NO Re-excision MelanomA - NORMA 2

Phase 3RecruitingNCT07530887

Marieke Goodijk1,749 enrolled

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.

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

Re-excisionPROCEDURE

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 discretion. Preservation of anatomical structures, such as veins or nerves is allowed, if they are not clearly involved with tumor. In case of melanoma ≥pT3a any margin between 1 and 2 centimeter is accepted according to the surgeons preference. The amount of margin (in mm) taken during the re-excision needs to be documented perioperatively by the surgeon in the operation report. The specimen should be marked for anatomical navigation and sent off for pathological assessment.

No re-excisionPROCEDURE

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.

Eligibility

Sex: ALL

Medical Language ↔ Plain English

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

Locations (21)

Jeroen Bosch Ziekenhuis

's-Hertogenbosch, Netherlands

RECRUITING

Noordwest Ziekenhuisgroep

Alkmaar, Netherlands

RECRUITING

Flevoziekenhuis

Almere Stad, Netherlands

RECRUITING

Antoni van Leeuwenhoek

Amsterdam, Netherlands

RECRUITING

Gelre ziekenhuizen

Apeldoorn, Netherlands

RECRUITING

Rijnstate Ziekenhuis

Arnhem, Netherlands

RECRUITING

Catharina ziekenhuis

Eindhoven, Netherlands

NOT_YET_RECRUITING

Medisch Spectrum Twente

Enschede, Netherlands

RECRUITING

Groene Hart Ziekenhuis

Gouda, Netherlands

NOT_YET_RECRUITING

Martini ziekenhuis

Groningen, Netherlands

NOT_YET_RECRUITING

...and 11 more locations

Outcomes

Primary Outcomes

Relapse-Free Survival (RFS)

RFS, defined as time from randomization to any first melanoma recurrence or melanoma-related death, whichever occurs first. Any new primary melanoma and/or melanoma in situ will be registered. However, it will not be considered an event for the primary endpoint of RFS.

Time frame: From randomization to the first occurrence of melanoma recurrence or melanoma-related death, assessed up to 5 years.

Secondary Outcomes

Overall Survival (OS)

OS, defined as time from randomization to death, no matter what the cause of death was.

Time frame: From randomization to death from any cause, assessed up to 5 years.

Local Recurrence Rate (LRR)

LRR, defined as the frequency of local recurrences within the study population. A local recurrence is defined as recurrence within the scar and/or any satellite metastasis within 2 cm.

Time frame: From randomization up to 5 years

Recurrence rate of in-transit metastases

Recurrence rate of in-transit metastases, defined as the frequency of in-transit metastasis recurrences within the study population. An in-transit metastasis is defined as any skin or subcutaneous metastasis that occurs more than 2 cm from the primary lesion, but not beyond the regional nodal basin.

Time frame: From randomization up to 5 years

Recurrence rate of lymph node metastases

Recurrence rate of lymph node metastases, defined as the frequency of lymph node metastases within the study population.

Time frame: From randomization up to 5 years

Distant Metastasis-Free Survival (DMFS)

DMFS, defined as time from randomization until the occurrence of a distant metastasis.

Time frame: From randomization to the first occurrence of distant metastasis, assessed up to 5 years

Surgical complication rates

Surgical complication rates according to Clavien-Dindo surgical classification and frequency of reconstructive surgery.

Time frame: From the date of surgery up to 30 days post-surgery

Quality of Life (EORTC QLQ-C30)

Quality of life assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Scores range from 0 to 100, with higher scores indicating better functioning and quality of life (for functional scales) and worse symptoms (for symptom scales).

Time frame: Baseline, 3, 6, 12, and 24 months.

Quality of Life (FACT-M Melanoma Surgery Scale)

Quality of life assessed using the Functional Assessment of Cancer Therapy - Melanoma (FACT-M). Scores range from 0 to 96 with higher scores indicating worse quality of life.

Time frame: Baseline, 3, 6, 12, and 24 months.

Quality of Life (Cancer Worry Scale)

Cancer related worry assessed using the 8 item Cancer Worry Scale (CWS). Each item is scored on a 4 point scale ranging from 1 (not at all) to 4 (very much). Total scores range from 8 to 32, with higher scores indicating greater cancer-related worry.

Time frame: Baseline, 3, 6, 12, and 24 months.

Quality of Life (POSAS)

Subjective scar quality assessed by the patient using the Patient and Observer Scar Assessment Scale (POSAS), patient component. The patient scale consists of 18 items scored on a 5 point scale (1 = not relevant, 5 = extremely relevant). Total scores range from 18 to 90, with higher scores indicating worse scar quality.

Time frame: 3 and 12 months after randomization.

Health Technology Assessment (EQ-5D-5L)

Health-related quality of life assessed using the EuroQol 5-Dimension 5-Level (EQ-5D-5L) questionnaire. The instrument includes five dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each with five levels of severity. Responses are converted into a utility index score ranging from less than 0 (worse than death) to 1 (full health), with higher scores indicating better health status. Additionally, patients rate their overall health on a visual analogue scale (EQ VAS) ranging from 0 (worst imaginable health) to 100 (best imaginable health), with higher scores indicating better perceived health.

Time frame: 3, 6, and 12 months after randomization.

Health Technology Assessment (iMCQ)

Healthcare utilization assessed using the iMTA Medical Consumption Questionnaire (iMCQ). This questionnaire measures medical resource use over the past 3 months, including contacts with healthcare providers (e.g., general practitioner, specialists, therapists), hospital admissions, emergency visits, medication use, and informal care. Resource use is reported as frequencies (e.g., number of visits, days, or hours). Higher values indicate greater healthcare utilization.

Time frame: 3, 6, and 12 months after randomization.

Health Technology Assessment (iPCQ)

Productivity losses assessed using the iMTA Productivity Cost Questionnaire (iPCQ). This questionnaire measures productivity losses over the past 3 months, including absenteeism (days absent from paid work), presenteeism (reduced productivity while at work, scored on a scale from 0 \[unable to work\] to 10 \[normal productivity\]), and losses in unpaid work. Higher values indicate greater productivity loss.

Time frame: 3, 6, and 12 months after randomization.

NO Re-excision MelanomA - NORMA 2

Overview

Conditions

Interventions

Eligibility

Locations (21)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts