New Treatments for Melanoma

Marie-France Demierre; Sandy Allten; Rebecca Brown

Disclosures

Dermatology Nursing. 2005;17(4):287-295. 

In This Article

Chemoprevention of Melanoma

Chemoprevention is a strategy that was first proposed by Sporn, Dunlop, Newton, and Smith (1976). It referred to the use of natural or synthetic agents to reverse, suppress, or prevent molecular or histologic premalignant lesions from progressing to invasive cancer. The original definition also included treating patients who had undergone successful primary cancer treatment but were at increased risk of a second primary cancer. More recently, cancer delay has been emphasized as yet another goal of chemoprevention (Lippman & Hong, 2002). In breast and other cancers, chemoprevention has proven successful. Tamoxifen, the first Food and Drug Administration (FDA)-approved chemopreventive agent, has been used effectively for reducing breast cancers, and both topical diclofenac and imiquimod were FDA approved for actinic keratoses.

Chemoprevention is being explored as a new strategy against melanoma (Demierre & Nathanson, 2003) based on the principle that ultraviolet-induced melanoma is a multistep process, and that molecular events and pathways associated with these steps can be targeted. Recent improvements in the understanding of ultraviolet (UV) carcinogenesis and growing data on melanocyte biology and transformation suggest the ras-signaling pathway as a chemoprevention target in UV-induced melanoma (Demierre & Merlino, 2004). In a chemoprevention strategy, ideally, several principles should be followed (Demierre & Sondak, 2005): (a) focus on the underlying molecular mechanisms of melanoma genesis; (b) use of genetic markers of early events of carcinogenesis; (c) follow leads from epidemiologic data, basic science, and cancer research literature with regards to the selection of candidate prevention agents; (d) screen low-toxicity drugs that target pathways involved in carcinogenesis (for example, taking advantage of animal models to facilitate preclinical trials of efficacy and toxicity); and (e) appropriate chemoprevention clinical trial design and need for inclusion of defined groups at very high risk for the disease. The availability of molecular or histologic markers of the carcinogenic process to be used as endpoints is critical to the final design of clinical chemoprevention studies. The greatest challenge in developing chemopreventive studies will be to identify and validate surrogate endpoint biomarkers in melanoma that have both prognostic value (ability to predict subsequent cancer) and predictive value (ability to predict effectiveness of chemopreventive agents) (Arm strong, Taylor, & Meyskens, 2003).

To date among possible candidate melanoma chemoprevention agents, pre-clinical data and unanticipated secondary clinical observations from cardiovascular disease trials indicate that certain cholesterol-lowering agents — the statins — may have a role in melanoma prevention, by targeting ras signaling. Other data suggest that COX-II inhibitors, retinoids, imiquimod, and antioxidants may also represent potential melanoma chemoprevention agents (see Table 4 ). Melanoma vaccines could also represent ideal chemoprevention agents because of their minimal morbidity and potential for clinical efficacy.

The need to develop a clinical research model, in accordance with rigorous chemoprevention trial de signs, to allow for the evaluation of candidate chemoprevention agents in melanoma, is critical. As a first step, the Southwest Oncology Group (SWOG) is proposing a phase IIB chemoprevention study of statins versus placebo in a population of patients with already treated early-stage melanomas and the presence of clinically atypical nevi. The SWOG phase IIB trial, which will involve dermatologists and medical and surgical oncologists, will permit the prospective evaluation of biological markers in both blood and biopsied nevi. This model should provide valuable information that will help build the field of chemoprevention in melanoma.

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