Topotecan

Multiple phase-I and phase-II single-agent studies have tested topotecan in neuroblastoma, using either a continuous 72-h infusion regimen (Pratt et al. 1994; Blaney et al. 1998) or a daily 1-h infusion for 5 days (Tubergen et al. 1996; Kretschmar et al. 1995; Nitschke et al. 1998; Langler et al. 2002). Responses were reported with both schedules in the phase-I studies, but in the phase-II studies there were no responses with the 72-h continuous infusion, though the response rate was significant in both relapsed patients (10-20%) and in a phase-II window using the 5-day schedule in newly diagnosed patients (37%). Oral topotecan has also been tested with some modest responses (Garcia-Carbonero and Supko 2002; Kramer et al. 2003; Zamboni et al. 1999). Topotecan in combination regimens with other agents active in neuroblastoma, such as cyclophosphamide, cisplatin, and etoposide, have been reported. A phase-I study of topotecan with cyclophosphamide showed that the maximum tolerated dose of topotecan was 0.75 mg/m2 day-1 when given with a daily dose of 250 mg/m2 day-1 of cyclophosphamide for 5 days (Saylors et al. 1998).A phase-II window study showed a significant response rate in newly diagnosed pa tients, and the results are pending for a recently completed randomized study (P9462) in the Children's Oncology Group in relapse patients, comparing topotecan alone at 2 mg/m2 day-1 to the combined regimen of cyclophosphamide with topotecan (Frantz et al. 2004). Preclinical studies suggest that other cytotoxic agents, such as vincristine (Thompson et al. 1999) or MGI114 (iludin; Weitman et al. 2000), might provide synergistic cytotoxicity with topotecan. A few studies have investigated high-dose regimens incorporating topotecan with thiotepa and carboplatin using stem-cell support, but the dose of topotecan could not be substantially escalated in this regimen beyond standard dose due to mucositis (Park et al. 2000; Kushner et al. 2001). It is possible that further escalation of topotecan in combinations with other agents with less extra-hematopoietic toxi-city,such as cyclophosphamide,may be possible with autologous stem-cell support.

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