Melanoma is a genetically heterogeneous condition that will likely result in more diversified clinical management in the future.
Therapy has become personalized in the management of some cancers and will likely take that shape in the management of melanoma, as further clues about the genetic and molecular signature of melanoma are revealed, according to Charles M. Balch M.D., F.A.C.S., a professor of surgery, University of Texas Southwestern Medical Center, Dallas.
"Breast cancer and lung cancer are models of what we will do with melanoma in the future," Dr. Balch says. "We will use genetic and molecular biomarkers to select patients for targeted therapy, including patients who may benefit from immunotherapy."
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With the availability of targeted therapies, the development of treatment algorithms continues to evolve in melanoma, a disease that is very heterogeneous genetically, but that has been treated clinically in a homogeneous fashion, Dr. Balch says.
"If patients have stage IV disease, and they go into remission, one question to ask is how long to keep treating them," Dr. Balch says. "There will be many subsets of patients. BRAF and a number of other receptors yet to be employed at a clinical level. For example, acral lentiginous melanoma is different than sun-induced skin melanoma.
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"There will be more biomarkers than BRAF that will be identified in the future to help sort out the diversity of melanoma, and in doing so, we will be able to select patients for more effective treatment," Dr. Balch says. "Conversely, we can avoid certain treatments in patients who will not benefit because their biomarkers will identify tumors which are resistant to certain drugs."
Neo-adjuvant therapy will likely be the first line of therapy in advanced melanoma cases, according to Dr. Balch.
"Any patient with stage IV disease or clinically significant nodal metastases will be treated with neo-adjuvant therapy up front," said Dr. Balch. "They would eventually have the tumor taken out after exposure to one or more systemic agents. This will enable us to precisely determine how much of the tumor is viable and how much consists of an inflammatory mass."
The role of surgery
There still remains a major role for surgery in patients with stage IV melanoma who have limited disease, noted Dr. Balch.
"The conditions and timing of when to take the tumor out will be determined," he says. "We will look at the pathological response and the genetic and molecular signature of residual tumor cells."
Approval of emerging pharmacological therapies will need to be based on outcomes other than survival, Dr. Balch says.
"Using overall survival as a benchmark for approving drugs to market is too expensive and takes too long," Dr. Balch says. "As has been the case with other agents to treat conditions like breast cancer, the FDA (Food and Drug Administration) has approved agents based on other endpoints."
Those other measures of efficacy can include progression-free survival and relapse-free survival, said Dr. Balch. "Pegylated interferon was approved based on relapse-free survival," said Dr. Balch.
A study published last year concluded progression-free survival to be a robust proxy for overall survival in dacarbazine-controlled, randomized trials of metastatic melanoma.[i]
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The search for effective combinations of therapies may lead to strategic partnerships amongst pharmaceutical firms, Dr. Balch notes.
The affordability of emerging therapies for melanoma will have to be examined, likely in the near future, adds.
"Something that we will have to address that at the macroeconomic level is the high cost of the drugs, that in some patients can run as high as $500,000," Dr. Balch says.
The survival benefit produced by removal of the lymph nodes is warranted in melanoma patients, even if the surgical procedure means they are at slightly increased risk of lymphedema, according to Dr. Balch, who pointed to data from the Multi-center Selective Lymphadenectomy Trial (MSLT-1) published in February 2014 that demonstrated the clinical value of the sentinel lymph node biopsy (SLNB).
Researchers found melanoma patients with intermediate-thickness lesions who had their lymph nodes removed after a SLNB tested positive were 44% more likely to survive their disease.[ii]
Dr. Balch had no relevant disclosures.
1. Flaherty KT, Hennig M, Lee SJ, et al. Surrogate endpoints for overall survival in metastatic melanoma: a meta-analysis of randomised controlled trials. Lancet Oncol. 2014;15(3):297-304.
2. Morton DL, Thompson JF, Cochran AJ, et al. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med. 2014;370(7):599-609.