Current treatments using interval compression of multiagent chemotherapy combined with surgery and/or radiation can now cure the majority of patients with localized Ewing sarcoma [1
]. However, outcomes are much worse for patients who develop disease recurrence after initial therapy, or who have metastases at diagnosis. For example, fewer than 20% of patients with relapsed Ewing sarcoma are likely to be long-term survivors [2
], and patients who present with metastatic bone and/or bone marrow disease at initial diagnosis share a similarly poor prognosis [3
]. New therapeutic approaches are clearly necessary to improve overall survival for these patients.
Chemotherapy for Ewing sarcoma has historically consisted of alkylating agents and anthracyclines. Two modifications of this backbone have led to significant improvements in outcome and have helped to define the current standard of care. First, the addition of cassettes of ifosfamide and etoposide onto the 3-drug combination of vincristine, doxorubicin, and cyclophosphamide has improved survival for patients with localized disease [4
]. Building on these results, Womer et al. have shown that compression of the interval between treatment courses from 3 weeks to 2 weeks provides additional improvement in 3-year event-free survival, which is now up to 76% for nonmetastatic patients [1
]. Since further modification of this 5-drug regimen seems unlikely to produce additional benefits [5
], future regimens will likely need to incorporate new drugs in order to continue progress in the field.
Camptothecin agents have been evaluated in Ewing sarcoma patients for the last decade. This class of agents is attractive because of commercial availability, modest single-agent activity, and demonstrated tolerability and synergy with alkylating agents. Camptothecins exert cytotoxicity by stabilizing the covalent complex between DNA and topoisomerase I, the enzyme which relieves torsional strain of DNA. This stabilization process prevents religation of DNA, and the ensuing collision of the stabilized complex with the advancing replication fork results in double strand breaks and cell death. Preclinical studies have suggested that activity of camptothecins is greatest when given in combination with alkylating agents [6
]. Mechanistically, DNA damage from alkylators may increase the importance of topoisomerase I for cell repair, thus rendering tumor cells more sensitive to topoisomerase I inhibition [7
]. This activity is also enhanced in preclinical experiments when protracted, low-dose administration is used compared to single large doses [8
], which is consistent with the S-phase-specific mechanism of action.
This paper summarizes past Ewing sarcoma clinical trials of the two most commonly used camptothecins, topotecan, and irinotecan. Emphasis is placed on differences in their toxicity profiles, schedules, and routes of administration, and partnering alkylating agents. Finally, an outline is provided regarding potential future directions in which these agents may be further developed.