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Originally published as JCO Early Release 10.1200/JCO.2004.03.976 on May 3 2004 © 2004 American Society of Clinical Oncology.
Chemotherapy for Melanoma: The Resultant of Conflicting VectorsVan Elslander Cancer Center, Grosse Pointe, MI 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 nitro-soureas (bischloroethylnitrosourea [BCNU], chloroethyl-cyclohexylnitrosourea [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"1), have not been shown to be superior to single-agent DTIC.2 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 high-dose IL-2 alone.3 The ethical dilemma now faced by oncologists who routinely treat melanoma is whether to offer patients single-agent chemotherapy with DTIC or to consider first-line treatment with an experimental biologic approach. The article by Lev et al4 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.5 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 methyl-congener temozolomide has caused objective regressions in advanced melanoma, but, significantly in light of the present results, principally when given with the antiangiogenic agent thalidomide.6 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.7 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.8 Xenogenization, with chlorinated benzenes, is a strategy used by Berd et al to increase the immunogenicity of autologous melanoma vaccines in patients.9 Interestingly, DTIC is among the materials added to tumor cells to produce this effect in animals.7 Goldin et al showed in the 1970s that DTIC-treated leukemia L-1210 cells had increased immunogenicity in vivo, but were useful as immunotherapy for advanced disease only when they were given with effective antileukemic chemotherapy.10 However, most forms of chemotherapy at most schedules are immunosuppressive. As a class, the alkylating agents are among the most immunosuppressive of all.11 If the immune response to the tumor is blunted, an undesirable activity of the drug has occurred, and could cause the tumor to behave more aggressively. In mice, Spreafico12 showed that daunorubicin was immunosuppressive but had potent antitumor cytotoxic activity. On the other hand, the hydroxy-congener doxorubicin had strong antitumor activity accompanied by little immunosuppression. When daunorubicin was used against a tumor that was highly sensitive to its cytotoxic effects, cures were obtained in the mice regardless of the immunosuppression; however, when the tumor was relatively resistant, the immunosuppressive effects predominated, and the tumor flourished. In contrast, the negative consequences of the less immunosuppressive agent doxorubicin were less marked under most circumstances, and it was the more useful antitumor agent. While this may seem an extreme example, doxorubicin has exhibited similar advantages in a virally induced rat osteosarcoma,13 with potent net antitumor activity. Doxorubicin has proved to be a chemotherapy more broadly useful for cancers than daunorubicin, perhaps due to this felicitous combination of cytotoxicity and minimal immunosuppression. In this regard, DTIC, while immunosuppressive in humans,14 seems to be among the relatively weak immunosuppressive agents as compared with cyclophosphamide and the nitrosoureas.15 While the in vitro methods used in the late 1970s were undoubtedly inferior to more modern, sensitive in vitro tests of cell-mediated immunity (such as ELISPOT assays for cytolytic T cells), there was a clear difference between the profound, though transient, decline in circulating cytolytic T cells caused by the nitrosoureas, and the inability of DTIC to cause any discernible change.15 This relative lack of immunosuppressive potency may serve as a countervailing force against the in vivo induction of tumorigenic or angiogenic cytokines found by Lev et al. It may be useful to think of vector forces at work when considering the actions of any chemotherapeutic agent. None is entirely free of toxicity or adverse effects on the host, but at the same time, none is entirely pernicious to the host. In considering what these agents ultimately achieve, one might think of the resultant of the vectors. On the positive side is cytotoxicity against the tumor, augmentation of the immune response at certain schedules, and enhancement through xenogenization of the tumor, versus the negative effects of augmentation of tumorigenic or angiogenic cytokines, and immunosuppression. This set of opposing vectors is not unique to chemotherapy but is also found with immunological "adjuvants," many of which have caused depressed immunity in vitro and at certain dose schedules in mice.16,17 In at least one experimental system, this led to more rapid growth of the tumor in vivo—a phenomenon called "immunological enhancement."17 The most useful agents are those that most often have a positive resultant, where the antitumor vectors outweigh those directed against the host. The in vitro and preclinical results of Lev et al and the previous work from this group must be validated carefully in the human setting. If they are validated, one must at least consider the possibility that chemotherapy for melanoma, at least with DTIC, may not only be futile, but actually detrimental to the host. It might not be too outrageous then to suggest that biologic approaches to melanoma, comprising both immunotherapy and attacks on specific intracellular pathways used by the tumor cell, are not only inevitable in the long-run, but should be considered as an alternative to chemotherapy for melanoma as soon as clinically feasible. Author's Disclosures of Potential Conflicts of Interest The following author or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: Malcolm S. Mitchell, I Rx. Performed contract work within the last 2 years: Malcolm S. Mitchell, Covance, Maxim. Served as an officer or member of the Board of a company: Malcolm S. Mitchell, I Rx. REFERENCES
1. Eton O, Legha SS, Bedikian AY, et al: Sequential biochemotherapy versus chemotherapy for metastatic melanoma: Results from a phase III randomized trial. J Clin Oncol 20:2045–2052, 2002 2. Lens MB, Eisen TG: Systemic chemotherapy in the treatment of malignant melanoma. Expert Opin Pharmacother 4:2205–2211, 2003[CrossRef][Medline] 3. Atkins MB, Kunkel L, Sznol M, et al: High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: Long-term survival update. Cancer J Sci Am 6:S11–14, 2000 (suppl 1)
4. Lev DC, Onn A, Melinkova VO, et al: Exposure of melanoma cells to dacarbazine results in enhanced tumor growth and metastasis in vivo. J Clin Oncol 22:2092–2100, 2004
5. Lev DC, Ruiz M, Mills L, et al: Dacarbazine causes transcriptional up-regulation of interleukin 8 and vascular endothelial growth factor in melanoma cells: A possible escape mechanism from chemotherapy. Mol Cancer Ther 2:753–763, 2003
6. Hwu WJ, Krown SE, Menell JH, et al: Phase II study of temozolomide plus thalidomide for the treatment of metastatic melanoma. J Clin Oncol 21:3351–3356, 2003 7. Ben-Efraim S, Bizzini B, Relyveld EH: Use of xenogenized (modified) tumor cells for treatment in experimental tumor and in human neoplasia. Biomed Pharmacother 54:268–273, 2000[CrossRef][Medline] 8. Kobayashi H: Viral xenogenization of intact tumor cells. Adv Cancer Res 30:279–299, 1979[Medline] 9. Berd D: Autologous hapten-modified vaccine as a treatment for human cancers. Vaccine 19:2565–2570, 2001[CrossRef][Medline]
10. Contessa AR, Bonmassar A, Giampietri A, et al: In vitro generation of a highly immunogenic subline of L1210 leukemia following exposure to 5-(33'-dimethyl-1-triazeno)imidazole-4-carboxamide. Cancer Res 41:2476–2482, 1981
11. Mitchell MS: Combining chemotherapy with biological response modifiers in the treatment of cancer. J Natl Cancer Inst 80:1445–1450, 1988 12. Spreafico F: Heterogeneity of the interaction of anticancer agents with the immune system and its possible relevance in chemoimmunotherapy. Oncology 37:9–18, 1980 (suppl 1) 13. Kempf RA, Cebul RD, Mitchell MS: Antitumor effects of doxorubicin against a virally-induced rat osteosarcoma with minimal immunosuppression. J Immunopharmacol 2:509–525, 1981
14. Bruckner HW, Mokyr MB, Mitchell MS: Effect of imidazole-4-carboxamide 5-(33-dimethyl-1-triazeno) on immunity in patients with malignant melanoma. Cancer Res 34:181–183, 1974 15. Mitchell MS, Mokyr MB, Davis JM: Effect of chemotherapy and immunotherapy on tumor-specific immunity in melanoma. J Clin Invest 57:517–526, 1977 16. Murahata RI, Mitchell MS: Modulation of the immune response by BCG: A review. Yale J Biol Med 49:283–291, 1976[Medline]
17. Berd D, Mitchell MS: Immunologic enhancement of leukemia L-1210 by Corynebacterium parvum in allogeneic mice. Cancer Res 36:4119–4124, 1976
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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