Temozolomide for melanoma: new toxicities and new opportunities.

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-methyltriazen1yl)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/m/d for 5 days out of a 28-day cycle, compared to DTIC at 250 mg/m/d intravenously for 5 days of a 21-day cycle. Response rates and overall survival were comparable between the two groups, and progressionfree 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 O position of guanine residues. Melanoma cells express high levels of O-alkylguanine-DNA alkyltransferase (AGT), which actively repairs methylated guanine lesions before DNA crosslinking 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/m/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/m/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. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 22 NUMBER 4 FEBRUARY 15 2004