Multicenter Phase 3 Randomized Controlled Trial of NO Re-excision MelanomA - NORMA 2

This multicenter, phase III randomized controlled non-inferiority trial evaluates the oncologic safety and clinical impact of omitting re-excision after complete diagnostic excision of primary cutaneous melanoma. Although current guidelines recommend re-excision with margins of 1-2 cm depending on Breslow thickness, the clinical benefit of this procedure in all patients remains uncertain.

Patients with histologically confirmed pT1b-pT4b (AJCC 8th edition) cutaneous melanoma who have undergone complete primary excision with tumor-free margins and show no evidence of regional or distant metastases will be randomized in a 1:1 ratio to either standard re-excision according to local protocols (control arm) or omission of re-excision (experimental arm). Sentinel lymph node biopsy (SLNB) will be performed according to current guidelines and local practice, and may be omitted in selected patients at the discretion of the treating physician. Randomization will be stratified by tumor T stage and SLNB status and adjuvant systemic therapy is permitted according to national guidelines.

Re-excision, when performed, should take place within 12 weeks of the initial diagnostic excision and follow standardized surgical principles, including documentation of surgical margins and pathological assessment of the specimen. Patients will be followed for up to 5 years according to current clinical guidelines. Recurrences will be categorized as local, in-transit, nodal, or distant, and histological confirmation will be obtained whenever feasible. Management of recurrences and use of systemic therapies will be at the discretion of the treating physicians and recorded throughout the study.

In addition to oncologic outcomes, the study evaluates surgical morbidity, including postoperative complications classified according to the Clavien-Dindo system and the need for reconstructive procedures. Patient-reported outcomes will be collected longitudinally to assess health-related quality of life and scar-related outcomes using validated questionnaires. Health economic evaluation will include cost-effectiveness and cost-utility analyses from healthcare and societal perspectives, incorporating resource use, productivity losses, and quality-adjusted life years over a lifetime horizon using model-based approaches.

The trial is designed as a non-inferiority study to compare relapse-free survival between re-excision and no re-excision. The sample size is sufficient to detect non-inferiority with respect to a predefined margin, corresponding to an acceptable absolute decrease in 5-year relapse-free survival of 5%. Time-to-event endpoints will be analyzed using Kaplan-Meier methods and Cox proportional hazards models adjusted for stratification factors, with hazard ratios and 90% confidence intervals reported. The primary analysis will follow the intention-to-treat principle, with a supportive per-protocol analysis. Secondary endpoints will be analyzed using appropriate regression methods for time-to-event and binary outcomes, and longitudinal patient-reported outcomes will be evaluated using mixed-effects models. Sensitivity analyses will assess the potential influence of adjuvant systemic therapy on outcomes. An interim analysis for futility is planned after a subset of events has occurred.