Although considerable work is underway in the development of new approaches to therapy for melanoma, an aggressive form of skin cancer that begins in skin cells called melanocytes, primary prevention continues to serve as the leading strategy. While not as common as other major types of skin cancer, including basal cell and squamous cell carcinoma, the average lifetime risk of developing skin melanoma is about 1%.

Speaking at the 69th Annual Meeting of the American Academy of Dermatology (Academy) Allan C. Halpern, M.D., chief of dermatology service, Memorial Sloan Kettering Cancer Center, New York, addressed these strategies and developments, including stem-cell targeted, pathway-targeted and immunologic-checkpoint blockade approaches, during his ‘Hot Topics’ presentation “Exciting New Developments in Melanoma Prevention and Treatment.”

Protection
“We have known for decades that ultraviolet light has been a major implicator of melanoma,” he said. “Sun-protective clothing and sunscreens have improved. That being said, while we are out there teaching sun protection, there have been major challenges to our message.”

Those recent challenges include assertions that there’s no direct evidence that UV radiation has a pathogenic role in human melanoma or that sun protection in general, and sunscreens in particular, can prevent melanoma. Also emerging is the vitamin D controversy where some claims have been made that people should actually increase their sun exposure as a source of vitamin D intake.

One recent study reported by Dr. Halpern determined that regular application of SPF 15+ sunscreen in a five-year period appeared to reduce the incidence of new primary melanomas for up to 10 years after the trial’s cessation. Also, sunscreen has a proven protective effect for invasive melanoma ? a 73% decrease in those randomly assigned to daily sunscreen after 15 years of follow-up.

In terms of the vitamin D claims, he agreed with the Institute of Medicine’s 2001 conclusion that states the following: “Scientific evidence indicates that calcium and vitamin D play key roles in bone health. The current evidence, however, does not support other benefits for vitamin D or calcium intake. More targeted research should continue. However, the committee emphasizes that, with a few exceptions, all North Americans are receiving enough calcium and vitamin D. Higher levels have not been shown to confer greater benefits, and in fact, they have been linked to other health problems, challenging the concept that ?more is better.'”

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Treatment of melanoma
In terms of therapies, only two drugs have been approved for melanoma in the U.S.: dacarbazine (DTIC-Dome?, Bedfordlabs), an antineoplastic chemotherapy, and high-dose recombinant human interleukin-2 or rIl-2 (Proleukin?/Aldesleukin, Prometheus). While DTIC is considered to be the most active chemotherapy drug for metastatic melanoma with tumor shrinkage seen in 8 to 20% of treated patients, most people respond only partially and the benefit lasts only for a few months.

Response to Interleukin-2 regimens is in the 10% to 20% range when given in high doses. In some people treated with high dose IL-2, the benefit can be long-lasting. However, high dose IL-2 can cause serious and toxic side effects and it is generally reserved for people who are otherwise healthy. Additional therapies for melanoma also include nitrosoureas, cisplatin, interfer-a, taxol, and vincristine, all with response rates under 20 percent. Only IL-2 actually results in melanoma cures.

New therapies
In terms of new therapies, one exciting development includes stem-cell targeted therapy. “Instead of killing the cancer cells in the tumor, kill the stem cells, and the tumor will die off on its own,” he said. Another development includes a simplified scheme of targeting melanoma pathways, including mutations in cell cycle regulation. Disrupting any one of the mutations stalls the advancement of melanoma.

One clinical trial of immunologic-checkpoint blockade agents showed that patients did not improve during the time frame the clinical trial was set ? six to eight weeks. However, these patients started to improve three and four months later, requiring that the criteria for this trial change. By waiting longer, investigators found dramatically improved response rates ? 40% to 50%, compared to 20% average response rates of other melanoma therapies. “There are other similar immune checkpoint molecules for which other drugs are being developed,” Dr. Halpern noted.

Illustration courtesy of the American Society of Clinical Oncology.

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