Irinotecan and Temozolamide Treatment for Relapsed Ewing Sarcoma: A Single-Center Experience and Review of the Literature

Abstract

Long-term survival in relapsed Ewing sarcoma (ES) is less than 20%. Encouraging results have been reported with irinotecan and temozolomide combinations (IRN/TMZ). We aimed to share our experience and compare it with previously published studies using this combination to treat relapsed ES. We retrospectively evaluated 20 patients treated with a combination of IRN (20 mg/m(2)/d × 5 for 2 weeks) and temozolomide (100 mg/m(2)/d × 5). Patients received a total of 97 courses. An objective response was achieved in 11 patients (55%) and maintained for a median of 12 months. Five patients were alive for a median of 12 months. Median time to progression was 5.5 (2-57) months. After the IRN/TMZ treatment, 1-year overall and event-free survival rates were 54.2% and 44.4%, respectively. Grade 3-4 toxicities included diarrhea (9.2%), neutropenia (11.3%), and thrombocytopenia (6.2%). Three retrospective trials were found in our literature review, which used an IRN/TMZ combination to treat ES. There was one other study which retrospectively evaluated the efficacy of vincristine, IRN, and TMZ combination in relapsed ES. A total of 81 patients were treated with IRN/TMZ in four studies including ours. The objective response rate was 55.1%, and median time to progression ranged from 5.5 to 8.3 months. Twenty-six (7.5%) of a total of 346 courses were associated with grade 3-4 diarrhea. Grade 3-4 neutropenia and thrombocytopenia were reported in 9.2% and 7.2% of the courses, respectively. Results showed that an IRN/TMZ combination is effective and tolerable in patients with relapsed ES.

Irinotecan and temozolomide in recurrent Ewing sarcoma: an analysis in 51 adult and pediatric patients

“…Predictive factors for response to chemotherapy are still to be identified. TEMIRI has been studied in retrospective studies mainly including pediatric patients [13,[22][23][24][25][26][27][28][29][30] however, none of these studies have reported on putative predictive markers of response and PFS. Only one study has been published with single agent temozolomide [11] while different schedules of single agent irinotecan are reported in different trials [14,32,33].…”

“…Only few salvage schedules have emerged for 'routine' use, including cyclophosphamide and topotecan [16,17] as well as temozolomide and irinotecan (TEMIRI), gemcitabine and docetaxel (GEM-TXT) [18,19], and high-dose ifosfamide (HDIFO) [20,21]. Most of the available data regarding the activity and toxicity of TEMIRI are from retrospective studies on pediatric EWS populations (Table 1) [13,[22][23][24][25][26][27][28][29][30].…”

Fifteen years of irinotecan therapy for pediatric sarcoma: where to next?

“…This is consistent with the proposed mechanism in which temozolomide-induced methylation of DNA causes localization of topoisomerase I-DNA complexes that are more susceptible to the cytotoxic effects of irinotecan [ 32 ]. This temozolomide + irinotecan (TI) combination has been particularly active in Ewing sarcoma, with reported response rates between 29 and 63 % [ 33 – 35 ]. The dose-limiting toxicities of irinotecan (diarrhea) and temozolomide (myelosuppression) are non-overlapping, and the combination is well-suited for oral administration.…”

Management of Ewing sarcoma family of tumors: Current scenario and unmet need

“…Gemcitabine and docetaxel[ 60 ] combination failed to show any clinically meaningful activity in recurrent ESFT. The mostly studied chemotherapeutic regimen in recurrent ESFT is of irinotecan and temozolamide from a phase 1 trial and from few institutional experiences[ 61 - 65 ], like in other pediatric solid tumors. This combination used protracted course of irinotecan with synergistic activity of temozolamide and produced overall response rate of 25%-60% (Table 4 ).…”