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Therapeutic Strategies for the Treatment of Metastatic Melanoma—What is New is Old

US Oncology Review, 2005;1(1):1-4 DOI:


Unfortunately, the incidence of cutaneous melanoma continues to increase over time in both men and women. While some investigators suggest that the increase is related to changes in diagnostic criteria, the parallel increase in melanoma death rate supports that the increase in incidence is real. The cause for the higher melanoma incidence remains elusive, but may have to do with increasing outdoor activity and a decrease in the Earth's ozone layer.

While the melanoma etiologic pathways are critical in developing prevention strategies, the increase in this disease has propelled melanoma into the sixth most common cancer and a significant cause for death of patients in their prime of life. Metastatic disease remains a formidable hurdle for oncologists today.

The prognosis of a patient with melanoma is primarily related to the depth of invasion into the skin as measured by Breslow thickness (T-stage), whether regional nodal spread is present (N-stage), and whether distant metastases have developed (M-stage).Within the group of patients with distant disease, the prognosis is determined by the site and burden of metastases.Patients with distant skin, subcutaneous or nodal metastases only (M1a) have a median survival of 12.8 months; patients with lung metastases (M1b) have an 11.8-month median survival; and patients with visceral metastases or elevation of lactate dehydrogenase (LDH) (M1c) have a 7.8-month median survival. Metastatic melanoma arising from the choriod of the eye (the second most common site for melanomas to develop) has an even poorer response to treatment than metastases arising from primary skin location, suggesting that choriodal melanomas have a different clinical biology and should be considered a separate disease.

Simple wide excision of the primary site is curative when cutaneous melanomas are found early and have a shallow depth of invasion. Unfortunately, once distant metastases have developed,therapeutic options are limited and those available have had little impact on survival except in a small minority of patients.

Those treatments that do provide durable remissions in a small minority of patients are typically associated with a high likelihood of serious adverse events including a risk of death. Therefore, an open discussion of expectations, risk, and benefits with the patient and their family is an important first step in setting the stage for intervention.

As with other types of cancer that have limited treatment possibilities, participation in clinical trials designed to evaluate new therapeutic strategies should be considered as a first-line option. Many new treatment strategies being evaluated in phase II and randomized phase III studies are available through national cooperative groups or through the National Cancer Institute's Clinical Trials Program and may be accessible in the community oncologist office. If not, referral to a melanoma center should be considered.

Current standard therapy for metastatic melanoma includes chemotherapy, biotherapy, and bio- chemotherapy. These treatments have never been tested against best supportive care, making it difficult to form firm conclusions about clinical benefit. Since the 1970s, numerous phase II studies have identified several alkylating agents with activity, most notably dacarbazine (DTIC) and carmustine (BCNU). DTIC has an objective response rate of 19%, with a median duration of response of four months. The six-year survival for metastatic melanoma patients treated with DTIC is less than 2%.Temozolomide (TMZ), an oral alkylating agent, is chemically converted in the body to monomethyl triazenoimidazole carboxamide (MTIC), the active metabolite in DTIC. By virtue of being oral, TMZ allows exploration of low dose chronic administration. One advantage of this approach is the ability to modulate O (6)- methylguanine-DNA methyltransferase, one of the major resistant pathways for this class of alkylating agents. Of note is the observation that TMZ induces significant changes in peripheral blood helper T-cell status, resulting in an increased risk of opportunistic infections. The exploratory studies with TMZ have not yet been confirmed in larger multicenter trials. In a randomized study comparing fotemustine, a third generation nitrosurea, and DTIC, fotemustine was associated with a slightly higher response rate compared with DTIC (15% versus 7.2%) and a 1.6- month survival advantage.