Medication Summary
High-dose interferon (IFN) alfa-2b is the only adjuvant therapy approved by the FDA for high-risk resected melanoma, defined as deep primaries greater than 4 mm in Breslow depth (AJCC stage IIB) and regional lymph node metastasis (stage III). Various trials of low-dose IFN have shown no benefit in disease-free relapse or overall survival (OS) rates.[46]
Similarly, multiple melanoma vaccine trials are in progress, predominantly for stage III and IV disease, but they have not demonstrated an OS advantage to date.
Ipilimumab, a CTLA-4 blocker, enhances the T-cell response in HLA2-positive patients and demonstrates remarkable promise in patients with metastatic melanoma. It is being studied by itself and in combination with other immunotherapies and vaccines.[41]
Antineoplastic Agents
Class Summary
These agents inhibit cell growth and differentiation. Chemotherapeutic agents used to treat melanoma include dacarbazine, cisplatin, vinblastine, carmustine, and tamoxifen.
Dacarbazine
Although the mechanism of action for dacarbazine is unknown, possible actions include alkylating agent, purine metabolite, or interaction with sulfhydryl groups. The end result is inhibition of DNA, ribonucleic acid (RNA), and protein synthesis.
Cisplatin
Cisplatin is an alkylating agent that inhibits DNA synthesis and, thus, cell proliferation by causing DNA cross-links and denaturation of the double helix.
Vinblastine
Vinblastine inhibits microtubule formation, which disrupts formation of the mitotic spindle, causing cell proliferation to arrest at metaphase. It is a component of the CVD regimen.
Carmustine (BiCNU)
This agent alkylates and cross-links DNA strands, inhibiting cell proliferation. It is used in the Dartmouth regimen.
Tamoxifen
Tamoxifen competitively binds to the estrogen receptor, producing a nuclear complex that decreases DNA synthesis and inhibits estrogen effects. It is used in the Dartmouth regimen to possibly abrogate the multidrug resistance phenotype.
Biological Response Modulators
Class Summary
Immunotherapy (biotherapy) currently used to treat patients with melanoma includes IFN and interleukin (IL)-2. An oncologist should administer these treatments.
Interferon alfa 2b (Intron A)
IFN alfa-2b is a protein product manufactured by recombinant DNA technology. The mechanism of antitumor activity is not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles. It is the drug of choice for adjuvant therapy in patients with high-risk melanoma. Its immunomodulatory effects include suppression of tumor cell proliferation, enhancement of macrophage phagocytic activity, and augmentation of lymphocyte cytotoxicity.
IFN alfa-2b is generally initiated within 56 days of surgery and typically administered by medical oncologists.
Peginterferon alfa 2b (Sylatron)
Peginterferon alfa-2b is an immunomodulatory cytokine that enhances phagocyte and lymphocyte activity. Alfa interferons act through high-affinity cell surface receptors, which, once activated, are known to inhibit cellular growth, alter the state of cellular differentiation, interfere with oncogene expression, alter cell surface antigen expression, increase the phagocytic activity of macrophages, and enhance the cytotoxicity of lymphocytes for target cells.
A covalent attachment of polyethylene glycol polymer chains to interferon molecules (known as PEGylation) can significantly increase the time the drug remains in the bloodstream, which, in turn, can reduce the frequency of dosing and potentially reduce the severity and frequency of adverse effects.
It was approved by the FDA in March 2011 as adjuvant therapy following definitive surgical resection, including complete lymphadenectomy. It is the first therapy approved for the adjuvant treatment of melanoma in 15 years.
Ipilimumab (Yervoy)
Anticytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a humanized antibody that overcomes CTLA-4-mediated T-cell suppression to enhance the immune response against tumors. The marker CTLA-4 is associated with promoting a regulatory response by the immune system. This regulatory response has a dampening effect on the immune system. Ipilimumab is able to inhibit the effects of CTLA-4 on T cells and allows the expansion of naturally developed melanoma-specific cytotoxic T-cells. This agent is the first new agent to be approved for melanoma in over a decade.
Ipilimumab has demonstrated remarkable promise in patients with metastatic melanoma. Clinical trials for monotherapy and in combination with other immunotherapies and vaccines have been concluded or are currently underway. Ipilimumab was approved by the FDA in March 2011 for unresectable or metastatic melanoma.
Interleukin 2 (Proleukin)
IL-2 is the only therapy known to cure advanced-stage melanoma. It activates T cells and amplifies their responses. It enhances natural killer cell antitumor activity.
Vemurafenib (Zelboraf)
Inhibits some mutated forms of BRAF serine-threonine kinase, including BRAF-V600E. The drug is indicated for unresectable or metastatic melanoma with BRAF-V600 mutation as detected by the cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems). Vemurafenib has not been studied with wild-type BRAF melanoma.
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