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Impact of tumor location and pathological discordance on survival of children with midline high-grade gliomas treated on Children’s Cancer Group high-grade glioma study CCG-945

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Abstract

Children with high-grade glioma (HGG) have a poor prognosis compared to those with low-grade glioma (LGG). Adjuvant chemotherapy may be beneficial, but its optimal use remains undetermined. Histology and extent of resection are important prognostic factors. We tested the hypothesis that patients with midline HGG treated on Children’s Cancer Group Study (CCG) CCG-945 have a worse prognosis compared to the entire group. Of 172 children eligible for analysis, 60 had midline tumors primarily localized to the thalamus, hypothalamus and basal ganglia. Time-to-progression and death were determined from the date of initial diagnosis, and survival curves were calculated. Univariate analyses were undertaken for extent of resection, chemotherapy regimen, anatomic location, histology, proliferation index, MGMT status and p53 over-expression. For the entire midline tumor group, 5-year PFS and OS were 18.3 ± 4.8 and 25 ± 5.4 %, respectively. Many patients only had a biopsy (43.3 %). The sub-groups with near/total resection and hypothalamic location appeared to have better PFS and OS. However, the effect of tumor histology on OS was significant for children with discordant diagnoses on central pathology review of LGG compared to HGG. Proliferative index (MIB-1 > 36 %), MGMT and p53 over-expression correlated with poor outcomes. Children treated on CCG-945 with midline HGG have a worse prognosis when compared to the entire group. The midline location may directly influence the extent of resection. Central pathology review and entry of patients on clinical trials continue to be priorities to improve outcomes for children with HGG.

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References

  1. Sposto R, Ertel IJ, Jenkin RD, Boesel CP, Venes JL, Ortega JA, Evans AE, Wara W, Hammond D (1989) The effectiveness of chemotherapy for treatment of high grade astrocytoma in children: results of a randomized trial. A report from the Children’s Cancer Study Group. J Neurooncol 7:165–177

    Article  CAS  PubMed  Google Scholar 

  2. Finlay JL, Boyett JM, Yates AJ, Wisoff JH, Milstein JM, Geyer JR, Bertolone SJ, McGuire P, Cherlow JM, Tefft M et al (1995) Randomized phase III trial in childhood high-grade astrocytoma comparing vincristine, lomustine, and prednisone with the eight-drugs-in-1-day regimen. Children’s Cancer Group. J Clin Oncol 13:112–123

    CAS  PubMed  Google Scholar 

  3. Pollack IF, Hamilton RL, Burnham J, Holmes EJ, Finkelstein SD, Sposto R, Yates AJ, Boyett JM, Finlay JL (2002) Impact of proliferation index on outcome in childhood malignant gliomas: results in a multi-institutional cohort. Neurosurgery 50:1238–1244 discussion 1244–1235

    PubMed  Google Scholar 

  4. Pollack IF, Hamilton RL, Sobol RW, Burnham J, Yates AJ, Holmes EJ, Zhou T, Finlay JL (2006) O6-methylguanine-DNA methyltransferase expression strongly correlates with outcome in childhood malignant gliomas: results from the CCG-945 Cohort. J Clin Oncol 24:3431–3437. doi:10.1200/JCO.2006.05.7265

    Article  CAS  PubMed  Google Scholar 

  5. Pollack IF, Finkelstein SD, Woods J, Burnham J, Holmes EJ, Hamilton RL, Yates AJ, Boyett JM, Finlay JL, Sposto R (2002) Expression of p53 and prognosis in children with malignant gliomas. N Engl J Med 346:420–427. doi:10.1056/NEJMoa012224

    Article  CAS  PubMed  Google Scholar 

  6. Lee ET (1992) Non-parametric methods of estimating survival functions. Wiley, New York

    Google Scholar 

  7. Wisoff JH, Boyett JM, Berger MS, Brant C, Li H, Yates AJ, McGuire-Cullen P, Turski PA, Sutton LN, Allen JC, Packer RJ, Finlay JL (1998) Current neurosurgical management and the impact of the extent of resection in the treatment of malignant gliomas of childhood: a report of the Children’s Cancer Group trial no. CCG-945. J Neurosurg 89:52–59

    Article  CAS  PubMed  Google Scholar 

  8. Bucci MK, Maity A, Janss AJ, Belasco JB, Fisher MJ, Tochner ZA, Rorke L, Sutton LN, Phillips PC, Shu HK (2004) Near complete surgical resection predicts a favorable outcome in pediatric patients with non brainstem, malignant gliomas: results from a single center in the magnetic resonance imaging era. Cancer 101:817–824. doi:10.1002/cncr.20422

    Article  PubMed  Google Scholar 

  9. Wolff JE, Driever PH, Erdlenbruch B, Kortmann RD, Rutkowski S, Pietsch T, Parker C, Metz MW, Gnekow A, Kramm CM (2010) Intensive chemotherapy improves survival in pediatric high-grade glioma after gross total resection: results of the HIT-GBM-C protocol. Cancer 116:705–712. doi:10.1002/cncr.24730

    Article  PubMed  Google Scholar 

  10. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996. doi:10.1056/NEJMoa043330

    Article  CAS  PubMed  Google Scholar 

  11. Cohen KJ, Pollack IF, Zhou T, Buxton A, Holmes EJ, Burger PC, Brat DJ, Rosenblum MK, Hamilton RL, Lavey RS, Heideman RL (2011) Temozolomide in the treatment of high-grade gliomas in children: a report from the Children’s Oncology Group. Neuro Oncol 13:317–323. doi:10.1093/neuonc/noq191

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Broniscer A, Chintagumpala M, Fouladi M, Krasin MJ, Kocak M, Bowers DC, Iacono LC, Merchant TE, Stewart CF, Houghton PJ, Kun LE, Ledet D, Gajjar A (2006) Temozolomide after radiotherapy for newly diagnosed high-grade glioma and unfavorable low-grade glioma in children. J Neurooncol 76:313–319. doi:10.1007/s11060-005-7409-5

    Article  PubMed  Google Scholar 

  13. Jakacki RI, Yates A, Blaney SM, Zhou T, Timmerman R, Ingle AM, Flom L, Prados MD, Adamson PC, Pollack IF (2008) A phase I trial of temozolomide and lomustine in newly diagnosed high-grade gliomas of childhood. Neuro Oncol 10:569–576. doi:10.1215/15228517-2008-019

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Parekh C, Jubran R, Erdreich-Epstein A, Panigrahy A, Bluml S, Finlay J, Dhall G (2011) Treatment of children with recurrent high grade gliomas with a bevacizumab containing regimen. J Neurooncol 103:673–680. doi:10.1007/s11060-010-0444-x

    Article  CAS  PubMed  Google Scholar 

  15. Fouladi M, Hunt DL, Pollack IF, Dueckers G, Burger PC, Becker LE, Yates AJ, Gilles FH, Davis RL, Boyett JM, Finlay JL (2003) Outcome of children with centrally reviewed low-grade gliomas treated with chemotherapy with or without radiotherapy on Children’s Cancer Group high-grade glioma study CCG-945. Cancer 98:1243–1252. doi:10.1002/cncr.11637

    Article  PubMed  Google Scholar 

  16. Louis DNOH, Wiestler OD, Cavenee WK (eds) (2007) World Health Organization classification of tumours of the central nervous system. IARC Press, Lyon

    Google Scholar 

  17. Pollack IF, Boyett JM, Yates AJ, Burger PC, Gilles FH, Davis RL, Finlay JL (2003) The influence of central review on outcome associations in childhood malignant gliomas: results from the CCG-945 experience. Neuro Oncol 5:197–207. doi:10.1215/S1152-8517-03-00009-7

    Article  PubMed Central  PubMed  Google Scholar 

  18. Gilles FH, Tavare CJ, Becker LE, Burger PC, Yates AJ, Pollack IF, Finlay JL (2008) Pathologist interobserver variability of histologic features in childhood brain tumors: results from the CCG-945 study. Pediatr Dev Pathol 11:108–117. doi:10.2350/07-06-0303.1

    Article  PubMed  Google Scholar 

  19. Esteller M, Garcia-Foncillas J, Andion E, Goodman SN, Hidalgo OF, Vanaclocha V, Baylin SB, Herman JG (2000) Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med 343:1350–1354. doi:10.1056/NEJM200011093431901

    Article  CAS  PubMed  Google Scholar 

  20. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003. doi:10.1056/NEJMoa043331

    Article  CAS  PubMed  Google Scholar 

  21. Lee JY, Park CK, Park SH, Wang KC, Cho BK, Kim SK (2011) MGMT promoter gene methylation in pediatric glioblastoma: analysis using MS-MLPA. Childs Nerv Syst 27:1877–1883. doi:10.1007/s00381-011-1525-7

    Article  PubMed  Google Scholar 

  22. Buttarelli FR, Massimino M, Antonelli M, Lauriola L, Nozza P, Donofrio V, Arcella A, Oliva MA, Di Rocco C, Giangaspero F (2010) Evaluation status and prognostic significance of O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation in pediatric high grade gliomas. Childs Nerv Syst 26:1051–1056. doi:10.1007/s00381-010-1191-1

    Article  PubMed  Google Scholar 

  23. Srivastava A, Jain A, Jha P, Suri V, Sharma MC, Mallick S, Puri T, Gupta DK, Gupta A, Sarkar C (2010) MGMT gene promoter methylation in pediatric glioblastomas. Childs Nerv Syst 26:1613–1618. doi:10.1007/s00381-010-1214-y

    Article  PubMed  Google Scholar 

  24. Pollack IF, Finkelstein SD, Burnham J, Holmes EJ, Hamilton RL, Yates AJ, Finlay JL, Sposto R (2001) Age and TP53 mutation frequency in childhood malignant gliomas: results in a multi-institutional cohort. Cancer Res 61:7404–7407

    CAS  PubMed  Google Scholar 

  25. Pollack IF, Hamilton RL, James CD, Finkelstein SD, Burnham J, Yates AJ, Holmes EJ, Zhou T, Finlay JL (2006) Rarity of PTEN deletions and EGFR amplification in malignant gliomas of childhood: results from the Children’s Cancer Group 945 cohort. J Neurosurg 105:418–424. doi:10.3171/ped.2006.105.5.418

    Article  PubMed  Google Scholar 

  26. Faury D, Nantel A, Dunn SE, Guiot MC, Haque T, Hauser P, Garami M, Bognar L, Hanzely Z, Liberski PP, Lopez-Aguilar E, Valera ET, Tone LG, Carret AS, Del Maestro RF, Gleave M, Montes JL, Pietsch T, Albrecht S, Jabado N (2007) Molecular profiling identifies prognostic subgroups of pediatric glioblastoma and shows increased YB-1 expression in tumors. J Clin Oncol 25:1196–1208. doi:10.1200/JCO.2006.07.8626

    Article  CAS  PubMed  Google Scholar 

  27. Haque T, Faury D, Albrecht S, Lopez-Aguilar E, Hauser P, Garami M, Hanzely Z, Bognar L, Del Maestro RF, Atkinson J, Nantel A, Jabado N (2007) Gene expression profiling from formalin-fixed paraffin-embedded tumors of pediatric glioblastoma. Clin Cancer Res 13:6284–6292. doi:10.1158/1078-0432.CCR-07-0525

    Article  CAS  PubMed  Google Scholar 

  28. Pollack IF, Hamilton RL, Burger PC, Brat DJ, Rosenblum MK, Murdoch GH, Nikiforova MN, Holmes EJ, Zhou T, Cohen KJ, Jakacki RI (2010) Akt activation is a common event in pediatric malignant gliomas and a potential adverse prognostic marker: a report from the Children’s Oncology Group. J Neurooncol 99:155–163. doi:10.1007/s11060-010-0297-3

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. McLendon R et al (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068. doi:10.1038/nature07385

    Article  CAS  Google Scholar 

  30. Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA Jr, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807–1812. doi:10.1126/science.1164382

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Pollack IF, Hamilton RL, Sobol RW, Nikiforova MN, Lyons-Weiler MA, LaFramboise WA, Burger PC, Brat DJ, Rosenblum MK, Holmes EJ, Zhou T, Jakacki RI (2011) IDH1 mutations are common in malignant gliomas arising in adolescents: a report from the Children’s Oncology Group. Childs Nerv Syst 27:87–94. doi:10.1007/s00381-010-1264-1

    Article  PubMed Central  PubMed  Google Scholar 

  32. Schwartzentruber J, Korshunov A, Liu XY, Jones DT, Pfaff E, Jacob K, Sturm D, Fontebasso AM, Quang DA, Tonjes M, Hovestadt V, Albrecht S, Kool M, Nantel A, Konermann C, Lindroth A, Jager N, Rausch T, Ryzhova M, Korbel JO, Hielscher T, Hauser P, Garami M, Klekner A, Bognar L, Ebinger M, Schuhmann MU, Scheurlen W, Pekrun A, Fruhwald MC, Roggendorf W, Kramm C, Durken M, Atkinson J, Lepage P, Montpetit A, Zakrzewska M, Zakrzewski K, Liberski PP, Dong Z, Siegel P, Kulozik AE, Zapatka M, Guha A, Malkin D, Felsberg J, Reifenberger G, von Deimling A, Ichimura K, Collins VP, Witt H, Milde T, Witt O, Zhang C, Castelo-Branco P, Lichter P, Faury D, Tabori U, Plass C, Majewski J, Pfister SM, Jabado N (2012) Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482:226–231. doi:10.1038/nature10833

    Article  CAS  PubMed  Google Scholar 

  33. Sturm D, Bender S, Jones DT, Lichter P, Grill J, Becher O, Hawkins C, Majewski J, Jones C, Costello JF, Iavarone A, Aldape K, Brennan CW, Jabado N, Pfister SM (2014) Paediatric and adult glioblastoma: multiform (epi)genomic culprits emerge. Nat Rev Cancer 14:92–107. doi:10.1038/nrc3655

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Bender S, Tang Y, Lindroth AM, Hovestadt V, Jones DT, Kool M, Zapatka M, Northcott PA, Sturm D, Wang W, Radlwimmer B, Hojfeldt JW, Truffaux N, Castel D, Schubert S, Ryzhova M, Seker-Cin H, Gronych J, Johann PD, Stark S, Meyer J, Milde T, Schuhmann M, Ebinger M, Monoranu CM, Ponnuswami A, Chen S, Jones C, Witt O, Collins VP, von Deimling A, Jabado N, Puget S, Grill J, Helin K, Korshunov A, Lichter P, Monje M, Plass C, Cho YJ, Pfister SM (2013) Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas. Cancer Cell 24:660–672. doi:10.1016/j.ccr.2013.10.006

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Biological analyses were supported by RO1NS37704 (IFP).

Conflict of interest

None of the study authors declares any conflicts of interest.

Author information

Authors and Affiliations

  1. Division of Pediatric Hematology, Oncology, and Palliative Care, Department of Pediatrics, Faculty of Medicine & Dentistry, Stollery Children’s Hospital, University of Alberta, 8-43B Medical Sciences Building, Edmonton, AB, T6G 2H7, Canada

    David D. Eisenstat

  2. Department of Neurosurgery, Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA

    Ian F. Pollack

  3. Department of Epidemiology, CancerCare Manitoba, Winnipeg, MB, Canada

    Alain Demers & Pascal Lambert

  4. Department of Community Health Sciences, University of Manitoba, Winnipeg, Canada

    Alain Demers

  5. Women and Children’s Hospital, Huntsville Hospital Systems, Huntsville, AL, USA

    Mark V. Sapp

  6. Departments of Pediatrics and Genetics & Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA

    James D. Weisfeld-Adams

  7. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Peter C. Burger

  8. Department of Pathology, Children’s Hospital Los Angeles, Los Angeles, CA, USA

    Floyd Gilles

  9. Department of Pathology, University of California, San Francisco, San Francisco, CA, USA

    Richard L. Davis

  10. Brain Tumor Institute, Children’s National Medical Center, Washington, DC, USA

    Roger Packer

  11. Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN, USA

    James M. Boyett

  12. Division of Hematology/Oncology/BMT, Nationwide Children’s Hospital, The Ohio State University, 700 Children’s Drive, Columbus, OH, 43205-2664, USA

    Jonathan L. Finlay

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  1. David D. Eisenstat
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  2. Ian F. Pollack
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  3. Alain Demers
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  4. Mark V. Sapp
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  5. Pascal Lambert
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  6. James D. Weisfeld-Adams
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  7. Peter C. Burger
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  8. Floyd Gilles
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  9. Richard L. Davis
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  10. Roger Packer
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  11. James M. Boyett
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  12. Jonathan L. Finlay
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Corresponding authors

Correspondence to David D. Eisenstat or Jonathan L. Finlay.

Additional information

Sapp M, Boyett JM, Yates AJ, Burger P, Becker L, Davies R, Gilles F and Finlay JL. Outcome for children with midline primary site high grade astrocytoma (HGA) treated on the Childrens Cancer Group Trial (CCG-945). Oral presentation: Seventh International Symposium on Pediatric Neuro-oncology, Washington DC, J Neuro-oncol 1996; 33:269.

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Eisenstat, D.D., Pollack, I.F., Demers, A. et al. Impact of tumor location and pathological discordance on survival of children with midline high-grade gliomas treated on Children’s Cancer Group high-grade glioma study CCG-945. J Neurooncol 121, 573–581 (2015). https://doi.org/10.1007/s11060-014-1669-x

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