Chemotherapy for Melanoma: The Resultant of Conflicting Vectors
Authors: Malcolm S. Mitchell
Journal: Journal of Clinical Oncology (2004)

The familiar admonition to physicians, often quoted simply as, “First, do no harm,” is perhaps better rendered, “Always attempt to do good, but, if you cannot, at least do no harm.” This is particularly applicable to chemotherapy for cancers, and especially melanoma. Melanoma, as even the strongest advocates of chemotherapy now admit, is remarkably and frustratingly resistant to that modality. Single drugs, particularly the alkylating agents such as diethyl-triazeno-imidazole carboxamide (DTIC; dacarbazine), its newer congener temozolomide, and the nitrosoureas (bischloroethylnitrosourea [BCNU], chloroethylcyclohexylnitrosourea [CCNU], and methyl-CCNU), have all been tried throughout the last 30 years, but with limited success. Even if judged by the less stringent criterion of response rate rather than survival, no more than 10% to 15% of patients with metastatic melanoma have demonstrated objective benefit in large series. After initial enthusiastic results at a single institution, combinations of chemotherapeutic agents at high doses, alone, or combined with interleukin (IL-) 2 and interferon-alfa, (“biochemotherapy”), have not been shown to be superior to singleagent DTIC. Long-term responses have been elicited in approximately 10% of patients given biochemotherapy, but whether that is more attributable to the immunotherapy portion of the regimen (specifically IL-2) than the chemotherapy is an arguable point. Approximately the same percentage of durable responses has been reported after highdose IL-2 alone. The ethical dilemma now faced by oncologists who routinely treat melanoma is whether to offer patients singleagent chemotherapy with DTIC or to consider first-line treatment with an experimental biologic approach. The article by Lev et al in this issue of the Journal of Clinical Oncology provides provocative information to help one decide whether treatment with DTIC may not only be futile, but may perhaps cause harm. While no one advocates leaping from experimental data in mice to immediate conclusions about treatment of patients, it is difficult to ignore the adverse biologic effects that chronic treatment of melanoma cell lines can cause on the metastatic behavior of those cells. Chronic treatment with DTIC caused two cell lines, MeWo and SB2, to become resistant to the drug in vitro. In addition, and far more ominous, whereas SB2 parental cells were rarely metastatic, DTIC-resistant lines were routinely metastatic. Moreover, the MeWo parental cells, which had a tendency to metastasize, gave rise to far more widespread metastases after chronic DTIC treatment. The size of tumors derived from both cell lines was also increased with the DTIC-resistant lines. As in previous studies from their laboratory, the induction of tumorigenic/angiogenic factors such as IL-8 and vascular endothelial growth factor was increased after DTIC exposure, presumably accounting for the observed changes in metastatic potential. Obviously, alkylating agents, with DTIC among them, have cytotoxic effects on tumor cells, which, from the patient’s point of view, is a positive effect. The methylcongener temozolomide has caused objective regressions in advanced melanoma, but, significantly in light of the present results, principally when given with the antiangiogenic agent thalidomide. DTIC has also been shown to interact with tumor cells to make them more immunogenic. This so-called “xenogenization” of the tumor cell adds a foreign chemical group to the cell membrane and makes it more “foreign” (xenogeneic) to the host. This phenomenon is akin to the well-established practice of adding a chemical group (hapten) to improve the delayed hypersensitivity reaction to a weakly immunogenic protein, and the method has been extended to the incorporation of viruses into tumor cells. Xenogenization, with chlorinated benzenes, is a strategy used by Berd et al to increase the immunogenicity of autologous melanoma vaccines in patients. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 22 NUMBER 11 JUNE 1 2004