Melanoma Margins Trial-II: 1cm v 2cm Wide Surgical Excision Margins for AJCC Stage II Primary Cutaneous Melanoma

Study Overview
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Brief Summary
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Patients with a primary invasive melanoma are recommended to undergo excision of the primary lesion with a wide margin. There is evidence that less radical margins of excision may be just as safe. This is a randomised controlled trial of 1 cm versus 2 cm margin of excision of the primary lesion for adult patients with stage II primary invasive cutaneous melanomas (AJCC 8th edition) to determine differences in disease-free survival. A reduction in margins is expected to improve patient quality of life.

Detailed Description
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This study will determine whether there is a difference in disease-free survival rates for patients with primary cutaneous melanoma with Breslow thickness > 2mm or 1-2mm with ulceration (pT2b-pT4b, AJCC 8th edition), treated with either a 1cm excision margin or 2cm margin. The study is designed to be able to prove or disprove that there is no difference in risk of the tumour recurring around the scar or anywhere else in the body between the two groups of patients. If the study shows no risk of tumour recurrence then we will also be able to determine how much of an impact the narrower excision has on patients in terms of improved quality of life and reduced side effects from the surgery and melanoma disease. This trial will also evaluate and determine the economic impact of narrower excision margins on the health services and society in general.

Official Title
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Melanoma Margins Trial-II - A Phase III, Multi-centre Randomised Controlled Trial Investigating 1cm v 2cm Wide Surgical Excision Margins for AJCC Stage II Primary Cutaneous Melanoma (02.18 MelMarT-II)

Conditions
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Cutaneous Melanoma, Stage II

Intervention / Treatment
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* Procedure: Wide Local Excision = 1cm Margin
* Procedure: Wide Local Excision = 2cm Margin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have a stage II primary invasive cutaneous melanoma with Breslow thickness >2mm without ulceration), or >1mm (with ulceration only) (pT2b-pT4b, AJCC 8th edition) as determined by diagnostic biopsy (narrow excision, incision or punch biopsy) and subsequent histopathological analysis. Must have a primary melanoma that is cutaneous (including head, neck, trunk, extremity, scalp, palm or sole). An uninterrupted 2cm margin must be technically feasible around biopsy scar or primary melanoma. Surgery (which refers to the staging sentinel node biopsy and wide local excision as these are both to be done on the same day) must be completed within 120 days of the original diagnosis. Patients must be 18 years or older at time of consent. Patient must be able to give 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 PI. Patients must have an ECOG performance score between 0 and 1. 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, There has been no evidence of recurrence of any prior malignancies for at least FIVE years (except for successfully treated cervical or non-melanoma skin cancer with no evidence of recurrence), and The patient is deemed by their treating physician to be at low risk of recurrence from previous malignancies. Exclusion Criteria: Patients will be excluded from the study for ANY of the following reasons: Uncertain diagnosis of melanoma i.e. so-called 'melanocytic lesion of unknown malignant potential'. Patient has already undergone wide local excision at the site of the primary index lesion. Patient unable or ineligible to undergo staging sentinel lymph node biopsy of the primary index lesion. Desmoplastic or neurotropic melanoma: with any patient where pathology determines melanoma as PURE desmoplastic (as per WHO definition of >90% desmoplasia), they are not eligible for this study. However other desmoplasia or mixed subtypes are eligible unless there is neurotropism present (peri-neural invasion).Peri-neural invasion does not include entrapment of nerves within the main primary tumour mass. Microsatellitosis as per AJCC 8th edition definition Subungual melanoma Patient has already undergone a local flap reconstruction of the defect after excision of the primary and determination of an accurate excision margin is impossible. History of previous or concurrent (i.e., second primary) invasive melanoma. Melanoma located distal to the metacarpophalangeal joint; on the tip of the nose; the eyelids or on the ear; genitalia, perineum or anus; mucous membranes or internal viscera. Physical, clinical, radiographic or pathologic evidence of satellite, in-transit, regional, or distant metastatic melanoma. Patient has undergone surgery on a separate occasion to clear the lymph nodes of the probable draining lymphatic field, including sentinel lymph node biopsy, of the index melanoma. Any additional solid tumour or hematologic malignancy during the past 5 years except T1 skin lesions of squamous cell carcinoma, basal cell carcinoma, or uterine/cervical cancer. Melanoma-related operative procedures not corresponding to criteria described in the protocol. Planned adjuvant radiotherapy to the primary melanoma site after Wide Local Excision is not permitted as part of the protocol and any patients given this treatment would be excluded from the study. History of organ transplantation. Oral or parenteral immunosuppressive agents (not topical or inhaled steroids) at enrolment or within 6 months prior to enrolment. Pregnancy is not a specific exclusion criterion for this trial, though it may not be clinically appropriate to perform a wide excision and sentinel node biopsy until the pregnancy has been completed, which is likely to exclude the patient due to violation of inclusion criterion 4. We would advise careful counselling of the patient prior to enrolling the patient, which would include a discussion at the treating centre's multidisciplinary team meeting or tumour board. We would strongly advise contacting the central trial office to discuss the case prior to enrolling on the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (Wide Local Excision = 1cm Margin)<br>1cm Wide Local Excision margin + Sentinel Lymph Node Biopsy +/- Reconstruction | Procedure: Wide Local Excision = 1cm Margin<br>* A wide local excision involves removing an extra safety margin of skin surrounding the original melanoma site, to ensure that any remaining scattered melanoma tumour cells that may have been left behind after the first initial biopsy/surgery are removed.<br>|
| Active Comparator: Arm B (Wide Local Excision = 2cm Margin)<br>2 cm Wide Local Excision margin + Sentinel Lymph Node Biopsy +/- Reconstruction | Procedure: Wide Local Excision = 2cm Margin<br>* A wide local excision involves removing an extra safety margin of skin surrounding the original melanoma site, to ensure that any remaining scattered melanoma tumour cells that may have been left behind after the first initial biopsy/surgery are removed.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-Free Survival | Time from randomisation to clinically, histologically or radiologically confirmed recurrence of melanoma | 0-60 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local Recurrence | Time from randomisation to any clinically, histologically or radiologically confirmed local recurrence of melanoma including satellite lesions and in transit metastases to regional draining lymph nodes | Day 0-Trial Completion (max. 120 months) | 
| Distant Disease-Free Survival | Time from randomisation to any clinically, histologically or radiologically confirmed distant recurrence of melanoma | Day 0-Trial Completion (max. 120 months) | 
| Melanoma-Specific Survival | Time from randomisation to death due to melanoma | Day 0-Trial Completion (max. 120 months) | 
| Overall Survival | Time from randomisation to death from any cause | Day 0-Trial Completion (max. 120 months) | 
| Melanoma-specific Quality of Life: FACT-M questionnaire | Measured by FACT-M (Functional Assessment of Cancer Therapy - Melanoma) questionnaire - It consists of two subsections: The FACT-G subsection is a 27-item compilation of general questions divided into four primary QOL domains: Physical Well-Being, Social/Family Well-Being, Emotional Well-Being, and Functional Well-Being. It is considered appropriate for use with patients with any form of cancer. The Melanoma Surgery Subscale evaluates melanoma-specific symptoms such as surgical morbidity and side effects. | Baseline, 3, 6, 12 & 24 months | 
| Neuropathic Pain: PainDetect questionnaire | Measured by PainDetect questionnaire | Baseline, 3, 6, 12 & 24 months | 
| Health-related Quality of Life: EQ-5D-5L questionnaire | Measured by EuroQoL EQ-5D-5L questionnaire - This tool contains 5 domains including mobility, self-care, usual activities, pain/discomfort and anxiety/depression. | Baseline, 3, 6, 12 & 24 months | 
| Surgery Related Adverse Events | The following surgical adverse events will be recorded from the time of surgery to 90 days following surgery (inclusive): wound dehiscence seroma/haematoma haemorrhage infection skin graft failure necrosis of flap used for reconstruction deep venous thrombosis urinary tract infection pneumonia cardiac complications lymphoedema | Up to 90 days from the date of surgery | 
| Adverse Events | An Adverse Event (AE) is any untoward medical occurrence in a participant administered a treatment which does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavourable or unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the treatment timing, whether or not considered related to the treatment. An AE is any adverse change (developing or worsening) from the participant's pre-treatment condition, including intercurrent illness. | Within 1 year from randomisation | 
| Health Economic Evaluation | Data collected for economic analysis will be from hospital notes, MBS and PBS data (Australia) and patient reported outcome measures (including an employment questionnaire) at baseline, 3, 6, 12 and 24 months and at melanoma recurrence. | Baseline, 3, 6, 12 & 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Malignant, Melanoma, Cancer, Surgery