What is the most promising strategy for the treatment of metastasizing melanoma?

Abstract

The treatment of patients with metastasizing melanoma, still one of the most deadly diseases in modern medicine, ranks among the greatest challenges that a clinician has to face. Metastatic melanoma also is one of the most profound sources of clinical frustration, since it provides far more ultimately defeating experiences than clinical victories. At the same time, the fascinating biology of melanoma has invited the study of this neuroectodermal tumor as a model system for dissecting many of the key problems of modern oncology, ranging from molecular oncogenesis via the controls of tumor proliferation, apoptosis, invasion, metastasis, and angiogenesis to tumor immunosurveillance and tumor drug resistance. Together with the dire need to develop more effective treatment modalities for improving both life expectancy and quality of life of affected patients, this has made metastatic melanoma a favorite model Viewpoint 1Melanoma is one of the tumors that most frequently metastasizes to regional lymphnodes and to distant sites. The high degree of malignancy and the poor final outcome correlated with this disease has strongly stimulated in the past decades many studies and clinical trials to help defining the most suitable therapy in these cases. Even though in the area of treatment of nodal metastases important innovations have been introduced in the recent past, for distant metastases, no convincing solution is available at the moment. 439for the exploration of innovative strategies for tumor management. Encouragingly, many of these have already generated very promising results in animal models. However, this impressive level of research progress in conquering melanoma in the animal room contrasts rather pitifully with the actual progress made on the ward. This CONTROVERSIES feature, therefore, critically and soberly reviews the state of the art of treating metastatic melanoma today (distinguishing between nodal and distant metastases), and sharply defines unresolved or comparatively neglected key problems. In addition, this feature highlights several novel, provocative, hitherto underappreciated, yet potentially promising treatment approaches that deserve systematic exploration. Hopefully, this will offer further inspiration for the design and pursuit of innovative anti-melanoma strategies off-the-beaten-track. How to treat nodal melanoma metastases todaySurgery remains the only effective option for treating nodal metastases from cutaneous melanoma since chemotherapy and radiotherapy do not achieve the same cure in patients with nodal disease. However the indication for performing an elective lymph node dissection (ELND) or a delayed one (DLND) is contested (1-8).The supporters of ELND invoke the following arguments: 1) the significant incidence of silent

Angiogenesis, lymphangiogenesis, and melanoma metastasis

“…Currently, surgical removal of the primary tumor and of the draining regional lymph nodes remains the most effective treatment in patients with nodal disease, whereas systemic mono-, poly , or immunochemotherapy regimens have achieved only marginal response rates without significant impact on patient survival (Cascinelli et al, 2000). Consequently, early detection and prevention of disease progression has remained the most efficient strategy to reduce melanoma mortality, and innovative therapies for advanced human melanoma are urgently needed.…”

Inhibitors of melanogenesis increase toxicity of cyclophosphamide and lymphocytes against melanoma cells

“…Melanoma represents the most rapidly increasing malignancy in the white population, and its mortality rate is surpassed only by lung cancer 1,3,5. The high mortality rate among melanoma patients is related to its progression to the therapy resistance in stages III and IV of the disease; clinical cure of melanomas is only possible by surgery at the radial growth phase (RGP) when the disease is still localized and restricted to the skin 1,3,10–12. The subsequent progression from RGP to the vertical growth phase (VGP), signals metastatic potential with important negative impact on survival; once the metastatic process has started, the tumor becomes resistant to current methods of therapy 1,11–15…”

“…Therapeutic selectivity towards cells of melanocytic origin (and hence increase of local effectiveness) has likely focused on immunotargeting 10,11,13,18–27. Among the proposed antigens are the melanocyte related proteins (MRP) that include tyrosinase, tyrosinase related proteins type 1 and 2 (TRP-1, TRP-2) and melanosomal antigens HMB-45 and MART 1 25,26,28.…”

Locoregional Cutaneous Metastases of Malignant Melanoma and their Management

“…These findings indicate that imiquimod offers a new treatment method for certain patients with cutaneous melanoma metastases, especially when palliative therapy is indicated. [26][27]…”