Global guidelines for the management of penile cancer: evaluating clinical alignment and methodological rigor

Penile cancer (PC) is a rare malignancy with significant geographic variability in its incidence and clinical management. In the absence of large-scale trials, international guidelines serve as primary tools for therapeutic decision-making. This review aims to systematically compare current recommendations and methodological quality across three major guidelines - EAU-ASCO (2025), NCCN (2025), and ESMO (2024) - focusing on treatment strategies for primary tumors, lymph node management, systemic therapy, and follow-up protocols.

A structured comparative analysis was conducted using a predefined protocol. Guideline content was independently reviewed by two uro-oncology experts across four domains. The strength of recommendation (SoR) and level of evidence (LoE) were extracted when available. Methodological rigor was evaluated using the AGREE II instrument, with two independent reviewers scoring 23 items across six domains. Domain scores were standardized and categorized as high (>70%), moderate (50-70%), or low quality (<50%). All the disagreements were solved by a senior reviewer.

There was substantial concordance in early-stage tumor management and the use of platinum-based chemotherapy for advanced diseases. However, discrepancies emerged in surgical margins, lymph node evaluation thresholds, and second-line systemic therapy. Follow-up strategies varied widely in structure and comprehensiveness. AGREE II appraisal revealed marked differences in guideline development quality: EAU-ASCO scored highest across all domains, followed by NCCN and ESMO. Limitations include exclusion of regional guidelines and heterogeneity in evidence grading systems.

International PC guidelines align on core principles; however, notable divergences persist due to evidence gaps and regional practices. Evaluating both clinical content and development quality enhances understanding of guideline credibility and applicability.