Molecular biology: Researchers introduce new, advanced melanoma treatment options

August 1, 2008

Researchers' growing understanding of melanoma's molecular biology is facilitating the development of more effective treatments that may be combined with some existing agents, an expert says.

Key Points

Boston - The future of advanced melanoma treatment might involve combining some existing treatments with promising new agents, an expert says.

"According to the American Joint Committee on Cancer, the average survival for patients with advanced melanoma is less than one year. And more than 90 percent of patients die within five years of diagnosis," says Linh K. Lu, M.D., Ph.D., instructor of dermatology and a Mohs micrographic surgery fellow at Tufts Medical Center in Boston.

As a fellow, Dr. Lu works with Gary Rogers, M.D.; Daniel Finn, M.D.; and Dennis Lee, M.D., in the division of surgical oncology. She completed her dermatology residency at the University of Colorado Health Sciences Center in Denver.

Oncology options

"It's important for dermatologists to know of some new and exciting treatment options that are available in the oncology community," Dr. Lu says.

National Comprehensive Cancer Network 2008 guidelines for systemic therapies in melanoma include chemotherapy, immunomodulators and targeted therapies - frequently in combination, Dr. Lu tells Dermatology Times.

"Combining the different modalities may sometimes be more effective than using a single agent," she says.

Among cytotoxic chemotherapeutic drugs, dacarbazine earned Food and Drug Administration (FDA) approval for metastatic melanoma more than 30 years ago.

"To underscore how difficult it is to treat advanced melanoma," Dr. Lu says, "the response rate for dacarbazine is only 15 to 20 percent. Response usually lasts four to six months (Gogas H et al. Cancer. 2007;109:455-464). These numbers are horrible. But unfortunately, dacarbazine remains the standard of care."

Temozolomide represents a newer option. Like dacarbazine, it's a precursor to the reactive compound methyltriazenoimidazole carboxamide (MTIC).

"In one study," Dr. Lu says, "temozolomide was as effective, if not better than, dacarbazine in terms of overall survival (Middleton MR et al. J Clin Oncol. 2000 Jan;18(1):158-166).

However, manufacturer studies of temozolomide compared this drug with dacarbazine, but not with a placebo; therefore, it has not earned FDA approval for treating metastatic melanoma, she says.

Among immunomodulatory agents, interleukin (IL)-2 earned FDA approval for advanced melanoma in 1998. Registration trials with single-agent, high-dose IL-2 showed complete response rates of 6 percent and partial response rates of 16 percent (Atkins MG et al. J Clin Oncol. 1999;17:2105-2116), Dr. Lu says.

In another study, 5 percent of patients achieved a complete response with no residual metastases, she says.

Interferon alpha, which increases p53 and MHC class I expression, is approved as an adjuvant therapy in stage II and III melanoma. In the Eastern Oncology Group Trial EST 1684, high-dose interferon proved more effective than placebo (Kirkwood JM et al. J Clin Oncol. 1996 Jan;14(1):7-17).

"However," Dr. Lu says, "in long-term follow-up, the survival benefit for interferon seemed to fade."

Targeting specific molecules

Conversely, therapeutic agents that target specific molecules reflect researchers' growing understanding of the progression of melanoma, Dr. Lu says.

"Sorafenib (Nexavar, Bayer/Onyx) is one such drug. It inhibits RAF of the Ras effector pathway." This is important, because 67 percent of melanomas possess a RAF mutation, she says.

"Sorafenib is an exciting drug, because it inhibits key proteins, including RAF, known to be important in cell proliferation. But as a monotherapy, sorafenib is an abysmal failure," she says.