Melanoma is a type of skin cancer originating in the pigment-producing melanocytes between the epidermis and the dermis. The primary risk factor for melanoma is UV exposure, and thus it is a largely preventable cancer. Melanoma is one of the 13 skin conditions identified as having a significant burden of disease by the WHO Global Burden of Disease Project (2010). The worldwide incidence of melanoma was approximately 232,130 cases in 2012, with 55,488 deaths recorded (WHO/IARC). The Irish National Cancer Registry predicts that skin cancers (melanoma and non-melanoma skin cancers) will see the greatest increase in incidence of all cancers in the years 2015 to 2040. Metastatic melanoma is diagnosed at a younger median age than many cancers, resulting in a significant impact for patients, family and wider society. The health burden and economic costs of cutaneous melanoma in the USA has been estimated at $3.5billion annually in the period 2002-2006. The objective of this review is to assess the effects of neoadjuvant treatments for Stage III and IV melanoma in adults. Historically Stage III and IV melanoma have been associated with a very poor prognosis, and available treatments have had very little impact on the disease course. Various clinical options have been explored, including combinations of surgical procedures, chemotherapy, immunotherapy, vaccines, and radiotherapy, in both neoadjuvant and adjuvant settings. Since 2011, there has been a dramatic increase in the availability of systemic treatments which improve the prognosis of patients with melanoma, and now there is an emphasis on determining the optimal clinical use of these agents. In tandem with this, there has been a renewed interest in neo-adjuvant treatment of melanoma, not just in Stage IIIc and IV patients, but also in Stage IIIa and IIIb patients who are considered to be at increased risk of developing malignant or metastatic disease. It is hypothesised that the neoadjuvant uses of the new immunotherapies and other targeted treatments have the potential to ‘shrink’ existing tumours so that complete surgical resection of the disease may be possible (Johnson et al. 2015). There is already a considerable body of literature relating to neoadjuvant treatment in melanoma, but there are no high-quality systematic reviews or meta analyses published to quantify the treatment effects of the various regimens. This review aims to address this gap in the literature, and should act as a reference point for the relative efficacy of future neoadjuvant treatments. It is intended to include only randomised controlled trials (RCT’s) in the systematic review, to ensure that unbiased estimates of clinical effect are identified. The population will be limited to adults with American Joint Committee on Cancer (AJCC) Stage III or IV melanoma. The interventions of interest are neoadjuvant treatments for metastatic melanoma. This includes, but is not limited to the following agents (alone or in combination)-radiotherapy, vemurafenib, dabrafenib, trametinib, cobimetinib, ipilimumab, nivolumab, pembrolizumab, talimogene laherparepvec, epacadostat, electrochemotherapy, temozolamide, dacarbazine, interferon, bevacizumab, GM-CSF, interleukin-2, axitinib. The relevant comparators will be placebo, observation or standard of care. Currently there are no standardised set of outcomes measures in melanoma trials. As the treatment landscape evolves, newer agents are granted regulatory approval on the basis of surrogate outcomes such as progression free survival. The selection of endpoints for neo-adjuvant trials is an even greater challenge for regulators. The FDA and EMA have approved a neo-adjuvant treatment for breast cancer based on an endpoint of pathological complete response (pCR), but it is unclear if they will accept this endpoint for neoadjuvant treatments in other disease areas. It is intended that the outcomes collected are relevant to decision makers (clinicians and patients) and thus the following outcomes are suggested: Primary outcomes: 1. Pathological Response rate (complete, partial, stable or progressive disease) 2. Safety, adverse events and tolerability
3. Disease free survival
Secondary outcomes: 1. Survival outcomes (overall survival and progression-free survival) 2. Patient reported outcomes e.g. health related quality of life
3. Economic evaluation
