Vorinostat, temozolomide or bevacizumab with irradiation and maintenance BEV/TMZ in pediatric high-grade glioma: A Children’s Oncology Group Study

Author:

Lulla Rishi R1ORCID,Buxton Allen2,Krailo Mark D2,Lazow Margot A3,Boue Daniel R4,Leach James L5,Lin Tong6,Geller James I7,Kumar Shiva Senthil8,Nikiforova Marina N9,Chandran Uma10,Jogal Sachin S11,Nelson Marvin D12ORCID,Onar-Thomas Arzu6,Haas-Kogan Daphne A13,Cohen Kenneth J14,Kieran Mark W15,Gajjar Amar16,Drissi Rachid17ORCID,Pollack Ian F18,Fouladi Maryam3ORCID

Affiliation:

1. Department of Pediatrics, Hasbro Children’s Hospital, The Warren Alpert Medical School of Brown University , Providence, Rhode Island , USA

2. Department of Biostatistics, Children’s Oncology Group , Monrovia, California , USA

3. Pediatric Neuro‑Oncology Program, Nationwide Children’s Hospital, The Ohio State University College of Medicine , Columbus, Ohio , USA

4. Department of Pathology and Laboratory Medicine, Nationwide Children’s Hospital, The Ohio State University College of Medicine , Columbus, Ohio , USA

5. Department of Radiology and Medical Imaging, Cincinnati Children’s Hospital Medical Center, Department of Radiology, University of Cincinnati College of Medicine , Cincinnati, Ohio , USA

6. Department of Biostatistics, St. Jude Children’s Research Hospital , Memphis, Tennessee , USA

7. Division of Oncology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati , Cincinnati, Ohio , USA

8. Center for Childhood Cancer Research, Nationwide Children’s Hospital , Columbus, Ohio , USA

9. Division of Molecular & Genomic Pathology, University of Pittsburgh Medical Center , Pittsburgh, Pennsylvania , USA

10. Department of Biomedical Informatics, University of Pittsburgh , Pittsburgh, Pennsylvania , USA

11. Department of Pediatrics, Medical College of Wisconsin , Milwaukee, Wisconsin , USA

12. Department of Radiology, Children’s Hospital Los Angeles, Keck University of Southern California School of Medicine , Los Angeles, California , USA

13. Department of Radiation Oncology, Brigham and Women’s Hospital, Boston Children’s Hospital, Dana-Farber Cancer Institute, Harvard Medical School , Boston, Massachusetts , USA

14. Division of Pediatric Oncology, Department of Pediatrics, The Johns Hopkins University School of Medicine , Baltimore, Maryland , USA

15. Department of Pediatric Oncology, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Harvard Medical School , Boston, Massachusetts , USA

16. Department of Pediatric Medicine, St Jude Children’s Research Hospital , Memphis, Tennessee , USA

17. Center for Childhood Cancer Research, Nationwide Children’s Hospital, Columbus, OH, The Ohio State University College of Medicine , Columbus, Ohio , USA

18. Department of Neurosurgery, UPMC Children’s Hospital of Pittsburgh, University of Pittsburgh , Pittsburgh, Pennsylvania , USA

Abstract

Abstract Background Outcomes for children with high-grade gliomas (HGG) remain poor. This multicenter phase II trial evaluated whether concurrent use of vorinostat or bevacizumab with focal radiotherapy (RT) improved 1-year event-free survival (EFS) compared to temozolomide in children with newly diagnosed HGG who received maintenance temozolomide and bevacizumab. Methods Patients ≥ 3 and < 22 years with localized, non-brainstem HGG were randomized to receive RT (dose 54–59.4Gy) with vorinostat, temozolomide, or bevacizumab followed by 12 cycles of bevacizumab and temozolomide maintenance therapy. Results Among 90 patients randomized, the 1-year EFS for concurrent bevacizumab, vorinostat, or temozolomide with RT was 43.8% (±8.8%), 41.4% (±9.2%), and 59.3% (±9.5%), respectively, with no significant difference among treatment arms. Three- and five-year EFS for the entire cohort was 14.8% and 13.4%, respectively, with no significant EFS difference among the chemoradiotherapy arms. IDH mutations were associated with more favorable EFS (P = .03), whereas H3.3 K27M mutations (P = .0045) and alterations in PIK3CA or PTEN (P = .025) were associated with worse outcomes. Patients with telomerase- and alternative lengthening of telomeres (ALT)-negative tumors (n = 4) had an EFS of 100%, significantly greater than those with ALT or telomerase, or both (P = .002). While there was no difference in outcomes based on TERT expression, high TERC expression was associated with inferior survival independent of the telomere maintenance mechanism (P = .0012). Conclusions Chemoradiotherapy with vorinostat or bevacizumab is not superior to temozolomide in children with newly diagnosed HGG. Patients with telomerase- and ALT-negative tumors had higher EFS suggesting that, if reproduced, mechanism of telomere maintenance should be considered in molecular-risk stratification in future studies.

Funder

National Institutes of Natural Sciences

Publisher

Oxford University Press (OUP)

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