Mini-reviewResearch progress in advanced melanoma
Section snippets
Pathogenesis
How melanoma develops has not been entirely explained. Previous studies identified some risk factors for melanoma development. The main ones are male sex (especially men aged older than 60 years); phenotypic predisposition [1], [2] (people who are sun-sensitive, with red hair and blue eyes, those with atypical moles or a dysplastic nevus pattern etc); medical history and comorbidities [3], [4], [5] (sunburn; precancers such as actinic keratosis; non-melanoma skin cancer such as basal cell and
Progress in treatment
The therapeutic landscape has been rapidly changing in the past decade. Targeted therapy shows better efficacy than traditional chemotherapy. As immune checkpoint agents (e.g., anti-CTLA-4, anti-PD-1) and molecularly-targeted drugs (e.g., BRAF inhibitors, MEK inhibitors) have been included into the treatment of MM, they are gradually taking the place of standard chemotherapy with dacarbazine (DTIC).
In 2017, the National Comprehensive Cancer Network (NCCN) recommendations for patients with
Anti-CTLA-4 inhibitors
CTLA-4 is a member of the immunoglobulin family expressed on the surface of immature cytotoxic T lymphocytes and regulatory T cells. Once the receptor on immature T cell is activated, CTLA-4 competes with CD28 for binding to B7, shutting down the signaling cascade and then inhibiting the immune response. Ipilimumab is a monoclonal antibody against the immune checkpoint receptor CTLA-4. It prevents receptor–ligand interactions, removing the inhibition of T-cell activation and increasing the
BRAF inhibitor monotherapy
Vemurafenib and dabrafenib were developed to inhibit BRAF with mutations at V600 [43], [44], [45]. Results from phase III trials for previously untreated patients with unresectable stage IIIc or stage IV MM, such as BRIM-3 [46], [47] and BREAK-3 [48], [49], showed that monotherapy with either of these agents improved response rates (vemurafenib 48% vs. DTIC 5%, dabrafenib 50% vs. DTIC 5%), PFS (vemurafenib 6.9 months vs. DTIC 1.6 months, dabrafenib 5.1 months vs. DTIC 2.7 months), and OS
Chemotherapy
Common cytotoxic agents used in MM include dacarbazine (DTIC), temozolomide (TMZ), paclitaxel, albumin-bound paclitaxel, and nitrosourea. DTIC monotherapy is still the standard chemotherapy in melanoma treatment. TMZ has a similar mechanism of action as DTIC. A phase III trial showed that DTIC and TMZ were similar with respect to survival time, response rates, and toxicities. However, TMZ showed better efficacy in PFS and quality of life than DTIC [62]. Another study showed that for patients
Biochemotherapy
Biochemotherapy is the combination of chemotherapy and biological agents. Multiple phase II and III trials in patients with metastatic melanoma revealed that biochemotherapy (DTIC or TMZ, cisplatin, and vinblastine or nitrosourea, plus interferon-α [IFN-α] and interleukin-2 [IL-2]) led to overall response rates of 21%–64% and complete response (CR) rates of 7.5%–21% [64], [65], [66], [67]. However, some studies also showed that biochemotherapy had little survival benefit and increased toxicity
High-dose IL-2
High-dose IL-2 has been used extensively in the first-line and second-line settings for advanced melanoma. Though median OS is 11–12 months, approximately 10% patients achieve long-term survival of more than 5 years [70], [71], [72]. A retrospective study that analyzed 305 patients treated with high-dose IL-2 in the second-line setting showed that CR rate was 4% and median duration of response was more than 176 months [70]. However, high-dose IL-2 therapy is associated with significant
Prospects
The incidence of melanoma is rapidly increasing all over the world, with 5-year survival rates of approximately 6% for MM and a median OS of about 6–8 months. In recent years, the therapeutic landscape has rapidly changed with the development of novel agents including BRAF inhibitors, anti-CTLA-4 agents, and anti-PD-1 agents. These new therapies bring hope to patients with MM. However, it's still impractical for most patients because of the high cost and lack of availability in some places.
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