Background: Treatment for ES in North America has evolved to include cycles of VDC and IE. A regimen including these 5 agents with interval dose compression has achieved 5 year EFS of 73% for localized ES. At Memorial Sloan Kettering (MSK) we have instead used the strategy of increasing doses of alkylating agents to achieve dose intensification and reported similar results. The combination of i/T given as irinotecan 20 mg/m2/day for 10 days with temozolomide 100 mg/m2/day for 5 days has achieved objective responses for patients who recur after initial therapy with the 5 drug combination. Our prospective protocol incorporates cycles of i/T with cycles of VDC and IE for the treatment of newly diagnosed patients with ES. Methods: We have enrolled patients with and without clinically detectable metastatic disease at initial presentation. For patients with localized ES we administer high dose alkylator therapy with 4 cycles of VDC and 3 cycles of IE, followed by 6 cycles of i/T. For patients who present with metastases we intercalate 10 cycles of i/T with the same 7 cycles of high dose alkylating agent therapy. Results: We have enrolled 22 patients with localized and 16 patients with metastatic ES. With a median followup of 14 (3-51) months, patients with localized ES have achieved a 3 year EFS of 95% and overall survival (OS) of 95%. With a median followup of 20 (8-51) months, patients with metastatic ES have achieved a 3 year EFS of 55% and OS of 70%. Conclusions: The addition of multiple cycles of i/T to conventional 5 drug therapy for ES is feasible and may be associated with an improved probability for both EFS and OS. Clinical trial information: NCT01864109