Title: Melanoma Margins Trial-II: 1cm v 2cm Wide Surgical Excision Margins for AJCC Stage II Primary Cutaneous Melanoma (MelMarT-II)
Funder: Department of Health and Social Care

Abstract: Melanoma accounts for the great majority of skin cancer deaths in the UK. Since the 1990s the diagnosis of melanoma has more than doubled. According to World Health Organisation statistics, the UK has one of the highest death rates from skin cancer in the world. In contrast to most other cancers, melanoma tends to affect much younger people, with nearly half the patients diagnosed at <65 years old._x000D_ _x000D_ Melanoma has a tendency for recurring around the original biopsy site in a very aggressive manner, making it a very challenging problem to treat when it occurs. To prevent local recurrence, the standard treatment has been to take a further safety margin of normal skin and soft tissue around the original melanoma biopsy site. This treatment is offered to every patient diagnosed with melanoma. Surprisingly, this margin of safety has yet to be standardised for melanoma, with a significant variety of excision margins being recommended (from 1 cm to 3 cm depending on the initial stage of the disease) in different countries. Since melanoma commonly occurs on the head & neck region or on the limbs, the cosmetic and functional implications for patients with such large defects are substantial._x000D_ _x000D_ The rate of local recurrence for melanoma is quite low (2-8%) and, despite several large clinical trials, there is little evidence that performing such wide excisions changes recurrence rates or improves survival for our patients. Given that the overall 10-year survival for melanoma is now 90% internationally, with approximately 150,000 people in the UK currently living with the diagnosis, this has become a key survivorship issue for these patients. Accordingly, a clinical trial has been recommended by the international surgical community to test the safety of narrower surgical margins and to improve patients’ quality of life after surgery._x000D_ _x000D_ MelMarT-II is a simple randomised clinical trial. Patients from British and Australian melanoma charities helped to develop this trial. This study is designed to be able to prove or disprove that a 1 cm excision margin is just as safe as a 2 cm margin for high-risk melanoma of the skin. This study is designed to show that the risk of long-term pain associated with surgery can be halved and quality of life can be improved with a 1 cm margin due to reduced side effects and need for reconstructive surgery after treatment. This trial will also evaluate the economic impact of safely using less surgery for the NHS and society in general._x000D_ _x000D_ It is expected that this study will define the surgical treatment world-wide for all high-risk melanoma patients. Australian collaborators have been successfully awarded a major grant (AUD $2.76M) to manage this trial, and to recruit in Australia. Funding secured from NIHR gives UK patients the opportunity to contribute to this truly international collaboration. This trial is very relevant to the UK population - 1 in 4 of all patients with invasive melanomas will be affected by the outcome. The financial implications for future treatment in the NHS are significant. The centralised nature of cancer care in the NHS is perfectly positioned for the UK to make a leading contribution to this study, and we aim to recruit about 30% of the total needed. Other countries, such as Canada, Sweden and USA have also been awarded similar grants nationally to participate in this trial.

Lay abstract: RESEARCH QUESTION: Could a narrower excision margin of 1cm be safely performed without changing disease-free survival when compared to a 2cm excision margin in patients at risk of recurrence?_x000D_ _x000D_ BACKGROUND: Melanoma skin cancer is the 5th most common cancer in the UK, accounting for 4% of all new cancer cases. Since the early 1990s, incidence rates have more than doubled (increase of 134%) and are projected to continue to rise beyond 2034. In contrast to most cancer types, melanoma occurs relatively frequently at younger ages. Melanoma has a preponderance for extensive local recurrence (LR) and this event is often a very challenging problem to treat. The current standard treatment to prevent this is a wider excision of a prophylactic safety margin of normal skin and soft tissue (a wide local excision “WLE”) around the previous melanoma biopsy site. However, despite being offered as a treatment to every patient diagnosed with melanoma, the effective margins have yet to be standardised. In particular, for patients with high-risk melanomas (stage II) the optimal WLE margin is controversial. The current NICE Melanoma Guidelines (2015) recommend a 2cm or 3cm margin for patients with stage II melanoma, although other international guidelines recommend between 1-3cm margins, reflecting the paucity of the existing evidence._x000D_ _x000D_ AIMS/OBJECTIVES: The primary aim of the trial is to assess whether there is no difference in disease-free survival for patients treated with a 1cm excision margin when compared to a 2cm margin for stage II primary melanomas. The secondary aims are to assess whether health related quality of life (HRQoL) and surgical complication rates are improved for patients receiving the narrower excision and whether there is a benefit on resource use within the UK._x000D_ _x000D_ METHODS: This is a prospective, phase III, multinational, non-inferiority randomised controlled trial (RCT); a multinational effort between Australia, the UK, Canada, Sweden and the US. Overall, the aim is to recruit a total of 2998 adults with histologically confirmed, primary invasive cutaneous melanoma; it is expected that the UK will contribute 750 of this total (25%) from 20 NHS sites. Patients will be randomised 1:1 to receive a WLE with 1cm radial margin versus a WLE with 2cm radial margin. The primary outcome is time to disease free survival; secondary outcomes will assess local recurrence, distant recurrence, disease-specific and all-cause mortality, HRQoL and adverse events. A standalone health economic analysis will be performed for the UK cohort of patients to determine cost-effective and inform NICE guidelines._x000D_ _x000D_ ANTICIPATED IMPACT AND DISSEMINATION: This trial will provide important evidence to safely reduce the standard surgical procedure with the potential to benefit 1 in 4 of all patients with melanoma who are at highest risk of recurrence. It is anticipated that the narrower excision will maintain equivalent oncological outcomes compared to the wider excision whilst also improving HRQoL, reducing surgical complications and resulting in substantial cost savings for the NHS. If this trial shows that the narrower excision is beneficial to patients then it is anticipated that it will become standard of care and result in a change to current NICE Melanoma Guidelines. Participants will be informed of the study results via the Surgical Intervention Trials Unit (SITU) website and through the patient charity, Melanoma UK.

Research activity codes: 6.4 SURGERY
Health categories: CANCER AND NEOPLASMS