Sarah E S Leary1,2,3, Lindsay Kilburn4, J Russell Geyer1,2,3, Mehmet Kocak5, Jie Huang5, Kyle S Smith6, Jennifer Hadley6, Ralph Ermoian7, Tobey J MacDonald8, Stewart Goldman9, Peter Phillips10, Tina Young Poussaint11, James M Olson1,2,3, David W Ellison12, Ira J Dunkel13, Maryam Fouladi14, Arzu Onar-Thomas5, Paul A Northcott6. 1. Cancer and Blood Disorders Center, Seattle Children's Hospital, Seattle, Washington, USA. 2. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. 3. Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, USA. 4. Center for Cancer and Blood Disorders, Children's National Hospital, Washington, DC, USA. 5. Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. 6. Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. 7. Department of Radiation Oncology, University of Washington, Seattle, Washington, USA. 8. Aflac Cancer and Blood Disorders Center, Emory University, Atlanta, Georgia, USA. 9. Department of Child Health, Phoenix Children's Hospital, Phoenix, Arizona, USA. 10. Department of Pediatric Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. 11. Department of Radiology, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. 12. Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. 13. Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA. 14. Department of Pediatric Hematology & Oncology, Nationwide Children's Hospital, Columbus, Ohio, USA.
Abstract
BACKGROUND: Embryonal tumors of the CNS are the most common malignant tumors occurring in the first years of life. This study evaluated the feasibility and safety of incorporating novel non-cytotoxic therapy with vorinostat and isotretinoin to an intensive cytotoxic chemotherapy backbone. METHODS: PBTC-026 was a prospective multi-institutional clinical trial for children <48 months of age with newly diagnosed embryonal tumors of the CNS. Treatment included three 21-day cycles of induction therapy with vorinostat and isotretinoin, cisplatin, vincristine, cyclophosphamide, and etoposide; three 28-day cycles of consolidation therapy with carboplatin and thiotepa followed by stem cell rescue; and twelve 28-day cycles of maintenance therapy with vorinostat and isotretinoin. Patients with M0 medulloblastoma (MB) received focal radiation following consolidation therapy. Molecular classification was by DNA methylation array. RESULTS: Thirty-one patients with median age of 26 months (range 6-46) received treatment on study; 19 (61%) were male. Diagnosis was MB in 20 and supratentorial CNS embryonal tumor in 11. 24/31 patients completed induction therapy within a pre-specified feasibility window of 98 days. Five-year progression-free survival (PFS) and overall survival (OS) for all 31 patients were 55 ± 15 and 61 ± 13, respectively. Five-year PFS was 42 ± 13 for group 3 MB (n = 12); 80 ± 25 for SHH MB (n = 5); 33 ± 19 for embryonal tumor with multilayered rosettes (ETMR, n = 6). CONCLUSION: It was safe and feasible to incorporate vorinostat and isotretinoin into an intensive chemotherapy regimen. Further study to define efficacy in this high-risk group of patients is warranted.
BACKGROUND: Embryonal tumors of the CNS are the most common malignant tumors occurring in the first years of life. This study evaluated the feasibility and safety of incorporating novel non-cytotoxic therapy with vorinostat and isotretinoin to an intensive cytotoxic chemotherapy backbone. METHODS: PBTC-026 was a prospective multi-institutional clinical trial for children <48 months of age with newly diagnosed embryonal tumors of the CNS. Treatment included three 21-day cycles of induction therapy with vorinostat and isotretinoin, cisplatin, vincristine, cyclophosphamide, and etoposide; three 28-day cycles of consolidation therapy with carboplatin and thiotepa followed by stem cell rescue; and twelve 28-day cycles of maintenance therapy with vorinostat and isotretinoin. Patients with M0 medulloblastoma (MB) received focal radiation following consolidation therapy. Molecular classification was by DNA methylation array. RESULTS: Thirty-one patients with median age of 26 months (range 6-46) received treatment on study; 19 (61%) were male. Diagnosis was MB in 20 and supratentorial CNS embryonal tumor in 11. 24/31 patients completed induction therapy within a pre-specified feasibility window of 98 days. Five-year progression-free survival (PFS) and overall survival (OS) for all 31 patients were 55 ± 15 and 61 ± 13, respectively. Five-year PFS was 42 ± 13 for group 3 MB (n = 12); 80 ± 25 for SHH MB (n = 5); 33 ± 19 for embryonal tumor with multilayered rosettes (ETMR, n = 6). CONCLUSION: It was safe and feasible to incorporate vorinostat and isotretinoin into an intensive chemotherapy regimen. Further study to define efficacy in this high-risk group of patients is warranted.
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