Melanoma is the third most common cutaneous malignancy after basal cell carcinoma and squamous cell carcinoma. In 2016, it is estimated that 76,380 cases of melanoma will be diagnosed in the United States. Melanoma is the fifth and sixth most common malignancy in males and females, respectively. While most melanomas are at an early stage at diagnoses, a proportion of patients have metastatic disease at diagnoses or develop metastasis at a later stage. Skin and subcutaneous tissue followed by lungs, liver, bones, and brain are the most common sites of metastasis. The treatment paradigm of metastatic melanoma has changed dramatically within the last few years with the advent of immune checkpoint inhibitors and targeted therapy. The treatment modalities that are currently used for metastatic melanoma include surgery, immunotherapy, targeted therapy, and chemotherapy.
Melanoma is most likely caused by combined factors, both environmental and genetic. It is believed that ultraviolet radiation from the sun, tanning lamps, and tanning beds are the main etiology of melanoma.
Sun and ultraviolet (UV) radiation exposure is a major risk factor for melanoma. Unlike other skin cancers, the risk of melanoma for sun exposure is not cumulative. Intermittent high-intensity sunlight exposure and sunburns are risk factors for melanoma. Other risk factors for melanoma include strong family history, previous history of dysplastic nevus or melanomas, use of tanning beds, psoralen-ultraviolet A radiation [PUVA] therapy.
Exposure to harmful UV radiation results in melanoma-genesis by two different pathways. UVA light-mediated melanoma-genesis is melanin pigment dependent and induces oxidative damage to the DNA of melanocytes by oxidation. UVB rays trigger melanoma-genesis by direct DNA damage independent of the presence of melanin pigment. The main histopathological subtypes of melanoma are superficial spreading melanoma (commonest type), nodular melanoma, acral lentiginous melanoma and lentigo malignant melanoma.
ABCDE criteria for melanoma (Table 1) are a useful diagnostic tool for early melanoma lesions. When metastatic, the presenting symptoms depend on the organ of involvement. The patient may present with a cough, dyspnea, hemoptysis (lung metastasis), jaundice (liver), seizures (brain metastasis).
Patients with metastatic melanoma would need imaging of the chest, abdomen, and pelvis ( CT or PET/CT) and brain preferably with a magnetic resonance imaging. Serum LDH is a useful biomarker with prognostic value in patients with advanced melanoma.
Surgery has a role in the treatment of metastatic melanoma in a select group of patients who have good performance status, oligo-metastatic disease in accessible locations and good disease control at the primary site. Surgical resection in such patients has been shown to offer improvement in survival when the resection is complete (R0 resection).
Metastatic melanoma is one of the cancers in which the role for immunotherapy has been known for nearly two decades. High-dose interleukin-2 (HD-IL-2) treatment has been shown to be an effective therapy in metastatic melanoma with a very small percentage of patients achieving long-term cures. HD-IL2 has a response rate of about 16% (6% complete response and 10% partial responses) in patients with metastatic melanoma.
Immune checkpoint inhibitors are drugs that unmask the inhibition of host immune cells in the tumor microenvironment thereby activating a host immune response to fight cancer. Ipilimumab, an inhibitor of immune down-regulator CTLA4 inhibitors was the first approved immunotherapy in the melanoma. In the phase 3 trials that evaluated the efficacy of ipilimumab in patients with metastatic melanoma, the median overall survival was 10 to 12 months, and about 21% of patients had long-term survival (greater than 3 years). Programmed cell death protein-1 (PD-1) inhibitors nivolumab and pembrolizumab reverse the immune suppression in the tumor microenvironment and have been shown to be effective in both first line and second line setting in the treatment of metastatic melanoma. As a single agent, the PD-1 antibodies have about 35% to 45% response rates in metastatic melanomas. The combination of nivolumab with ipilimumab is associated with greater response rate (58%) albeit with greater toxicity.
Unlike conventional chemotherapy, responses seen with immune-checkpoint inhibitors tend to be slower but durable. Pseudo-progression can be seen initially with these agents and responses should be evaluated according to the immune-related response criteria. The main adverse effects of these checkpoint inhibitors are autoimmune in nature. Autoimmune colitis, pneumonitis, thyroiditis, and hypophysitis are some of the adverse events noted with these agents. In patients with mild to moderate toxicities, a temporary delay in treatment with or without the use of systemic steroids can reverse these side effects. In patients with severe adverse effects, a complete cessation of therapy would be warranted.
The mitogen-activated protein kinase (MAPK) pathway (Ras/Raf/MEK/ERK pathway) is activated in cutaneous melanomas. BRAF (V600E or V600K) is a driver mutation seen in about 50% of patients with metastatic melanoma. BRAF inhibitors have been shown to be effective in the treatment of BRAF mutated metastatic melanoma as single agents and as a combination with and MEK inhibitors. The median survival of metastatic melanoma patients treated with BRAF inhibitors alone ranges from 14 to 18 months. When combined with MEK inhibitors, the survival improves to greater than two years. Secondary cutaneous malignancies are a significant toxicity noted with BRAF inhibitors alone, and that risk is negated with the addition of a MEK inhibitor. Rash and pyrexia are some of the other adverse effects of these agents. The list of approved targeted agents for the treatment of melanoma is provided in Table 2.
Historically, chemotherapeutic agent dacarbazine was the standard of care for metastatic melanoma patients who were not IL-2 candidates. Taxanes and temozolomide are other agents that have activity in melanoma. However, with the advent of effective immunotherapy and targeted therapy, systemic chemotherapy is reserved only for patients who are not a candidate for both these treatment strategies.
Radiation therapy is indicated in-patient with brain metastasis (stereotactic radiosurgery). Stereotactic body radiation (SBRT) can be used for treating oligo-metastatic disease. Otherwise, radiation is reserved for palliation.
Table 1: ABCDE criteria for melanoma detection asymmetry
Table 2: Molecularly targeted therapy approved by FDA for the treatment of BRAF mutated melanoma
BRAF and MEK inhibitors combinations
Management of metastatic melanoma is complex and needs a multidisciplinary approach involving surgical oncologists, medical oncologists, radiation oncologist and radiologists. Surgical oncologist and interventional radiologist play a key role in sampling of the tumor. After this, a medical oncoloigst typically carries forward management with targeted therapy or immunotherapy. A radiation oncoligst is typically involved for treatment of brain metastasis or for pallative radiation to metastatic sites. Radiologist also play a key role in reading scans pre and post treatment so that the effectiveness of treatment can be measured. Nursing staff and pharmacist also play a very important role in proper verfication of drug doses, administration and side effects management. Furthermore other disciplines such as endocrinology, pulmonology may be involved in melanoma mangement should the patient develop simmune mediated adverse effects (Level I).
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