NO Re-excision MelanomA - NORMA 2
For patients and families
In plain language
An automatic summary of structured registry data. It is an orientation aid, not a substitute for the official protocol or a physician assessment.
- What is being studied
- The protocol lists: Re-excision, No re-excision.
- Who it may be relevant to
- Registry conditions: Melanoma (Skin Cancer). Basic parameters: No limits · All.
- What needs checking
- Age, condition and sex are only basic indicators. Prior treatment, laboratory values and other mandatory requirements appear in the eligibility criteria below.
- Where it takes place
- Netherlands
- Next step
- Save the trial, show it to the treating physician, and confirm current recruitment with the study center. Costs, documents and travel →
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Official title
Multicenter Phase 3 Randomized Controlled Trial of NO Re-excision MelanomA - NORMA 2
Overview
This multicenter, phase III randomized controlled trial evaluates whether omitting re-excision after complete primary excision of cutaneous melanoma affects patient outcomes. A total of 1,749 patients with pT1b-pT4b cutaneous melanoma without evidence of metastases will be randomized to either standard re-excision according to current guidelines or no re-excision. Sentinel lymph node biopsy and adjuvant systemic therapy will be performed as indicated in both groups. The primary objective is to compare relapse-free survival (RFS) between the two groups. Secondary objectives include comparisons of overall survival (OS), local recurrence rates, recurrence of in-transit and lymph node metastases, distant metastasis-free survival (DMFS), surgical morbidity, quality of life, and health economic outcomes.
Detailed description
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.
Interventions
- Procedure Re-excision
Prior to the re-excision, before any local anesthetic is given, the margin will be measured by a ruler and marked on the skin of the patient. The melanoma free margin of the diagnostic excision may be subtracted from the re-excision margin. The re-excision should be performed by cutting vertically down along the margins of the re-excision for its entire length until the required margin or until the fascia is reached in the depth. Removal of the fascia is left to the resecting surgeon's discretio - Procedure No re-excision
In case a patient is randomized toward the no-re-excision treatment arm, there is no need to perform any procedures to the primary tumor site.
Primary outcome measures
- Relapse-Free Survival (RFS) [Time frame: From randomization to the first occurrence of melanoma recurrence or melanoma-related death, assessed up to 5 years.]
Secondary outcome measures (12)
- Overall Survival (OS) [Time frame: From randomization to death from any cause, assessed up to 5 years.]
- Local Recurrence Rate (LRR) [Time frame: From randomization up to 5 years]
- Recurrence rate of in-transit metastases [Time frame: From randomization up to 5 years]
- Recurrence rate of lymph node metastases [Time frame: From randomization up to 5 years]
- Distant Metastasis-Free Survival (DMFS) [Time frame: From randomization to the first occurrence of distant metastasis, assessed up to 5 years]
- Surgical complication rates [Time frame: From the date of surgery up to 30 days post-surgery]
- Quality of Life (EORTC QLQ-C30) [Time frame: Baseline, 3, 6, 12, and 24 months.]
- Quality of Life (FACT-M Melanoma Surgery Scale) [Time frame: Baseline, 3, 6, 12, and 24 months.]
- Quality of Life (Cancer Worry Scale) [Time frame: Baseline, 3, 6, 12, and 24 months.]
- Quality of Life (POSAS) [Time frame: 3 and 12 months after randomization.]
- Health Technology Assessment (EQ-5D-5L) [Time frame: 3, 6, and 12 months after randomization.]
- Health Technology Assessment (iMCQ) [Time frame: 3, 6, and 12 months after randomization.]
Eligibility criteria
Inclusion criteria
- Patients must be 18 years or older at time of consent
- Patients must have an ECOG performance score between 0 and 2
- Histologically confirmed, stage pT1b - pT4b (TNM AJCC 8th edition) cutaneous primary melanoma
- Histological subtypes that are eligible are:
- Superficial Spreading Melanoma (SSM)
- Nodular Melanoma (NM)
- The primary melanoma must have been removed by diagnostic excision and must have at least a minimum of 1 mm tumor free margin for invasive melanoma AND any in situ melanoma
- Patient must provide informed consent and comply with the treatment protocol and follow-up plan
- Life expectancy of at least 5 years from the time of diagnosis, not considering the melanoma in question, as determined by the investigator
- A survivor of prior cancer is eligible provided that ALL of the following criteria are met and documented:
- The patient has undergone potentially curative therapy for all prior malignancies
- Life expectancy should be at least 5 years and
- The patient is deemed by their treating physician to be at low risk of recurrence from previous malignancies.
Exclusion criteria
- Non-cutaneous melanoma (uveal, mucosal)
- Acral melanoma
- Lentigo malignant melanoma (LMM)
- Desmoplastic melanoma
- Neurotropic melanoma
- Spitz melanoma/malignant Spitz tumor melanoma
- Satellites, in-transit melanomas or macroscopic melanoma metastases
- Uncertain diagnosis of melanoma i.e. so-called 'melanocytic lesions of unknown malignant potential' (MELTUMP or STUMP)
- Other non-SSM or NM subtypes
- Melanoma removed by shave excision, excogliation or core biopsy
- Patient has already undergone a local flap reconstruction of the defect after excision of the primary
- History of previous or concurrent (i.e., second primary) invasive melanoma
- Multiple melanomas
- Patient has undergone surgery on a separate occasion to clear the lymph nodes of the probable draining lymphatic field, except for previous SLNB
- Any additional solid tumor or hematologic malignancy during the past 5 years with a life expectancy of less than 5 years
- History of organ transplantation
Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.
Healthy volunteers: No
Study design
- Allocation
- Randomized
- Model
- Parallel assignment
- Masking
- Open label
- Primary purpose
- Treatment
Study locations
Netherlands · 21 centers
- Jeroen Bosch Ziekenhuis — 's-Hertogenbosch
- Noordwest Ziekenhuisgroep — Alkmaar
- Flevoziekenhuis — Almere Stad
- Antoni van Leeuwenhoek — Amsterdam
- Gelre ziekenhuizen — Apeldoorn
- Rijnstate Ziekenhuis — Arnhem
- Catharina ziekenhuis — Eindhoven
- Medisch Spectrum Twente — Enschede
- … and 13 more centers
Identifiers
NCT: NCT07530887 · NetherlandCI · NL-OMON57910