When there are distant metastases…
Once distant metastases are identified, the goal of therapy should be palliative care as this condition is generally incurable. Chemotherapy, radiation, and excision of solitary metastases are all interventions that have traditionally been employed.1 The primary site for metastasis is the skin, but all organs are potential sites of spread. Central nervous system metastasis is the most common cause of the death.2
Novel therapies include inhibition of BRAF, an enzyme of the mitogen-activated protein kinase pathway (MAPK), and blocking of cytotoxic T lymphocyte-associated antigen-4 (CTLA-4).
BRAF-enzyme inhibitor. Mutated BRAF contributes to uncontrolled cell growth and resistance to programmed cell death (apoptosis).9,10 In August 2011, vemurafenib (Zelboraf ), a BRAF-enzyme inhibitor, was approved by the US Food and Drug Administration (FDA) for the treatment of late-stage melanoma. It works only in patients with the BRAFV600E mutation, which is found in approximately 60% of melanomas.11,12 One phase 1 study showed partial to complete regression in 80% of patients treated, but this regression lasted only 2 to 18 months.13
Anti-CTLA-4 monoclonal antibody. Cytotoxic T-lymphocytes can recognize and potentially destroy cancer cells.14 However, CTLA-4, which is expressed on the surface of cytotoxic T-lymphocytes, has a suppressive effect on the T-lymphocyte response after interaction with the antigen-presenting cell. Researchers deduced that blocking CTLA-4 would allow the immune system to remain responsive to abnormal antigens, including those from melanoma.9
Ipilimumab (Yervoy), an anti-CTLA-4 monoclonal antibody, was approved by the FDA in March 2011 for the treatment of late-stage melanoma.11 Partial and complete responses have been shown in trials of ipilimumab as monotherapy and in combination with vaccines, chemotherapy, and interleukin-2, but these responses have not been sustained.9
Although these novel therapies represent significant advancements in the understanding of the pathogenesis of melanoma, the short duration of efficacy highlights the cancer’s ability to develop resistance to these treatments. This ability to adapt suggests that melanoma harbors multiple oncogenes and several pathways for carcinogenesis. Combination targeted therapies may be required to improve clinical results; research is ongoing.9 Toxicities associated with these medications are also a limiting factor.
What about vaccines? Vaccine studies are also ongoing. Although some have shown promising results, no clearly effective therapy has been produced to date.2
Factors that affect prognosis
The prognosis for melanoma is related to tumor thickness, presence or absence of melanoma in regional lymph nodes, and extent of metastases.1-4 The TNM classification system takes these factors into account in staging melanoma.4 Based on this staging, a 5- and 10-year survival estimate can be discussed with the patient.
Survival estimates based on depth of invasion alone are also used. As an example, one study cited a 5-year survival rate of 95% for a tumor thickness <.75 mm; 85% (.75-1.4 mm); 66% (1.5-3.9 mm); and 46% (≥4 mm).1
Other variables that affect prognosis include lymphocytic infiltrate (more brisk and tumor infiltrating is better prognostically), mitotic rate (less is better; >6/mm2 is worse), ulceration (worse prognostically), and regression of the tumor.2 Regression will appear as areas of depigmentation in a previously completely pigmented lesion; it is associated with a poorer prognosis.1