Journal of Neuro-Oncology

, Volume 124, Issue 3, pp 413–420 | Cite as

Phase II trial of pre-irradiation and concurrent temozolomide in patients with newly diagnosed anaplastic oligodendrogliomas and mixed anaplastic oligoastrocytomas: long term results of RTOG BR0131

  • Michael A. Vogelbaum
  • Chen Hu
  • David M. Peereboom
  • David R. Macdonald
  • Caterina Giannini
  • John H. Suh
  • Robert B. Jenkins
  • Nadia N. Laack
  • David G. Brachman
  • Dennis C. Shrieve
  • Luis Souhami
  • Minesh P. Mehta
Clinical Study


We report on the long-term results of a phase II study of pre-irradiation temozolomide followed by concurrent temozolomide and radiotherapy (RT) in patients with newly diagnosed anaplastic oligodendroglioma (AO) and mixed anaplastic oligoastrocytoma. Pre-RT temozolomide was given for up to 6 cycles. RT with concurrent temozolomide was administered to patients with less than a complete radiographic response. Forty eligible patients were entered and 32 completed protocol treatment. With a median follow-up time of 8.7 years (range 1.1–10.1), median progression-free survival (PFS) is 5.8 years (95 % CI 2.0, NR) and median overall survival (OS) has not been reached (5.9, NR). 1p/19q data are available in 37 cases; 23 tumors had codeletion while 14 tumors had no loss or loss of only 1p or 19q (non-codeleted). In codeleted patients, 9 patients have progressed and 4 have died; neither median PFS nor OS have been reached and two patients who received only pre-RT temozolomide and no RT have remained progression-free for over 7 years. 3-year PFS and 6-year OS are 78 % (95 % CI 61–95 %) and 83 % (95 % CI 67–98 %), respectively. Codeleted patients show a trend towards improved 6-year survival when compared to the codeleted procarbazine/CCNU/vincristrine (PCV) and RT cohort in RTOG 9402 (67 %, 95 % CI 55–79 %). For non-codeleted patients, median PFS and OS are 1.3 and 5.8 years, respectively. These updated results suggest that the regimen of dose intense, pre-RT temozolomide followed by concurrent RT/temozolomide has significant activity, particularly in patients with 1p/19q codeleted AOs and MAOs.


Oligodendroglioma Temozolomide 1p/19q loss of heterozygosity MGMT RTOG 



This project was supported by Grants U10CA21661, U10CA180868, U10CA180822, U10 CA37422, U24CA180803 from the National Cancer Institute (NCI). Portions of this work have been presented in abstract form (Society for NeuroOncology, 2012).

Conflict of interest

The following authors have disclosed financial relationships with commercial entities that may be impacted by this work. DMP—Merck (research support, honoraria). DRM—Merck Canada (honoraria, travel support), Roche Canada (honoraria, travel support). JHS—Varian Medical System (consultant). The following authors declare no conflicts of interests with respect this work: MAV, CH, CG, RBJ, NNL, DCS, LS, DB, MPM


  1. 1.
    Mork SJ, Lindegaard KF, Halvorsen TB, Lehmann EH, Solgaard T, Hatlevoll R, Harvei S, Ganz J (1985) Oligodendroglioma: incidence and biological behavior in a defined population. J Neurosurg 63(6):881–889CrossRefPubMedGoogle Scholar
  2. 2.
    Cairncross G, Wang M, Shaw E, Jenkins R, Brachman D, Buckner J, Fink K, Souhami L, Laperriere N, Curran W, Mehta M (2013) Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J Clin Oncol 31(3):337–343CrossRefPubMedGoogle Scholar
  3. 3.
    Cairncross JG, Wang M, Jenkins RB, Shaw EG, Giannini C, Brachman DG, Buckner JC, Fink KL, Souhami L, Laperriere NJ, Huse JT, Mehta MP, Curran WJ Jr (2014) Benefit from procarbazine, lomustine, and vincristine in oligodendroglial tumors is associated with mutation of IDH. J Clin Oncol 32(8):783–790Google Scholar
  4. 4.
    van den Bent MJ, Brandes AA, Taphoorn MJ, Kros JM, Kouwenhoven MC, Delattre JY, Bernsen HJ, Frenay M, Tijssen CC, Grisold W, Sipos L, Enting RH, French PJ, Dinjens WN, Vecht CJ, Allgeier A, Lacombe D, Gorlia T, Hoang-Xuan K (2013) Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. J Clin Oncol 31(3):344–350Google Scholar
  5. 5.
    Cairncross JG, Ueki K, Zlatescu MC, Lisle DK, Finkelstein DM, Hammond RR, Silver JS, Stark PC, Macdonald DR, Ino Y, Ramsay DA, Louis DN (1998) Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 90(19):1473–1479CrossRefPubMedGoogle Scholar
  6. 6.
    Ino Y, Betensky RA, Zlatescu MC, Sasaki H, Macdonald DR, Stemmer-Rachamimov AO, Ramsay DA, Cairncross JG, Louis DN (2001) Molecular subtypes of anaplastic oligodendroglioma: implications for patient management at diagnosis. Clin Cancer Res 7(4):839–845PubMedGoogle Scholar
  7. 7.
    Jenkins RB, Blair H, Ballman KV, Giannini C, Arusell RM, Law M, Flynn H, Passe S, Felten S, Brown PD, Shaw EG, Buckner JC (2006) A t(1;19)(q10;p10) mediates the combined deletions of 1p and 19q and predicts a better prognosis of patients with oligodendroglioma. Cancer Res 66(20):9852–9861CrossRefPubMedGoogle Scholar
  8. 8.
    Bauman GS, Ino Y, Ueki K, Zlatescu MC, Fisher BJ, Macdonald DR, Stitt L, Louis DN, Cairncross JG (2000) Allelic loss of chromosome 1p and radiotherapy plus chemotherapy in patients with oligodendrogliomas. Int J Radiat Oncol Biol Phys 48:825–830CrossRefPubMedGoogle Scholar
  9. 9.
    Smith JS, Perry A, Borell TJ, Lee HK, O’Fallon J, Hosek SM, Kimmel D, Yates A, Burger PC, Scheithauer BW, Jenkins RB (2000) Alterations of chromosome arms 1p and 19q as predictors of survival in oligodendrogliomas, astrocytomas, and mixed oligoastrocytomas. J Clin Oncol 18:636–645CrossRefPubMedGoogle Scholar
  10. 10.
    Chahlavi A, Kanner A, Peereboom D, Staugaitis SM, Elson P, Barnett G (2003) Impact of chromosome 1p status in response of oligodendroglioma to temozolomide: Preliminary results. J Neurooncol 61:267–273CrossRefPubMedGoogle Scholar
  11. 11.
    Thiessen B, Maguire JA, McNeil K, Huntsman D, Martin MA, Horsman D (2003) Loss of heterozygosity for loci on chromosome arms 1p and 10q in oligodendroglial tumors: Relationship to outcome and chemosensitivity. J Neurooncol 64:271–278CrossRefPubMedGoogle Scholar
  12. 12.
    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(22):7148–7155CrossRefPubMedGoogle Scholar
  13. 13.
    Cairncross G, Berkey B, Shaw E, Jenkins R, Scheithauer B, Brachman D, Buckner J, Fink K, Souhami L, Laperierre N, Mehta M, Curran W (2006) Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402. J Clin Oncol 24(18):2707–2714CrossRefPubMedGoogle Scholar
  14. 14.
    van den Bent MJ, Carpentier AF, Brandes AA, Sanson M, Taphoorn MJ, Bernsen HJ, Frenay M, Tijssen CC, Grisold W, Sipos L, Haaxma-Reiche H, Kros JM, van Kouwenhoven MC, Vecht CJ, Allgeier A, Lacombe D, Gorlia T (2006) Adjuvant Procarbazine, Lomustine and Vincristine Improves Progression-Free Survival but Not Overall Survival in Newly Diagnosed Anaplastic Oligodendrogliomas and Oligoastrocytomas: A Randomized European Organization for Research and Treatment of Cancer Phase III Trial. J Clin Oncol 24:2715CrossRefPubMedGoogle Scholar
  15. 15.
    Vogelbaum MA, Berkey B, Peereboom D, Macdonald D, Giannini C, Suh JH, Jenkins R, Herman J, Brown P, Blumenthal DT, Biggs C, Schultz C, Mehta M (2009) Phase II trial of preirradiation and concurrent temozolomide in patients with newly diagnosed anaplastic oligodendrogliomas and mixed anaplastic oligoastrocytomas: RTOG BR0131. Neuro Oncol 11(2):167–175CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Macdonald DR, Cascino TL, Schold SC, Cairncross JG (1990) Response criteria for phase II studies of malignant glioma. J Clin Oncol 8:1277–1280CrossRefPubMedGoogle Scholar
  17. 17.
    Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, Degroot J, Wick W, Gilbert MR, Lassman AB, Tsien C, Mikkelsen T, Wong ET, Chamberlain MC, Stupp R, Lamborn KR, Vogelbaum MA, van den Bent MJ, Chang SM (2010) Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 28(11):1963–1972CrossRefPubMedGoogle Scholar
  18. 18.
    Smith JS, Alderete B, Minn Y, Borell TJ, Perry A, Mohapatra G, Hosek SM, Kimmel D, O’Fallon J, Yates A, Feuerstein BG, Burger PC, Scheithauer BW, Jenkins RB (1999) Localization of common deletion regions on 1p and 19q in human gliomas and their association with histological subtype. Oncogene 18:4144–4152CrossRefPubMedGoogle Scholar
  19. 19.
    Esteller M, Risques RA, Toyota M, Capella G, Moreno V, Peinado MA, Baylin SB, Herman JG (2001) Promoter hypermethylation of the DNA repair gene O(6)-methylguanine-DNA methyltransferase is associated with the presence of G: C to A: T transition mutations in p53 in human colorectal tumorigenesis. Cancer Res 61(12):4689–4692PubMedGoogle Scholar
  20. 20.
    Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481CrossRefGoogle Scholar
  21. 21.
    Mantel N (1966) Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Reports 50:163–170Google Scholar
  22. 22.
    Roth P, Wick W, Weller M (2013) Anaplastic oligodendroglioma: a new treatment paradigm and current controversies. Curr Treat Options Oncol 14(4):505–513CrossRefPubMedGoogle Scholar
  23. 23.
    Cairncross G, Berkey B, Shaw E, Jenkins R, Scheithauer B, Brachman D, Buckner J, Fink K, Souhami L, Laperierre N, Mehta M, Curran W (2006) Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402. J Clin Oncol 24(18):2707–2714Google Scholar
  24. 24.
    Villano JL, Wen PY, Lee EQ, Nayak L, Reardon DA, Rosenfeld MR (2013) PCV for anaplastic oligodendrogliomas: back to the future or a step backwards? A point/counterpoint discussion. J Neurooncol 113(1):143–147CrossRefPubMedGoogle Scholar
  25. 25.
    Chinot OL, Honore S, Dufour H, Barrie M, Figarella-Branger D, Muracciole X, Braguer D, Martin PM, Grisoli F (2001) Safety and efficacy of temozolomide in patients with recurrent anaplastic oliodendrogliomas after standard radiotherapy and chemotherapy. J Clin Oncol 19:2449–2455CrossRefPubMedGoogle Scholar
  26. 26.
    van den Bent MJ, Keime-Guibert F, Brandes AA, Taphoorn MJ, Kros JM, Eskens FA, Carpentier AF (2001) Temozolomide chemotherapy in recurrent oligodendroglioma. Neurology 57(2):340–342CrossRefPubMedGoogle Scholar
  27. 27.
    van den Bent MJ, Taphoorn MJB, Brandes AA, Menten J, Stupp R, Frenay M, Chinot O, Kros JM, van der Rijt CC, Vecht ChJ, Allgeier A, Gorlia T; European Organization for Research and Treatment of Cancer Brain Tumor Group (2003) Phase II study of first line chemotherapy with temozolomide in recurrent oligodendroglial tumors: The European Organization for the Research and Treatment of Cancer Brain Tumor Group Study 26971. J Clin Oncol 21:2525–2528CrossRefGoogle Scholar
  28. 28.
    Anderson MD, Gilbert MR (2013) Treatment recommendations for anaplastic oligodendrogliomas that are codeleted. Oncology (Williston Park) 27(4):315–320Google Scholar
  29. 29.
    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(30):4601–4608CrossRefPubMedGoogle Scholar
  30. 30.
    Brandes AA, Franceschi E, Tosoni A, Blatt V, Pession A, Tallini G, Bertorelle R, Bartolini S, Calbucci F, Andreoli A, Frezza G, Leonardi M, Spagnolli F, Ermani M (2008) MGMT promoter methylation status can predict the incidence and outcome of pseudoprogression after concomitant radiochemotherapy in newly diagnosed glioblastoma patients. J Clin Oncol 26(13):2192–2197CrossRefPubMedGoogle Scholar
  31. 31.
    Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360(8):765–773CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Yip S, Butterfield YS, Morozova O, Chittaranjan S, Blough MD, An J, Birol I, Chesnelong C, Chiu R, Chuah E, Corbett R, Docking R, Firme M, Hirst M, Jackman S, Karsan A, Li H, Louis DN, Maslova A, Moore R, Moradian A, Mungall KL, Perizzolo M, Qian J, Roldan G, Smith EE, Tamura-Wells J, Thiessen N, Varhol R, Weiss S, Wu W, Young S, Zhao Y, Mungall AJ, Jones SJ, Morin GB, Chan JA, Cairncross JG, Marra MA (2012) Concurrent CIC mutations, IDH mutations, and 1p/19q loss distinguish oligodendrogliomas from other cancers. J Pathol 226(1):7–16CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Michael A. Vogelbaum
    • 1
  • Chen Hu
    • 2
  • David M. Peereboom
    • 1
  • David R. Macdonald
    • 3
  • Caterina Giannini
    • 4
  • John H. Suh
    • 1
  • Robert B. Jenkins
    • 4
  • Nadia N. Laack
    • 4
  • David G. Brachman
    • 5
  • Dennis C. Shrieve
    • 6
  • Luis Souhami
    • 7
  • Minesh P. Mehta
    • 8
  1. 1.Cleveland Clinic FoundationClevelandUSA
  2. 2.RTOG Statistical CenterPhiladelphiaUSA
  3. 3.University of Western Ontario London Regional Cancer CentreLondonCanada
  4. 4.Mayo ClinicRochesterUSA
  5. 5.Arizona Oncology Services FoundationPhoenixUSA
  6. 6.University of Utah Health Science CenterSalt Lake CityUSA
  7. 7.McGill UniversityMontrealCanada
  8. 8.University of MarylandBaltimoreUSA

Personalised recommendations