits adjuvant atezolizumab after cystectomy for adults with MIBC who have ctDNA MRD detected by an FDA-authorized test. Do not assume routine sequential checkpoint-inhibitor therapy after prior perioperative pembrolizumab or durvalumab; this remains an evidence-gap requiring individualized expert review.
        
        Perioperative enfortumab vedotin + pembrolizumab
        
        Administer neoadjuvant enfortumab vedotin + pembrolizumab, proceed to radical cystectomy, and complete the protocol-defined adjuvant phase when clinically appropriate. Use perioperative enfortumab vedotin + pembrolizumab for an appropriate adult with MIBC who is a candidate for radical cystectomy. The current FDA indication includes both cisplatin-suitable and cisplatin-unsuitable patients who are candidates for cystectomy. The treatment strategy includes: - Neoadjuvant enfortumab vedotin + pembrolizumab. - Radical cystectomy with pelvic lymph-node dissection. - Protocol-defined adjuvant treatment after adequate postoperative recovery. Do not delay definitive surgery because of avoidable treatment-related toxicity. Dose & toxicity management: - Enfortumab vedotin may be interrupted and dose-reduced for treatment-related toxicity. Recommended dose levels are 1.25 mg/kg → 1.0 mg/kg → 0.75 mg/kg → 0.5 mg/kg. - Pembrolizumab is not dose-reduced; withhold or permanently discontinue according to the severity of immune-mediated toxicity. - Closely monitor for skin reactions, peripheral neuropathy, hyperglycemia, pneumonitis/ILD, and ocular toxicity. - For Grade 2 peripheral neuropathy, withhold EV until improvement to Grade ≤1; recurrent Grade 2 toxicity may require one-level dose reduction. Permanently discontinue EV for Grade ≥3 neuropathy. - Severe skin reactions, suspected SJS/TEN, significant pneumonitis/ILD, or uncontrolled hyperglycemia require prompt treatment interruption and label-directed management.
        
        Restaging and Surgical Reassessment
        
        After neoadjuvant or perioperative treatment, reassess disease status and confirm that curative-intent radical cystectomy remains feasible. Reassess the patient after completion of the planned neoadjuvant phase and before radical cystectomy. Review: - Interval clinical and radiographic disease status. - Evidence of local or distant progression. - Recovery from treatment-related toxicity. - Performance status and organ function relevant to surgery. - Continued surgical candidacy and curative intent. If disease remains resectable and the patient remains an appropriate surgical candidate, proceed toward radical cystectomy without avoidable delay. If interval progression may preclude curative cystectomy, transition to the subsequent progression decision node and multidisciplinary reassessment. Do not use radiographic response alone to omit planned radical cystectomy in an otherwise appropriate cystectomy-intent patient.
        
        Has progression precluded curative cystectomy?
        
        Determine whether interval disease progression still permits definitive radical cystectomy with curative intent. Assess restaging findings after neoadjuvant or perioperative treatment. Answer YES when interval progression means curative-intent cystectomy is no longer appropriate, including: - New distant metastatic disease. - Locoregional progression that is no longer surgically resectable with curative intent. - Clinical deterioration that fundamentally changes the treatment goal. Answer NO when disease remains amenable to curative-intent radical cystectomy and the patient remains an appropriate surgical candidate. Apparent clinical or radiographic response alone should not be used to omit planned definitive local therapy outside an appropriate bladder-preservation strategy or clinical trial.
        
        Yes- Progression precludes cystectomy
        
        Open: Locally Advanced / Metastatic Urothelial Carcinoma Pathway
        
        Exit the cystectomy-intent pathway when progression prevents curative surgery and transition to advanced-disease management. If interval progression precludes curative radical cystectomy: - Confirm the extent and pattern of progression. - Reassess treatment intent in a multidisciplinary setting. - Transition to the appropriate locally advanced or metastatic urothelial carcinoma pathway. - Base subsequent systemic treatment on prior perioperative exposure, current disease extent, clinical status, and treatment-specific eligibility. Do not continue along the curative cystectomy pathway once definitive surgery is no longer clinically appropriate.
        
        No- Cystectomy remains feasible
        
        Radical cystectomy + pelvic lymph-node dissection
        
        Proceed with definitive radical cystectomy and pelvic lymph-node dissection when curative-intent surgery remains clinically appropriate. Proceed to definitive radical cystectomy with pelvic lymph-node dissection after completion of the planned neoadjuvant phase and confirmation that disease remains surgically manageable. Key principles: - Avoid unnecessary delay once the patient is ready for definitive surgery. - Confirm adequate recovery from neoadjuvant treatment and continued surgical fitness. - Perform pelvic lymph-node dissection as part of definitive surgical management. - Do not omit cystectomy solely because of an apparent clinical or radiographic response to neoadjuvant therapy. Postoperative systemic management depends on the perioperative strategy already received, recovery from surgery, and whether a protocol-defined adjuvant component is planned.
        
        Is a protocol-defined adjuvant component planned?
        
        Determine whether the perioperative regimen selected before cystectomy includes a planned post-cystectomy systemic-treatment phase. Answer YES when the selected perioperative strategy includes a protocol-defined adjuvant phase after radical cystectomy. This includes: - Perioperative enfortumab vedotin + pembrolizumab. - Perioperative durvalumab + gemcitabine/cisplatin followed by adjuvant durvalumab. Answer NO when no regimen-defined adjuvant phase was established before surgery, including: - Neoadjuvant cisplatin-based chemotherapy alone. - Upfront radical cystectomy without a perioperative systemic regimen. This decision identifies whether to complete the previously selected perioperative strategy or transition to postoperative risk-based management.
        
        Planned adjuvant phase
        
        Complete planned adjuvant component
        
        After adequate postoperative recovery, resume and complete the adjuvant phase defined by the perioperative regimen unless recurrence or unacceptable toxicity intervenes. Continue the postoperative component of the perioperative strategy selected before cystectomy. For perioperative enfortumab vedotin + pembrolizumab: - Resume the regimen-defined adjuvant EV + pembrolizumab phase after adequate surgical recovery. - Continue pembrolizumab according to the applicable perioperative schedule. - Use the schedule corresponding to the patient’s original cisplatin-eligible or cisplatin-ineligible treatment pathway. For perioperative durvalumab + gemcitabine/cisplatin: - Continue single-agent durvalumab after cystectomy. - Durvalumab is administered every 4 weeks for up to 8 postoperative cycles. Do not dose-reduce pembrolizumab or durvalumab for immune-mediated toxicity; withhold or discontinue according to toxicity severity. EV may be interrupted or dose-reduced for treatment-related toxicity. Discontinue or modify treatment for recurrence, unacceptable toxicity, or other clinical circumstances that make continuation inappropriate.
        
        Surveillance / Follow-Up and Postoperative Management Handoff
        
        Transition to risk-adapted oncologic surveillance, functional follow-up, and survivorship care after completion of perioperative treatment. After completion of planned perioperative therapy: - Monitor for local, nodal, and distant recurrence.- Continue functional follow-up after urinary diversion.- Monitor renal function and treatment-related late toxicity.- Address urinary, metabolic, sexual, rehabilitation, and survivorship needs.- Individualize surveillance intensity according to pathologic risk, patient fitness, and competing health risks. EAU provides a practice-based post-cystectomy surveillance framework rather than a single proven standardized schedule; CT imaging every 6 months through year 3 followed by annual imaging is one suggested approach.
        
        No planned adjuvant phase
        
        Open: Post-Cystectomy Risk & ctDNA MRD Pathway
        
        Transition to postoperative risk-based management when no regimen-defined adjuvant phase was established before cystectomy. Use the dedicated postoperative pathway to integrate: - Prior neoadjuvant systemic therapy. - Final pathologic stage and nodal status. - Surgical recovery and organ function. - Eligibility for adjuvant cisplatin-based chemotherapy when no neoadjuvant systemic therapy was given. - High-risk adjuvant immunotherapy considerations. - Serial ctDNA MRD assessment and ctDNA-guided adjuvant therapy. - Surveillance or clinical-trial options. Current FDA approval permits adjuvant atezolizumab after cystectomy for adults with MIBC who have ctDNA MRD detected by an FDA-authorized test. Do not assume routine sequential checkpoint-inhibitor therapy after prior perioperative pembrolizumab or durvalumab; this remains an evidence-gap requiring individualized expert review.
      - Cisplatin-unsuitable
        
        EV + pembrolizumab clinically appropriate?
        
        Assess whether both enfortumab vedotin and pembrolizumab are clinically appropriate and feasible before selecting the perioperative regimen. Assess treatment-specific suitability for both components of the regimen. Key considerations include: - Baseline peripheral neuropathy. - Diabetes control and clinically significant hyperglycemia. - Significant active or pre-existing skin disease. - Ocular conditions that may increase treatment risk. - Major contraindications or unacceptable risk related to immune-checkpoint inhibition. - Overall organ function, functional status, and ability to proceed with curative-intent cystectomy. Trial eligibility criteria and toxicity-risk factors should inform clinical judgment but should not automatically be converted into universal absolute contraindications. Answer YES when both agents are clinically feasible and the anticipated benefit-risk profile supports perioperative EV + pembrolizumab. Answer NO when one or both components are not clinically appropriate or treatment-related risk outweighs the expected benefit.
        
        EV/P appropriate
        
        Perioperative enfortumab vedotin + pembrolizumab
        
        Administer neoadjuvant enfortumab vedotin + pembrolizumab, proceed to radical cystectomy, and complete the protocol-defined adjuvant phase when clinically appropriate. Use perioperative enfortumab vedotin + pembrolizumab for an appropriate adult with MIBC who is a candidate for radical cystectomy. The current FDA indication includes both cisplatin-suitable and cisplatin-unsuitable patients who are candidates for cystectomy. The treatment strategy includes: - Neoadjuvant enfortumab vedotin + pembrolizumab. - Radical cystectomy with pelvic lymph-node dissection. - Protocol-defined adjuvant treatment after adequate postoperative recovery. Do not delay definitive surgery because of avoidable treatment-related toxicity. Dose & toxicity management: - Enfortumab vedotin may be interrupted and dose-reduced for treatment-related toxicity. Recommended dose levels are 1.25 mg/kg → 1.0 mg/kg → 0.75 mg/kg → 0.5 mg/kg. - Pembrolizumab is not dose-reduced; withhold or permanently discontinue according to the severity of immune-mediated toxicity. - Closely monitor for skin reactions, peripheral neuropathy, hyperglycemia, pneumonitis/ILD, and ocular toxicity. - For Grade 2 peripheral neuropathy, withhold EV until improvement to Grade ≤1; recurrent Grade 2 toxicity may require one-level dose reduction. Permanently discontinue EV for Grade ≥3 neuropathy. - Severe skin reactions, suspected SJS/TEN, significant pneumonitis/ILD, or uncontrolled hyperglycemia require prompt treatment interruption and label-directed management.
        
        Restaging and Surgical Reassessment
        
        After neoadjuvant or perioperative treatment, reassess disease status and confirm that curative-intent radical cystectomy remains feasible. Reassess the patient after completion of the planned neoadjuvant phase and before radical cystectomy. Review: - Interval clinical and radiographic disease status. - Evidence of local or distant progression. - Recovery from treatment-related toxicity. - Performance status and organ function relevant to surgery. - Continued surgical candidacy and curative intent. If disease remains resectable and the patient remains an appropriate surgical candidate, proceed toward radical cystectomy without avoidable delay. If interval progression may preclude curative cystectomy, transition to the subsequent progression decision node and multidisciplinary reassessment. Do not use radiographic response alone to omit planned radical cystectomy in an otherwise appropriate cystectomy-intent patient.
        
        Has progression precluded curative cystectomy?
        
        Determine whether interval disease progression still permits definitive radical cystectomy with curative intent. Assess restaging findings after neoadjuvant or perioperative treatment. Answer YES when interval progression means curative-intent cystectomy is no longer appropriate, including: - New distant metastatic disease. - Locoregional progression that is no longer surgically resectable with curative intent. - Clinical deterioration that fundamentally changes the treatment goal. Answer NO when disease remains amenable to curative-intent radical cystectomy and the patient remains an appropriate surgical candidate. Apparent clinical or radiographic response alone should not be used to omit planned definitive local therapy outside an appropriate bladder-preservation strategy or clinical trial.
        
        Yes- Progression precludes cystectomy
        
        Open: Locally Advanced / Metastatic Urothelial Carcinoma Pathway
        
        Exit the cystectomy-intent pathway when progression prevents curative surgery and transition to advanced-disease management. If interval progression precludes curative radical cystectomy: - Confirm the extent and pattern of progression. - Reassess treatment intent in a multidisciplinary setting. - Transition to the appropriate locally advanced or metastatic urothelial carcinoma pathway. - Base subsequent systemic treatment on prior perioperative exposure, current disease extent, clinical status, and treatment-specific eligibility. Do not continue along the curative cystectomy pathway once definitive surgery is no longer clinically appropriate.
        
        No- Cystectomy remains feasible
        
        Radical cystectomy + pelvic lymph-node dissection
        
        Proceed with definitive radical cystectomy and pelvic lymph-node dissection when curative-intent surgery remains clinically appropriate. Proceed to definitive radical cystectomy with pelvic lymph-node dissection after completion of the planned neoadjuvant phase and confirmation that disease remains surgically manageable. Key principles: - Avoid unnecessary delay once the patient is ready for definitive surgery. - Confirm adequate recovery from neoadjuvant treatment and continued surgical fitness. - Perform pelvic lymph-node dissection as part of definitive surgical management. - Do not omit cystectomy solely because of an apparent clinical or radiographic response to neoadjuvant therapy. Postoperative systemic management depends on the perioperative strategy already received, recovery from surgery, and whether a protocol-defined adjuvant component is planned.
        
        Is a protocol-defined adjuvant component planned?
        
        Determine whether the perioperative regimen selected before cystectomy includes a planned post-cystectomy systemic-treatment phase. Answer YES when the selected perioperative strategy includes a protocol-defined adjuvant phase after radical cystectomy. This includes: - Perioperative enfortumab vedotin + pembrolizumab. - Perioperative durvalumab + gemcitabine/cisplatin followed by adjuvant durvalumab. Answer NO when no regimen-defined adjuvant phase was established before surgery, including: - Neoadjuvant cisplatin-based chemotherapy alone. - Upfront radical cystectomy without a perioperative systemic regimen. This decision identifies whether to complete the previously selected perioperative strategy or transition to postoperative risk-based management.
        
        Planned adjuvant phase
        
        Complete planned adjuvant component
        
        After adequate postoperative recovery, resume and complete the adjuvant phase defined by the perioperative regimen unless recurrence or unacceptable toxicity intervenes. Continue the postoperative component of the perioperative strategy selected before cystectomy. For perioperative enfortumab vedotin + pembrolizumab: - Resume the regimen-defined adjuvant EV + pembrolizumab phase after adequate surgical recovery. - Continue pembrolizumab according to the applicable perioperative schedule. - Use the schedule corresponding to the patient’s original cisplatin-eligible or cisplatin-ineligible treatment pathway. For perioperative durvalumab + gemcitabine/cisplatin: - Continue single-agent durvalumab after cystectomy. - Durvalumab is administered every 4 weeks for up to 8 postoperative cycles. Do not dose-reduce pembrolizumab or durvalumab for immune-mediated toxicity; withhold or discontinue according to toxicity severity. EV may be interrupted or dose-reduced for treatment-related toxicity. Discontinue or modify treatment for recurrence, unacceptable toxicity, or other clinical circumstances that make continuation inappropriate.
        
        Surveillance / Follow-Up and Postoperative Management Handoff
        
        Transition to risk-adapted oncologic surveillance, functional follow-up, and survivorship care after completion of perioperative treatment. After completion of planned perioperative therapy: - Monitor for local, nodal, and distant recurrence.- Continue functional follow-up after urinary diversion.- Monitor renal function and treatment-related late toxicity.- Address urinary, metabolic, sexual, rehabilitation, and survivorship needs.- Individualize surveillance intensity according to pathologic risk, patient fitness, and competing health risks. EAU provides a practice-based post-cystectomy surveillance framework rather than a single proven standardized schedule; CT imaging every 6 months through year 3 followed by annual imaging is one suggested approach.
        
        No planned adjuvant phase
        
        Open: Post-Cystectomy Risk & ctDNA MRD Pathway
        
        Transition to postoperative risk-based management when no regimen-defined adjuvant phase was established before cystectomy. Use the dedicated postoperative pathway to integrate: - Prior neoadjuvant systemic therapy. - Final pathologic stage and nodal status. - Surgical recovery and organ function. - Eligibility for adjuvant cisplatin-based chemotherapy when no neoadjuvant systemic therapy was given. - High-risk adjuvant immunotherapy considerations. - Serial ctDNA MRD assessment and ctDNA-guided adjuvant therapy. - Surveillance or clinical-trial options. Current FDA approval permits adjuvant atezolizumab after cystectomy for adults with MIBC who have ctDNA MRD detected by an FDA-authorized test. Do not assume routine sequential checkpoint-inhibitor therapy after prior perioperative pembrolizumab or durvalumab; this remains an evidence-gap requiring individualized expert review.
        
        EV/P not appropriate
        
        Radical cystectomy + pelvic lymph-node dissection
        
        Proceed with definitive radical cystectomy and pelvic lymph-node dissection when curative-intent surgery remains clinically appropriate. Proceed to definitive radical cystectomy with pelvic lymph-node dissection after completion of the planned neoadjuvant phase and confirmation that disease remains surgically manageable. Key principles: - Avoid unnecessary delay once the patient is ready for definitive surgery. - Confirm adequate recovery from neoadjuvant treatment and continued surgical fitness. - Perform pelvic lymph-node dissection as part of definitive surgical management. - Do not omit cystectomy solely because of an apparent clinical or radiographic response to neoadjuvant therapy. Postoperative systemic management depends on the perioperative strategy already received, recovery from surgery, and whether a protocol-defined adjuvant component is planned.
        
        Is a protocol-defined adjuvant component planned?
        
        Determine whether the perioperative regimen selected before cystectomy includes a planned post-cystectomy systemic-treatment phase. Answer YES when the selected perioperative strategy includes a protocol-defined adjuvant phase after radical cystectomy. This includes: - Perioperative enfortumab vedotin + pembrolizumab. - Perioperative durvalumab + gemcitabine/cisplatin followed by adjuvant durvalumab. Answer NO when no regimen-defined adjuvant phase was established before surgery, including: - Neoadjuvant cisplatin-based chemotherapy alone. - Upfront radical cystectomy without a perioperative systemic regimen. This decision identifies whether to complete the previously selected perioperative strategy or transition to postoperative risk-based management.
        
        Planned adjuvant phase
        
        Complete planned adjuvant component
        
        After adequate postoperative recovery, resume and complete the adjuvant phase defined by the perioperative regimen unless recurrence or unacceptable toxicity intervenes. Continue the postoperative component of the perioperative strategy selected before cystectomy. For perioperative enfortumab vedotin + pembrolizumab: - Resume the regimen-defined adjuvant EV + pembrolizumab phase after adequate surgical recovery. - Continue pembrolizumab according to the applicable perioperative schedule. - Use the schedule corresponding to the patient’s original cisplatin-eligible or cisplatin-ineligible treatment pathway. For perioperative durvalumab + gemcitabine/cisplatin: - Continue single-agent durvalumab after cystectomy. - Durvalumab is administered every 4 weeks for up to 8 postoperative cycles. Do not dose-reduce pembrolizumab or durvalumab for immune-mediated toxicity; withhold or discontinue according to toxicity severity. EV may be interrupted or dose-reduced for treatment-related toxicity. Discontinue or modify treatment for recurrence, unacceptable toxicity, or other clinical circumstances that make continuation inappropriate.
        
        Surveillance / Follow-Up and Postoperative Management Handoff
        
        Transition to risk-adapted oncologic surveillance, functional follow-up, and survivorship care after completion of perioperative treatment. After completion of planned perioperative therapy: - Monitor for local, nodal, and distant recurrence.- Continue functional follow-up after urinary diversion.- Monitor renal function and treatment-related late toxicity.- Address urinary, metabolic, sexual, rehabilitation, and survivorship needs.- Individualize surveillance intensity according to pathologic risk, patient fitness, and competing health risks. EAU provides a practice-based post-cystectomy surveillance framework rather than a single proven standardized schedule; CT imaging every 6 months through year 3 followed by annual imaging is one suggested approach.
        
        No planned adjuvant phase
        
        Open: Post-Cystectomy Risk & ctDNA MRD Pathway
        
        Transition to postoperative risk-based management when no regimen-defined adjuvant phase was established before cystectomy. Use the dedicated postoperative pathway to integrate: - Prior neoadjuvant systemic therapy. - Final pathologic stage and nodal status. - Surgical recovery and organ function. - Eligibility for adjuvant cisplatin-based chemotherapy when no neoadjuvant systemic therapy was given. - High-risk adjuvant immunotherapy considerations. - Serial ctDNA MRD assessment and ctDNA-guided adjuvant therapy. - Surveillance or clinical-trial options. Current FDA approval permits adjuvant atezolizumab after cystectomy for adults with MIBC who have ctDNA MRD detected by an FDA-authorized test. Do not assume routine sequential checkpoint-inhibitor therapy after prior perioperative pembrolizumab or durvalumab; this remains an evidence-gap requiring individualized expert review.
Multidisciplinary Review

Review treatment intent and perioperative strategy in a multidisciplinary setting before treatment initiation. All patients with MIBC should undergo multidisciplinary review before treatment initiation. Ensure coordinated review of: - Pathology and TURBT findings. - Clinical stage and imaging. - Cystectomy candidacy and surgical considerations. - Suitability for perioperative systemic therapy. - Patient goals and treatment preferences. Complex features warrant particular attention, including: - cN1 disease. - Clinically significant variant histology. - Borderline organ function or treatment fitness. - Discordant pathology or imaging. - Situations in which treatment choice or timing could affect curative-intent surgery.
Consider a clinical trial

Consider clinical trial participation at key perioperative decision points when an appropriate study is available. Discuss clinical trial participation when an appropriate study is available and compatible with curative-intent management. Trial consideration should complement, not delay, timely definitive treatment.

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