MELANOMA III: Medical Therapy
National and Kapodistrian University of Athens, Athens, Greece
Introduction Melanoma is a malignancy arising from pigment-producing cells (melanocytes). It accounts for 4% of skin cancers; however, it causes most of skin cancer–related deaths. Melanoma metastasizes very commonly to the brain. Given the fact that patients with metastatic melanoma have only few months’ life expectancy, treatment of the metastases is pivotal. The aim of this research is to outline the pathogenesis of melanoma brain metastases and present currently used therapeutic modalities.
Methods Review of current literature.
Results Cerebral melanoma metastases are usually hematogenous. Neoangiogenesis and invasion are mediated via VEGF-A hyperexpression and altered Stat3 protein activity. Stat3 activation plays an important role in enhancing expression of angiogenetic factors b-FGF, VEGF, and MMP-2 by increasing their promoter's expression via transcriptional upregulation. Other genes implicated in brain colonization are Nm23, a metastasis suppressor gene, the neurotrophin receptor and heparanase. It is known that neurotrophins (NTs) modulate both brain invasion of melanoma cells and activity of the extracellular matrix degradative enzyme heparanase, a critical mediator of tumor metastasis and angiogenesis. What is more, astrocytes secret nerve growth factors that upregulate heparanase transcription and in this way provide an ideal environment for melanoma cell growth. Melanoma metastases to the brain are usually multifocal. For this reason surgery is limited to single small lesions, although there are those who advocate wide excision even in that setting. So far the mainstay of treatment has been whole brain irradiation, which improves neurologic deficits whereas it has little impact on survival. Stereotactic radiosurgery, a technique that permits precise delivery of a high dose of radiation to a small intracranial target while sparing the surrounding normal brain, has been successfully used with minimal complications in otherwise untreatable lesions and renders even better results when combined with whole brain irradiation. Traditional systemic chemotherapy with dacarbazine is complemented with the use of temozolomide, an alkylating agent with high CNS penetration, thalidomide and fotemustine. Other treatments currently investigated are lymphodepleting chemotherapy followed by the transfer of highly avid antitumor lymphocytes and production of anti-tumor synthetic peptide vaccines based on genes encoding cancer antigens press low-affinity.
Conclusion The brain is common target for metastatic melanoma cells. However, combination of therapeutical regimens consisting of surgery, irradiation, stereotactic radiosurgery, chemotherapy and bioimmunotherapy promises to provide palliation and extend overall survival in patients with multiple metastases.