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Originally published as JCO Early Release 10.1200/JCO.2004.11.957 on January 15 2004 © 2004 American Society of Clinical Oncology.
Temozolomide for Melanoma: New Toxicities and New OpportunitiesSection of Hematology/Oncology, The University of Chicago, Chicago, IL The efficacy of chemotherapy in patients with advanced melanoma remains disappointing. Dacarbazine (DTIC) is the only approved chemotherapeutic agent in the United States, yielding response rates in the range of 20%, with rare complete responses. Nitrosoureas, platinum analogs, vinca alkaloids, and taxanes show even more modest activity [1]. Although phase II studies of combination chemotherapy regimens initially showed promise, randomized trials of combinations compared to DTIC alone have failed to show survival benefit [2]. Moreover, despite encouraging phase II results of chemotherapy plus interleukin-2 and interferon-alfa, recent phase III studies have failed to show benefit of certain biochemotherapy combinations compared to chemotherapy alone [3]. For many melanoma investigators, these observations have brought the field back to square one, to the starting presumption that DTIC remains the most active single agent in this disease. Temozolomide is an oral compound that, like DTIC, is a prodrug of the alkylating agent 5-(3-methyltriazen-1yl)imidazole-4-carboximide (MTIC). Unlike DTIC, temozolomide is spontaneously converted to MTIC under physiologic conditions, and also shows 100% oral bioavailability. In a phase II study of temozolomide in 56 patients with advanced melanoma, a response rate of 21% was observed [4]. This led to a randomized trial of temozolomide given at 200 mg/m2/d for 5 days out of a 28-day cycle, compared to DTIC at 250 mg/m2/d intravenously for 5 days of a 21-day cycle. Response rates and overall survival were comparable between the two groups, and progression-free survival favored temozolomide [5]. Despite equivalent efficacy and the convenience of oral dosing, temozolomide was not recommended for approval by the Oncologic Drugs Advisory Committee to the US Federal Drug Administration, although it is approved for the treatment of anaplastic astrocytoma. Temozolomide is thought to exert its anticancer activity through the methylation of DNA at the O6 position of guanine residues. Melanoma cells express high levels of O6-alkylguanine-DNA alkyltransferase (AGT), which actively repairs methylated guanine lesions before DNA cross-linking can occur, thus negating the cytotoxic drug effect. As AGT is depleted during this process, it is expected that prolonged administration of temozolomide might show greater antitumor efficacy, as the MTIC exposure time should exceed the availability of AGT to repair damaged DNA. Brock et al [6] reported on an extended schedule of temozolomide administered at 75 mg/m2/d for 6 weeks of a 7-week cycle, which resulted in a two-fold greater drug exposure per month. Oncologists at several centers, including Memorial Sloan-Kettering Cancer Center (New York, NY), incorporated this extended dosing schedule of temozolomide into their treatment regimens. Evidence presented in this issue of the Journal of Clinical Oncology suggests that the prolonged administration schedule of temozolomide is associated with an unusual, but manageable, toxicity [7]. Ninety-seven patients with advanced melanoma were treated with one of several regimens that included temozolomide at 75 mg/m2/d for at least 6 weeks of an 8-week cycle. The majority of patients developed lymphopenia, with CD4+ T cells being preferentially affected. This selective T-cell depletion was associated with clinically significant opportunistic infections. One patient developed documented Pneumocystis carinii pneumonia, with another two patients meeting clinical criteria that were not biopsy-proven. In addition, one case of Aspergillus pneumonia, four cases of Herpes simplex, four cases of Herpes zoster, 11 cases of mucocutaneous candidiasis, and one case of Kaposi's sarcoma were observed. This incidence of opportunistic infections is noteworthy and is unlikely to be accounted for by chance alone in this patient population. These observations by Su et al [7] have several important implications. First, patients treated on a prolonged schedule of temozolomide should receive Pneumocystis carinii pneumonia prophylaxis and should be observed carefully for evidence of opportunistic infections, particularly after the point at which lymphopenia is documented. Second, the dose and schedule of temozolomide administered with immune-stimulating agents in cancer patients should be considered carefully. Combinations of tumor antigen-based vaccines, immune-enhancing cytokines (eg, interleukin-2), therapeutic monoclonal antibodies (eg, herceptin), or immunomodulatory monoclonal antibodies (eg, anti-CTLA-4) with a prolonged schedule of temozolomide might fail to show added benefit. Third, therapeutic clinical trials with other drugs should also pay greater attention to effects on lymphocyte counts, particularly if there are future plans to combine these new agents with immunologic treatment approaches. In our own group, we recently found that melanoma patients treated with the vascular endothelial growth factor receptor tyrosine kinase inhibitor SU5416 experienced significant lymphopenia, presumably as a result of the four doses of dexamethasone given per week as a premedication for the polyoxyethylated caster oil vehicle [8]. Fourth, consideration should be given to exploring a prolonged schedule of temozolomide in T-cell malignancies, such as cutaneous T-cell lymphoma, as perhaps transformed T-lineage cells may be as responsive to this agent as are normal T lymphocytes. Finally, anecdotal experience has suggested that the clinical activity of temozolomide in advanced melanoma may be greater when administered on a prolonged schedule, indicating new opportunities for further exploration of this agent in this disease. Based on these considerations, an international phase III trial of temozolomide given on a prolonged schedule compared to standard DTIC in previously untreated patients with metastatic melanoma is being initiated. Temozolomide given on a prolonged schedule plus thalidomide is being investigated by the Cancer and Leukemia Group B in patients with brain metastases. In addition, if the hypothesis is correct that the prolonged schedule may be more effective through depletion of AGT, then the addition of specific AGT inhibitors in combination with temozolomide may be more efficacious than temozolomide alone. O6-benzylguanine is one such inhibitor that has been through phase I and phase II clinical trial testing [9] and has recently been combined with carmustine in phase II trials in melanoma. Future studies of O6-benzylguanine plus temozolomide in patients with advanced melanoma could directly test the hypothesis that this mechanism of DNA repair represents a surmountable cause of tumor resistance to the cytotoxic effect of this alkylating agent. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. REFERENCES 1. Li Y, McClay EF: Systemic chemotherapy for the treatment of metastatic melanoma. Semin Oncol 29:413-426, 2002[CrossRef][Medline]
2. Chapman PB, Einhorn LH, Meyers ML, et al: Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol 17:2745-2751, 1999 3. Atkins MB, Lee S, Flaherty LE, et al: A prospective randomized phase III trial of concurrent biochemotherapy (BCT) with cisplatin, vinblastine, dacarbazine (CVD), IL-2 and interferon alpha-2b (IFN) versus CVD alone in patients with metastatic melanoma (E3695): An ECOG-coordinated intergroup trial. Proc Am Soc Clin Oncol 22:708, 2003 (abstr 2847) 4. Bleehen NM, Newlands ES, Lee SM, et al: Cancer Research Campaign phase II trial of temozolomide in metastatic melanoma. J Clin Oncol 13:910-913, 1995[Abstract]
5. Middleton MR, Grob JJ, Aaronson N, et al: Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 18:158-166, 2000
6. Brock CS, Newlands ES, Wedge SR, et al: Phase I trial of temozolomide using an extended continuous oral schedule. Cancer Res 58:4363-4367, 1998
7. Su YB, Sohn S, Krown SE, et al: Selective CD4+ lymphopenia in melanoma patients treated with temozolomide: A toxicity with therapeutic implications. J Clin Oncol 22: 610-616, 2004 8. Peterson AC, Swiger S, Stadler W, et al: Phase II study of the Flk-1 tyrosine kinase inhibitor SU5416 in patients with advanced melanoma. Proc Am Soc Clin Oncol 22:712, 2003 (abstr 2863)
9. Dolan ME, Posner M, Karrison T, et al: Determination of the optimal modulatory dose of O6-benzylguanine in patients with surgically resectable tumors. Clin Cancer Res 8:2519-2523, 2002
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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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