A New Era in the Treatment of Oligometastatic Melanoma {#sec2} ============================================================= For decades, melanoma has represented the main cause of death among skin cancer. The introduction of new effective drugs, as well as the development of new tools for treating cancer (e.g., checkpoint blockade, vaccine, and anti-angiogenic and anti-angiogenic-enhancer agents) represent, to date, the main factors underlying the 5% yearly increase in the incidence of this cancer. More specifically, the introduction of BRAF- and c-kit-targeting drugs and the use of checkpoint blockers have all allowed the reduction in the incidence of metastatic melanoma, with an increase in both overall survival (OS) and progression-free survival (PFS).[@bib6]^,^[@bib7] Thus, stage III and IV melanomas---characterized by high levels of lymph node and distant metastases---have been reported to have a median OS of 7 and 4 years, respectively, after chemotherapy or immunotherapy, while stage IVa and IVb melanoma patients with brain metastases have an OS of 5.7 and 3.7 years, respectively, in the presence of active systemic treatment.[@bib6]^,^[@bib7] Despite the introduction of these new drugs, however, the prognosis of patients with metastatic melanoma remains unsatisfactory and new therapies are needed to further improve the OS of these patients.[@bib8] In this light, it is believed that the development of a new therapeutic approach will also improve the outcome of patients with distant relapse. It is in this perspective that the use of local ablative treatments for the treatment of metastatic disease has been investigated. 2.1. The Use of Local Ablative Treatments in Melanoma {#sec2.1} ----------------------------------------------------- The use of local ablative treatments in metastatic melanoma is growing and more than 20 different modalities are being tested at an increasing rate.[@bib9]^,^[@bib10] These ablative techniques include surgical resection, radiotherapy, intra-arterial therapies (IAT), electrochemotherapy, and, more recently, radiofrequency-induced thermal therapies. ### 2.1.1. Surgery {#sec2.1.1} Surgical resection of metastatic lesions has been performed by physicians for over a century, with resection by surgical excision, surgical removal of tumor tissue via an open resection, or excisional biopsy or via minimally invasive surgical resection via needle insertion.[@bib11] Although surgical removal can be performed to reduce a high tumor burden, chemotherapy or immunotherapy has often been recommended as adjuvant therapy after surgery to enhance local control and improve OS.[@bib12]^,^[@bib13] In fact, surgery is not currently considered a standard of care after the achievement of a radiological response, because many metastatic lesions that can be removed show viable tumor cells in the margins of surgical resection and these can lead to local recurrence.[@bib14] ### 2.1.2. Radiotherapy {#sec2.1.2} The main indication for radiation is to palliate the symptoms of local disease rather than to provide a local cure of metastatic melanoma.[@bib15] Although it is generally accepted that radiotherapy is safe for treating the primary disease, radiation oncology guidelines recommend that radiotherapy is not a preferred local therapy for metastatic disease.[@bib16] Most radiotherapy treatment plans that aim to palliate symptomatic disease, such as pain from bone metastasis, do not benefit overall patient survival or increase disease-free survival.[@bib17] Moreover, systemic treatments are increasingly being used to control metastatic melanoma and can be used in combination with radiotherapy.[@bib15] ### 2.1.3. IAT {#sec2.1.3} IATs have been developed for primary melanoma with a high probability of lymph node involvement. The IATs include lymph node embolization and radioembolization, such as Yttrium-90-labeled glass microspheres or Iodine-125 brachytherapy and radiofrequency ablation (RFA).[@bib18] The main mechanism of action of these procedures is the obstruction of the lymphatic flow through the application of embolization material or the intra-arterial injection of microspheres. In the case of chemotherapy, the obstruction can be followed by the rapid delivery of the chemotherapeutic drug through the obstructed vessels, via the tumor-feeding vessels.[@bib19] The radiofrequency ablation acts by heating the tumor tissue until ablation or coagulative necrosis occurs.[@bib20] According to the 2015 NCCN guidelines, there are no recommendations for these IAT procedures in patients with metastatic melanoma.[@bib21] ### 2.1.4. Electrochemotherapy (ECT) {#sec2.1.4} ECT has been demonstrated as a safe and effective local therapy for metastatic lesions, resulting in high response rates with overall response rates (ORR) between 75% and 85% in melanoma patients.[@bib22]^,^[@bib23] This modality is based on the injection of bleomycin in combination with an electric field that allows for a transitory local disorganization of the tumor cells that results in tissue necrosis.[@bib24] The electric field is achieved by injecting the chemotherapy drug directly into the lesion, and then a high voltage electric current is applied to deliver a local electric shock (50--100 kV) that induces cell death.[@bib24] Recently, a randomized phase II trial confirmed the safety of ECT, in which the patients received ECT after a complete response (CR) to first-line chemotherapy with a median disease control rate (DCR) of 36 months. Additionally, the ECT-treated patients had a better PFS and OS compared with those treated with chemotherapy.[@bib25] ### 2.1.5. High-Intensity Focused Ultrasound {#sec2.1.5} High-intensity focused ultrasound (HIFU) is a technique that employs ultrasound beams to induce target tissue necrosis, based on two principles: the acoustic waves can focus at a specific location within the body to produce high temperature (overheating tissue); and low-frequency ultrasound beams can generate cavitation, which acts by rupturing cell membranes. However, to date, no convincing clinical data are available to support the use of HIFU for the treatment of advanced melanoma.[@bib26] 2.2. HIFU in Melanoma Treatment {#sec2.2} ------------------------------- Recently, an increasing number of trials have been conducted to evaluate the safety and efficacy of HIFU in the management of metastatic melanoma patients with limited systemic treatment options. However, the results of these trials showed a limited response rate and few complete responses.[@bib27], [@bib28], [@bib29], [@bib30] A prospective study by Iwase et al[@bib31] evaluated the effect of HIFU therapy in a total of 10 melanoma patients in the clinical study (four cases of primary, two of lymph nodes and four of skin metastases). They showed that HIFU therapy had a clinical benefit in eight of ten cases, with a median survival of 9.2 months, while the two patients who died had liver metastases, suggesting that the survival of patients with multiple metastatic tumors is shorter than that of patients with solitary lesions.[@bib31] Based on the evidence available from the literature, it is difficult to conclude that HIFU is an effective therapeutic option for the management of metastatic melanoma patients with liver metastases.[@bib32] Further research is needed to identify additional and potentially effective therapeutic approaches. ### 2.2.1. RFA {#sec2.2.1} RFA is another method of local tumor destruction that is useful for palliation of symptomatic cutaneous lesions or lesions that have not responded to radiation treatment. It is indicated for patients with painful cutaneous lesions, such as melanoma, Kaposi sarcoma, and lung carcinoma.[@bib33] This treatment can also be used as a therapeutic strategy for tumors with a large volume that is associated with significant local symptoms and is resistant to chemotherapy or radiotherapy. ### 2.2.2. RFA: Combination of IRT in Melanoma {#sec2.2.2} Recently, a pilot study investigated the efficacy and safety of electrochemotherapy after percutaneous RFA to treat cutaneous and subcutaneous lesions in patients with metastatic melanoma.[@bib34] This is a study on the combination of radiofrequency-induced thermal therapy with electrochemotherapy (ECT-RFA) to treat metastatic melanoma. A total of 16 patients were treated with ECT-RFA after a clinical evaluation showed that the lesion had no significant response to systemic treatments, including radiation. ECT-RFA improved the quality of life in the early months after treatment.[@bib34] 3. Melanoma and Nanotechnology {#sec3} ============================== The development of new anti-melanoma drugs is limited by the limited ability to deliver active agents to the tumor site.[@bib35] For this reason, new technologies, such as drug-carrying nanoparticles (NPs), which can be used for the specific drug targeting of tumors, are being investigated.[@bib36] NPs are defined as structures that range from 1 to 1000 nm in size. The use of NPs allows controlled, sustained, and local delivery of drugs, nucleic acids, and nucleic acid analogues to a targeted site. In particular, the use of these structures allows the active substances to be delivered to cells that are distant from their administration site, reducing the risk of adverse effects on normal cells, reducing systemic toxicity, and limiting the adverse effects induced by the drug.[@bib37] Moreover, the use of NPs increases the intracellular concentration of active molecules, even after systemic administration. Therefore, NP-mediated delivery of drugs improves the therapeutic