Irinotecan and Temozolomide for Ewing Sarcoma: The Memorial Sloan-Kettering Experience
ABSTRACT The prognosis for recurrent/progressive Ewing sarcoma (ES) remains poor. Pre-clinical, adult phase I and II trials have demonstrated the combination of irinotecan and temozolomide to have schedule-dependent synergy and significant antitumor activity. A pediatric phase I trial has shown this regimen to be safe and active in advanced ES.
We conducted a retrospective chart review to identify patients with recurrent/progressive ES treated with irinotecan [20 mg/m(2)/day x 5(x2)] and temozolomide (100 mg/m(2)/day x 5) in our institution. The best response achieved, time to progression (TTP), and associated toxicities were recorded.
Twenty patients received a total of 154 cycles of therapy. Of 19 evaluable patients, there were 5 complete and 7 partial responses (a 63% overall objective response). Median TTP for 20 evaluable patients with recurrent/progressive ES was 8.3 months; for the subset of 14 patients with recurrent ES, it was 16.2 months. Median TTP was better for patients who sustained a 2-year first remission than for those who relapsed < 24 months from diagnosis and for patients with primary localized vs. metastatic disease. Significant toxicities included grade 3 diarrhea (7 cycles), grade 3 colitis (1 cycle), grade 3 pneumonitis in one patient receiving concurrent whole-lung RT, grade 3-4 neutropenia (19 cycles), and grade 3-4 thrombocytopenia (16 cycles).
Irinotecan and temozolomide is a well-tolerated and active regimen for recurrent/progressive ES. Prospective trials are necessary to define the role of this regimen in newly diagnosed ES.
- SourceAvailable from: Neriman Sari
[Show abstract] [Hide abstract]
- "Temozolomide has relatively low incidence of toxicity and its dose limiting toxicity is myelosuppression, mainly neutropenia and thrombocytopenia . The most commonly demonstrated toxicities of the combination in the reported studies were diarrhea and neutropenia   . When the 346 courses of the three studies were collectively evaluated, 26 courses (7.5%) were associated with grade 3–4 diarrhea. "
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.Pediatric Hematology and Oncology 09/2014; 32(1). DOI:10.3109/08880018.2014.954070 · 0.96 Impact Factor
[Show abstract] [Hide abstract]
- "c o m / l o c a t e / b i o c h e m p h a r m over CPT-11, including improved therapeutic index, the novel camptothecin was selected for clinical development. Given the promising activity of CPT derivatives in clinical therapy of childhood solid tumors    , the present study was undertaken to explore the therapeutic potential of namitecan against pediatric sarcoma xenograft models, including bone and soft tissue sarcomas. The preclinical study provides evidence of outstanding efficacy of namitecan, exhibiting high cure rates. "
ABSTRACT: Namitecan (ST1968), a novel hydrophilic camptothecin analog of the 7-oxyiminomethyl series, was selected for clinical development on the basis of its promising preclinical efficacy. Since there is clinical evidence of efficacy of camptothecins against pediatric tumors, this study was performed to explore the antitumor and antiangiogenic activity of the camptothecin derivative in pediatric sarcoma models. With the exception of an undifferentiated rhabdomyosarcoma (A204), namitecan exhibited curative efficacy even at well-tolerated suboptimal doses in a panel of five models. The good therapeutic index of namitecan likely reflected a high and persistent drug accumulation at tumor site. The four responsive tumors were characterized by high topoisomerase I expression. In the RD/TE-671 rhabdomyosarcoma model the drug activity was associated with a marked antiangiogenic effect, which was consistent with the downregulation of proangiogenic factors, including VEGF, bFGF and the multifunctional chemokines CCL-2 and CXCL16. In agreement with this modulation, the combination of low doses of namitecan with other antiangiogenic agents, such as bevacizumab (a humanized anti-VEGF antibody) and sunitinib (a multitarget tyrosine kinase inhibitor effective against receptors implicated in the angiogenesis process), enhanced the antitumor effects. In conclusion, this preclinical study provides evidence of curative efficacy of namitecan at well-tolerated doses against pediatric sarcoma models, likely reflecting a contribution of antiangiogenic effects. Based on the promising therapeutic profile, namitecan is a good candidate for clinical evaluation in pediatric sarcomas.Biochemical pharmacology 04/2012; 84(2):163-71. DOI:10.1016/j.bcp.2012.04.005 · 4.65 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: In preclinical models, temozolomide, and vincristine are additive or synergistic with irinotecan. We examined this three-drug combination in children with relapsed solid tumors. Patients received orally administered irinotecan together with temozolomide and vincristine on two different schedules, using cefixime to reduce irinotecan-associated diarrhea. Oral irinotecan was given daily on days 1-5 and 8-12 (Schedule A), or on days 1-5 (Schedule B). Temozolomide was given on days 1-5, with vincristine 1.5 mg/m(2) administered on days 1 and 8 (Schedule A) or day 1 (Schedule B) in 21-day courses. On Schedule A, the maximum tolerated dose of oral irinotecan was 35 mg/m(2)/day combined with temozolomide 100 mg/m(2)/day and vincristine on days 1 and 8. Dose-limiting toxicities in 4 of 12 patients included hepatotoxicity, abdominal pain, anorexia, hypokalemia, and thrombocytopenia at 50 mg/m(2)/day. Using Schedule B, 0 of 6 patients experienced dose-limiting toxicity (DLT) at the highest doses studied of oral irinotecan 90 mg/m(2)/day, temozolomide 150 mg/m(2)/day x 5, and vincristine on day 1. First-course and cumulative toxicity was greater with Schedule A. UGT1A1*28 genotype did not correlate with DLT. At the irinotecan dose of 90 mg/m(2)/day, the mean SN-38 AUC(inf) was 63 ng/ml hr. Activity was seen in sarcoma patients, and overall eight patients received >or=6 courses. The 5-day schedule of VOIT was well tolerated and provided SN-38 exposures similar to those achieved with intravenous IRN. Activity on this and prior studies suggests a potential role for VOIT in a spectrum of childhood solid tumors.Pediatric Blood & Cancer 01/2009; 54(4):538-45. DOI:10.1002/pbc.22407 · 2.56 Impact Factor