Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)
Stage IV melanoma is defined by the American Joint Committee on Cancer's TNM classification system:
Analytic validity refers to how well a genetic assessment measures the property or characteristic it is intended to measure. In the case of family history, analytic validity refers to the accuracy of the reported family history information. In the case of a test for a specific mutation, analytic validity refers to the accuracy of a genetic test in identifying the presence or absence of the mutation. The technical accuracy and reliability of the testing procedure and the quality of the laboratory...
Standard Treatment Options for Patients With Stage IV and Recurrent Melanoma
Standard treatment options for patients with stage IV and recurrent melanoma include the following:
Palliative local therapy.
Signal transduction inhibitors.
Palliative local therapy
Melanoma metastatic to distant, lymph node-bearing areas may be palliated by regional lymphadenectomy. Isolated metastases to the lung, gastrointestinal tract, bone, or occasionally the brain may be palliated by resection with occasional long-term survival.[2,3,4]
Although melanoma is a relatively radiation-resistant tumor, palliative radiation therapy may alleviate symptoms. Retrospective studies have shown that patients with multiple brain metastases, bone metastases, and spinal cord compression may achieve symptom relief and some shrinkage of the tumor with radiation therapy.[5,6] (Refer to the PDQ summary on Pain for more information.) The most effective dose-fractionation schedule for palliation of melanoma metastatic to the bone or spinal cord is unclear, but high-dose-per-fraction schedules are sometimes used to overcome tumor resistance. A phase I and II clinical trial (MCC-11543) evaluated adjuvant radiation therapy plus interferon in patients with recurrent melanoma and results are pending.
Melanoma has been refractory to most standard systemic therapy. The two approved treatments, dacarbazine (DTIC) and interleukin-2 (IL-2), have not demonstrated an impact on overall survival (OS) in randomized trials. Attempts over the past two decades to develop novel regimens (e.g., multiagent chemotherapy;[7,8] combinations of chemotherapy and tamoxifen;[9,10,11] combinations of chemotherapy and immunotherapy or biochemotherapy;[7,12,13,14,15,16,17] vaccines; antisense bcl-2 oligonucleotide oblimersen; a reactive-oxide species inhibitor, elesclomol; and others) have also not impacted OS.
However, drug development in melanoma is changing. Significant strides have been made in cataloguing the genetic abnormalities that permit the formation and dissemination of melanoma and in better understanding immunologic checkpoints. The discovery of activating mutations in BRAF in 2002  was followed by the discovery of other mutations, which allowed melanoma to be classified into a group of diseases, and created the opportunity to develop therapies that target the activating molecules and their pathways. The most frequently mutated pathway, the mitogen-activated protein (MAP) kinase pathway, involves the BRAF, NRAS and KIT genes. The single most frequent mutation is in the BRAF gene, with 60% to 70% of malignant melanomas harboring a single nucleotide transversion. In smaller subsets of melanoma, activating mutations may occur in NRAS (15%-20%), c-kit (28%-39% of melanomas arising in chronically sun-damaged skin, or acral and mucosal melanomas), CDK4 (<5%), whereas GNAQ is frequently mutated in uveal melanomas. Drugs developed to target these mutations are currently in clinical trials.