Perioperative Systemic Therapies in Muscle-Invasive Bladder Cancer (GUARDIANS)

The GUARDIANS perioperative registry is a multicenter observational study designed to collect real-world data on perioperative systemic therapies in patients with muscle-invasive or locally advanced urothelial carcinoma of the bladder.

Perioperative systemic treatment strategies for muscle-invasive bladder cancer are rapidly evolving and include antibody-drug conjugate-based combinations such as Enfortumab Vedotin plus Pembrolizumab as well as cisplatin-based regimens including Gemcitabine/Cisplatin/Durvalumab and other standard neoadjuvant and adjuvant treatment approaches. While these regimens are increasingly used in routine care, systematic real-world evidence regarding feasibility, dose intensity, perioperative safety, patient-reported neurotoxicity, pathologic response, and long-term oncologic outcomes remains limited.

This registry evaluates perioperative treatment strategies with particular focus on real-world implementation, treatment completion, and comparative outcomes across different systemic therapy approaches. Patients are followed longitudinally from baseline and diagnosis through neoadjuvant therapy, radical cystectomy with pelvic lymph node dissection, adjuvant therapy when applicable, and long-term follow-up.

The primary objective is evaluation of event-free survival (EFS) and treatment feasibility. Feasibility includes completion of intended radical cystectomy, delivery of planned neoadjuvant and adjuvant treatment components, and reasons for treatment delay, modification, or discontinuation.

Secondary objectives include assessment of:

Pathologic complete response (pCR, ypT0N0) Pathologic downstaging Disease-free survival (DFS) Overall survival (OS) Local and distant recurrence patterns 90-day postoperative complications after radical cystectomy CTCAE version 5.0 treatment-related toxicities Patient-reported chemotherapy-induced peripheral neuropathy symptoms Treatment exposure and dose intensity The study is non-interventional. All diagnostic and therapeutic decisions are made independently of study participation according to local standard of care. No additional mandatory visits, diagnostic procedures, or therapeutic interventions are required.

Data are collected pseudonymized using REDCap across participating GUARDIANS centers. Prospective collection includes patient-reported outcome measures for neurotoxicity, while retrospective collection allows inclusion of previously treated patients according to ethics approval and local regulations. The registry supports evaluation of real-world outcomes across multiple perioperative treatment strategies and provides comparative evidence for routine clinical practice.

• Perioperative Systemic Therapy Registry (Other): Observational registry of patients with muscle-invasive bladder cancer receiving perioperative systemic therapy as part of routine clinical care. Treatments are not assigned by protocol and may include Enfortumab Vedotin plus Pembrolizumab, Gemcitabine/Cisplatin/Durvalumab, cisplatin-based chemotherapy, immunotherapy, and other standard neoadjuvant or adjuvant treatment approaches. All therapeutic decisions are made independently by treating physicians according to local standard of care.

Primary outcomes

• Event Free Survival (EFS) [From treatment initiation up to 36 months]

Secondary outcomes

• Pathologic Complete Response (pCR) [At radical cystectomy]
• Pathologic Downstaging [At radical cystectomy]: Defined as less than ypT2N0 in the cystectomy specimen, including pT0, pTis, pTa, and pT1.
• Disease-Free Survival (DFS) [Up to 36 months after surgery]: Time from curative surgery until recurrence or death.
• Overall Survival (OS) [Up to 60 months]: Time from treatment initiation until death from any cause.
• Change Over Time in Patient-Reported Peripheral Neuropathy Assessed by the EORTC QLQ-CIPN20 [Baseline; within 14 days before radical cystectomy; start of adjuvant therapy ±14 days; weeks 12, 21, and 30 of adjuvant therapy ±14 days; and end of treatment ±14 days]: Patient-reported peripheral neuropathy symptoms will be assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy 20 (EORTC QLQ-CIPN20). The questionnaire assesses sensory, motor, and autonomic symptoms of peripheral neuropathy. Subscale scores are calculated according to the EORTC scoring procedure and linearly transformed to a scale ranging from 0 to 100. Higher scores indicate greater peripheral neuropathy symptom burden and therefore a worse outcome. Changes from baseline will be assessed longitudinally during perioperative treatment through end of treatment.
• Treatment-Related Adverse Events [From first administration of neoadjuvant therapy through the end-of-treatment visit, up to approximately 12 months]: Occurrence, type, severity, attribution, management, and outcome of treatment-related adverse events associated with perioperative enfortumab vedotin and pembrolizumab. Adverse event severity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0.
• 90-Day Postoperative Complications [Up to 90 days after radical cystectomy]: Occurrence and severity of postoperative complications within 90 days after radical cystectomy, graded according to the Clavien-Dindo classification.
• 90-Day Perioperative Mortality [Up to 90 days after radical cystectomy]: All-cause mortality occurring within 90 days after radical cystectomy following perioperative systemic therapy. This includes deaths related to surgical complications, treatment-related toxicity, or other causes during the perioperative period.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Age ≥18 years
* Histologically confirmed muscle-invasive or locally advanced urothelial carcinoma of the bladder
* Planned, ongoing, or completed perioperative systemic therapy, including but not limited to Enfortumab Vedotin plus Pembrolizumab, Gemcitabine/Cisplatin/Durvalumab, cisplatin-based chemotherapy, immunotherapy, or other standard perioperative treatment approaches
* Radical cystectomy planned or performed as part of curative-intent treatment strategy
* Written informed consent for prospective data collection, where required
* Sufficient clinical documentation available for retrospective inclusion, including at least one follow-up assessment

Exclusion Criteria:

* Missing informed consent where prospectively required
* Insufficient documentation of key baseline data or treatment exposure
* No perioperative systemic therapy or inability to assign patient to a study cohort
* Follow-up data unavailable or inconsistent documentation preventing endpoint assessment