Advertisement

Journal of Neuro-Oncology

, Volume 123, Issue 1, pp 129–134 | Cite as

Radiotherapy and temozolomide for anaplastic astrocytic gliomas

  • Lakshmi Nayak
  • Katherine S. Panageas
  • Anne S. Reiner
  • Jason T. Huse
  • Elena Pentsova
  • Stephanie G. Braunthal
  • Lauren E. Abrey
  • Lisa M. DeAngelis
  • Andrew B. Lassman
Clinical Study

Abstract

We previously reported results of a phase II non-comparative trial that randomized patients with glioblastoma following radiotherapy to one of two different temozolomide schedules, followed by 13-cis-retinoic acid (RA) maintenance. Here we report the results of an exploratory cohort of patients accrued with anaplastic astrocytic tumors. Patients with newly diagnosed anaplastic astrocytoma (AA) or anaplastic oligo-astrocytoma (AOA) were treated with concurrent radiotherapy (60 Gy over 6 weeks) and temozolomide (75 mg/m2), and six adjuvant 28-day cycles of either dose-dense (150 mg/m2, days 1–7, 15–21) or metronomic (50 mg/m2, days 1–28) temozolomide. Subsequently, maintenance RA (100 mg/m2, days 1–21/28) was administered until disease progression. All outcome measures were descriptive without intention to compare between treatment arms. Survival was measured by the Kaplan–Meier method. There were 31 patients (21 men, 10 women) with median age 48 years (range 28–74), median KPS 90 (range 60–100). Extent of resection was gross-total in 35 %, subtotal 23 %, and biopsy 42 %. Histology was AA in 90 %, and AOA in 10 %. MGMT promoter methylation was methylated in 20 %, unmethylated in 50 %, and uninformative in 30 % of 30 tested. Median progression-free survival was 2.1 years (95 % CI 0.95–Not Reached), and overall survival 2.9 years (95 % CI 2.0–Not Reached). We report outcomes among a homogeneously treated population with anaplastic astrocytic tumors. Survival was unexpectedly short compared to other reports. These data may be useful as a contemporary historic control for other ongoing or future randomized trials.

Keywords

Anaplastic astrocytoma Temozolomide Radiotherapy Chemotherapy Clinical trial 

Notes

Acknowledgments

Financial support was received from Merck (formerly Schering Plough) for MGMT analyses and for partial study costs. K.S.P. and A.S.R. were supported in part by P30 CA008748.

Conflict of interest

ABL previously received honoraria from Merck/Schering-Plough for speaking and consulting. LEA is currently a full time employee of F-Hoffman-La Roche Ltd. LN, KSP, ASR, JTH, EP, SGB, and LMD have no relevant disclosures.

Supplementary material

11060_2015_1771_MOESM1_ESM.tif (433 kb)
Supplementary material 1 (TIFF 433 kb)

References

  1. 1.
    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 352:987–996CrossRefPubMedGoogle Scholar
  2. 2.
    Newlands ES, Blackledge GR, Slack JA, Rustin GJ, Smith DB, Stuart NS, Quarterman CP, Hoffman R, Stevens MF, Brampton MH et al (1992) Phase I trial of temozolomide (CCRG 81045: M&B 39831: NSC 362856). Br J Cancer 65:287–291CrossRefPubMedCentralPubMedGoogle Scholar
  3. 3.
    Tolcher AW, Gerson SL, Denis L, Geyer C, Hammond LA, Patnaik A, Goetz AD, Schwartz G, Edwards T, Reyderman L, Statkevich P, Cutler DL, Rowinsky EK (2003) Marked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules. Br J Cancer 88:1004–1011CrossRefPubMedCentralPubMedGoogle Scholar
  4. 4.
    Brada M, Stenning S, Gabe R, Thompson LC, Levy D, Rampling R, Erridge S, Saran F, Gattamaneni R, Hopkins K, Beall S, Collins VP, Lee SM (2010) Temozolomide versus procarbazine, lomustine, and vincristine in recurrent high-grade glioma. J Clin Oncol 28:4601–4608CrossRefPubMedGoogle Scholar
  5. 5.
    Gilbert MR, Wang M, Aldape KD, Stupp R, Hegi ME, Jaeckle KA, Armstrong TS, Wefel JS, Won M, Blumenthal DT, Mahajan A, Schultz CJ, Erridge S, Baumert B, Hopkins KI, Tzuk-Shina T, Brown PD, Chakravarti A, Curran WJ Jr, Mehta MP (2013) Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol 31:4085–4091CrossRefPubMedCentralPubMedGoogle Scholar
  6. 6.
    Bouterfa H, Picht T, Kess D, Herbold C, Noll E, Black PM, Roosen K, Tonn JC (2000) Retinoids inhibit human glioma cell proliferation and migration in primary cell cultures but not in established cell lines. Neurosurgery 46:419–430CrossRefPubMedGoogle Scholar
  7. 7.
    Rodts GE Jr, Black KL (1994) Trans retinoic acid inhibits in vivo tumour growth of C6 glioma in rats: effect negatively influenced by nerve growth factor. Neurol Res 16:184–186PubMedGoogle Scholar
  8. 8.
    Costa SL, Paillaud E, Fages C, Rochette-Egly C, Plassat JL, Jouault H, Perzelova A, Tardy M (2001) Effects of a novel synthetic retinoid on malignant glioma in vitro: inhibition of cell proliferation, induction of apoptosis and differentiation. Eur J Cancer 37:520–530CrossRefPubMedGoogle Scholar
  9. 9.
    Wismeth C, Hau P, Fabel K, Baumgart U, Hirschmann B, Koch H, Jauch T, Grauer O, Drechsel L, Brawanski A, Bogdahn U, Steinbrecher A (2004) Maintenance therapy with 13-cis retinoid acid in high-grade glioma at complete response after first-line multimodal therapy—a phase-II study. J Neurooncol 68:79–86CrossRefPubMedGoogle Scholar
  10. 10.
    Clarke JL, Iwamoto FM, Sul J, Panageas K, Lassman AB, DeAngelis LM, Hormigo A, Nolan CP, Gavrilovic I, Karimi S, Abrey LE (2009) Randomized phase II trial of chemoradiotherapy followed by either dose-dense or metronomic temozolomide for newly diagnosed glioblastoma. J Clin Oncol 27:3861–3867CrossRefPubMedCentralPubMedGoogle Scholar
  11. 11.
    Macdonald DR, Cascino TL, Schold SC Jr, Cairncross JG (1990) Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 8:1277–1280PubMedGoogle Scholar
  12. 12.
    Grauer O, Pascher C, Hartmann C, Zeman F, Weller M, Proescholdt M, Brawanski A, Pietsch T, Wick W, Bogdahn U, Hau P (2011) Temozolomide and 13-cis retinoic acid in patients with anaplastic gliomas: a prospective single-arm monocentric phase-II study (RNOP-05). J Neurooncol 104:801–809CrossRefPubMedGoogle Scholar
  13. 13.
    Prados MD, Seiferheld W, Sandler HM, Buckner JC, Phillips T, Schultz C, Urtasun R, Davis R, Gutin P, Cascino TL, Greenberg HS, Curran WJ Jr (2004) Phase III randomized study of radiotherapy plus procarbazine, lomustine, and vincristine with or without BUdR for treatment of anaplastic astrocytoma: final report of RTOG 9404. Int J Radiat Oncol Biol Phys 58:1147–1152CrossRefPubMedGoogle Scholar
  14. 14.
    Wick W, Hartmann C, Engel C, Stoffels M, Felsberg J, Stockhammer F, Sabel MC, Koeppen S, Ketter R, Meyermann R, Rapp M, Meisner C, Kortmann RD, Pietsch T, Wiestler OD, Ernemann U, Bamberg M, Reifenberger G, von Deimling A, Weller M (2009) NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol 27:5874–5880CrossRefPubMedGoogle Scholar
  15. 15.
    Brandes AA, Nicolardi L, Tosoni A, Gardiman M, Iuzzolino P, Ghimenton C, Reni M, Rotilio A, Sotti G, Ermani M (2006) Survival following adjuvant PCV or temozolomide for anaplastic astrocytoma. Neuro Oncol 8:253–260CrossRefPubMedCentralPubMedGoogle Scholar
  16. 16.
    Hildebrand J, Gorlia T, Kros JM, Afra D, Frenay M, Omuro A, Stupp R, Lacombe D, Allgeier A, van den Bent MJ (2008) Adjuvant dibromodulcitol and BCNU chemotherapy in anaplastic astrocytoma: results of a randomised European Organisation for Research and Treatment of Cancer phase III study (EORTC study 26882). Eur J Cancer 44:1210–1216CrossRefPubMedGoogle Scholar
  17. 17.
    Combs SE, Nagy M, Edler L, Rausch R, Bischof M, Welzel T, Debus J, Schulz-Ertner D (2008) Comparative evaluation of radiochemotherapy with temozolomide versus standard-of-care postoperative radiation alone in patients with WHO grade III astrocytic tumors. Radiother Oncol 88:177–182CrossRefPubMedGoogle Scholar
  18. 18.
    Kim YH, Park CK, Cho WH, Kim IA, Moon S, Choe G, Park SH, Kim IH, Kim DG, Jung HW, Lee MM, Bae SH, Cha SH, Kim CY (2011) Temozolomide during and after radiation therapy for WHO grade III gliomas: preliminary report of a prospective multicenter study. J Neurooncol 103:503–512CrossRefPubMedGoogle Scholar
  19. 19.
    Minniti G, Scaringi C, Arcella A, Lanzetta G, Di Stefano D, Scarpino S, Bozzao A, Pace A, Villani V, Salvati M, Esposito V, Giangaspero F, Enrici RM (2014) IDH1 mutation and MGMT methylation status predict survival in patients with anaplastic astrocytoma treated with temozolomide-based chemoradiotherapy. J Neurooncol 118:377–383CrossRefPubMedGoogle Scholar
  20. 20.
    DeAngelis LM (2009) Anaplastic glioma: how to prognosticate outcome and choose a treatment strategy. [corrected]. J Clin Oncol 27:5861–5862CrossRefPubMedGoogle Scholar
  21. 21.
    Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP, Alexe G, Lawrence M, O’Kelly M, Tamayo P, Weir BA, Gabriel S, Winckler W, Gupta S, Jakkula L, Feiler HS, Hodgson JG, James CD, Sarkaria JN, Brennan C, Kahn A, Spellman PT, Wilson RK, Speed TP, Gray JW, Meyerson M, Getz G, Perou CM, Hayes DN, Cancer Genome Atlas Research N (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer cell 17:98–110CrossRefPubMedCentralPubMedGoogle Scholar
  22. 22.
    Hartmann C, Hentschel B, Wick W, Capper D, Felsberg J, Simon M, Westphal M, Schackert G, Meyermann R, Pietsch T, Reifenberger G, Weller M, Loeffler M, von Deimling A (2010) Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: implications for classification of gliomas. Acta Neuropathol 120:707–718CrossRefPubMedGoogle Scholar
  23. 23.
    Noushmehr H, Weisenberger DJ, Diefes K, Phillips HS, Pujara K, Berman BP, Pan F, Pelloski CE, Sulman EP, Bhat KP, Verhaak RG, Hoadley KA, Hayes DN, Perou CM, Schmidt HK, Ding L, Wilson RK, Van Den Berg D, Shen H, Bengtsson H, Neuvial P, Cope LM, Buckley J, Herman JG, Baylin SB, Laird PW, Aldape K (2010) Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17:510–522CrossRefPubMedCentralPubMedGoogle Scholar
  24. 24.
    van den Bent MJ, Gravendeel LA, Gorlia T, Kros JM, Lapre L, Wesseling P, Teepen JL, Idbaih A, Sanson M, Smitt PA, French PJ (2011) A hypermethylated phenotype is a better predictor of survival than MGMT methylation in anaplastic oligodendroglial brain tumors: a report from EORTC study 26951. Clin Cancer Res 17:7148–7155CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Lakshmi Nayak
    • 1
    • 4
  • Katherine S. Panageas
    • 2
  • Anne S. Reiner
    • 2
  • Jason T. Huse
    • 3
  • Elena Pentsova
    • 1
  • Stephanie G. Braunthal
    • 1
  • Lauren E. Abrey
    • 1
    • 5
  • Lisa M. DeAngelis
    • 1
  • Andrew B. Lassman
    • 1
    • 6
  1. 1.Department of NeurologyMemorial Sloan Kettering Cancer CenterNew YorkUSA
  2. 2.Department of Epidemiology & BiostatisticsMemorial Sloan Kettering Cancer CenterNew YorkUSA
  3. 3.Department of PathologyMemorial Sloan Kettering Cancer CenterNew YorkUSA
  4. 4.Center for Neuro-OncologyDana-Farber/Brigham and Women’s Cancer CenterBostonUSA
  5. 5.Department of NeurologyUniversity of ZurichZurichSwitzerland
  6. 6.Department of Neurology and Herbert Irving Comprehensive Cancer CenterColumbia University Medical CenterNew YorkUSA

Personalised recommendations