MULTIDISCIPLINARY APPROACH TO PATIENTS WITH MALIGNANT MELANOMA

The incidence of melanoma is increasing worldwide and prognosis of melanoma patients is still poor. The median survival for melanoma patients with metastatic disease is 89 months, and the 3-year overall survival (OS) rate is less than 15% (1, 2). Surgical excision is the main treatment for primary cutaneous melanoma (3). However controversies about the necessary margins of excision still remain (4). Sentinel lymph node biopsy (SLNB) provides an important prognostic and staging data by the identification of regional node-negative patients who would not benefit from a complete nodal dissection. However there is no consensus about SNLB and the depth of the primary melanoma (5). To date, IFN-α is the only approved adjuvant treatment after surgical excision of melanoma. However its indication remains controversial because of the limited benefit upon disease-free survival and the smaller potential improvement of overall survival (2, 6). Dacarbazine has been the standard first-line therapy for patients with metastatic disease for a long time. However treatment with this agent was associated with a response rate less than 15% and no clinical trials have been reported to improve the overall survival (OS) (7). Recently, two drugs have been approved for the treating patients with metastatic melanoma. The first one, ipilimumab, is a monoclonal antibody which targets the Cytotoxic T-Lymphocyte Antigen 4 (CTLA4). Two phase III clinical trials, comparing ipilimumab with dacarbazine, demonstrated an improved survival for patients treated with ipilimumab. Nevertheless, this agent resulted to be effective only in a subset of patients and the toxicity caused by the treatment was considerable. Vemurafenib is the second drug that has been approved for the treatment of metastatic melanoma. It is an agent that selectively targets BRAF, a component of the MAPK pathway. Approximately 60% of all melanomas harbor activating mutations in BRAF oncogene such as the substitution of glutamic acid for valina at amino acid 600 (V600E). Treatment with vemurafenib has shown to improve OS and to induce tumor regression in approximately 50% of treated patients with metastatic melanoma carrying a BRAF V600E. However the response are rarely complete and the median time to disease progression is less than 7 months due to develop of intrinsic or secondary resistance. Several mechanisms of resistance have been described and clinical trials are testing new combinatorial strategies with the aim to overcome the intrinsic or the acquired BRAF-inhibitor resistance. In addition, several other biological agents are in phase of experimentations in melanoma but really promising drugs are not yet available.