Tumor Biology

, Volume 36, Issue 1, pp 153–162 | Cite as

Incorporation of biomarkers in phase II studies of recurrent glioblastoma

  • Toni Rose Jue
  • Elizabeth Hovey
  • Sara Davis
  • Oliver Carleton
  • Kerrie L. McDonald


The survival trends for glioblastoma (GBM) patients have remained largely static, reflecting a lack of improvement in the therapeutic options for patients. Less than 5 % of newly diagnosed GBM survives more than 5 years. Tumor relapse is nearly universal and the majority of patients do not respond to further systemic therapy. The results from phase II studies conducted with recurrent GBM patients have not translated to successful confirmatory studies and thus we have reached a significant roadblock in the development of new treatments for patients with recurrent GBM. The development of new, active, and potentially targeted drugs for the treatment of recurrent GBM represents a major unmet need. The incorporation of diagnostic/companion biomarker combinations into the phase II studies and appropriate stratification of the patients is lagging significantly behind other larger cancer groups such as breast, non-small cell lung cancer, and melanoma. We herein carried out a systematic review of the phase II clinical studies conducted in patients with recurrent GBM (2010–2013 inclusive) to assess the degree of biomarker incorporation within the clinical trial design.


Recurrent glioblastoma Biomarkers Phase II trials 


Conflicts of interest



  1. 1.
    Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987–96. doi: 10.1056/NEJMoa043330.CrossRefPubMedGoogle Scholar
  2. 2.
    Pham TM, Fujino Y, Matsuda S, Yoshimura T. Premature mortality due to cancer in Japan, 1995 and 2005. Int J Cancer J Int Cancer. 2010;127(1):190–4. doi: 10.1002/ijc.25021.CrossRefGoogle Scholar
  3. 3.
    Burnet NG, Jefferies SJ, Benson RJ, Hunt DP, Treasure FP. Years of life lost (YLL) from cancer is an important measure of population burden and should be considered when allocating research funds. Br J Cancer. 2005;92(2):241–5. doi: 10.1038/sj.bjc.6602321.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Chakrabarti I, Cockburn M, Cozen W, Wang YP, Preston-Martin S. A population-based description of glioblastoma multiforme in Los Angeles County, 1974–1999. Cancer. 2005;104(12):2798–806. doi: 10.1002/cncr.21539.CrossRefPubMedGoogle Scholar
  5. 5.
    Iwamoto FM, Reiner AS, Panageas KS, Elkin EB, Abrey LE. Patterns of care in elderly glioblastoma patients. Ann Neurol. 2008;64(6):628–34.CrossRefPubMedGoogle Scholar
  6. 6.
    Laperriere N, Weller M, Stupp R, Perry JR, Brandes AA, Wick W, et al. Optimal management of elderly patients with glioblastoma. Cancer Treat Rev. 2013;39(4):350–7. doi: 10.1016/j.ctrv.2012.05.008.CrossRefPubMedGoogle Scholar
  7. 7.
    Paszat L, Laperriere N, Groome P, Schulze K, Mackillop W, Holowaty E. A population-based study of glioblastoma multiforme. Int J Radiat Oncol Biol Phys. 2001;51(1):100–7.CrossRefPubMedGoogle Scholar
  8. 8.
    Wrensch M, Minn Y, Chew T, Bondy M, Berger MS. Epidemiology of primary brain tumors: Current concepts and review of the literature. Neuro-Oncology. 2002;4(4):278–99.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Friedman HS, Kerby T, Calvert H. Temozolomide and treatment of malignant glioma. Clin Cancer Res Off J Am Assoc Cancer Res. 2000;6(7):2585–97.Google Scholar
  10. 10.
    Roos WP, Kaina B. DNA damage-induced apoptosis: from specific DNA lesions to the DNA damage response and apoptosis. Cancer Lett. 2012. doi: 10.1016/j.canlet.2012.01.007.PubMedGoogle Scholar
  11. 11.
    Esteller M, Hamilton SR, Burger PC, Baylin SB, Herman JG. Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res. 1999;59(4):793–7.PubMedGoogle Scholar
  12. 12.
    Felsberg J, Thon N, Eigenbrod S, Hentschel B, Sabel MC, Westphal M, et al. Promoter methylation and expression of MGMT and the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2 in paired primary and recurrent glioblastomas. Int J Cancer J Int Cancer. 2011;129(3):659–70. doi: 10.1002/ijc.26083.CrossRefGoogle Scholar
  13. 13.
    Esteller M. Epigenetic lesions causing genetic lesions in human cancer: Promoter hypermethylation of DNA repair genes. Eur J Cancer. 2000;36(18):2294–300.CrossRefPubMedGoogle Scholar
  14. 14.
    Esteller M. CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future. Oncogene. 2002;21(35):5427–40. doi: 10.1038/sj.onc.1205600.CrossRefPubMedGoogle Scholar
  15. 15.
    Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352(10):997–1003. doi: 10.1056/NEJMoa043331.CrossRefPubMedGoogle Scholar
  16. 16.
    Reifenberger G, Hentschel B, Felsberg J, Schackert G, Simon M, Schnell O, et al. Predictive impact of MGMT promoter methylation in glioblastoma of the elderly. Int J Cancer J Int Cancer. 2011. doi: 10.1002/ijc.27385.Google Scholar
  17. 17.
    Stummer W, Nestler U, Stockhammer F, Krex D, Kern BC, Mehdorn HM, et al. Favorable outcome in the elderly cohort treated by concomitant temozolomide radiochemotherapy in a multicentric phase II safety study of 5-ALA. J Neuro-Oncol. 2010. doi: 10.1007/s11060-010-0400-9.Google Scholar
  18. 18.
    Baur M, Preusser M, Piribauer M, Elandt K, Hassler M, Hudec M, et al. Frequent MGMT (0(6)-methylguanine-DNA methyltransferase) hypermethylation in long-term survivors of glioblastoma: a single institution experience. Radiol Oncol. 2010;44(2):113–20. doi: 10.2478/v10019-010-0023-y.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Brandes AA, Franceschi E, Tosoni A, Bartolini S, Bacci A, Agati R, et al. O(6)-methylguanine DNA-methyltransferase methylation status can change between first surgery for newly diagnosed glioblastoma and second surgery for recurrence: Clinical implications. Neuro-Oncology. 2010;12(3):283–8. doi: 10.1093/neuonc/nop050.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Rivera AL, Pelloski CE, Gilbert MR, Colman H, De La Cruz C, Sulman EP, et al. MGMT promoter methylation is predictive of response to radiotherapy and prognostic in the absence of adjuvant alkylating chemotherapy for glioblastoma. Neuro-Oncology. 2010;12(2):116–21. doi: 10.1093/neuonc/nop020.CrossRefPubMedGoogle Scholar
  21. 21.
    Kim YS, Kim SH, Cho J, Kim JW, Chang JH, Kim DS, et al. MGMT gene promoter methylation as a potent prognostic factor in glioblastoma treated with temozolomide-based chemoradiotherapy: a single-institution study. Int J Radiat Oncol Biol Phys. 2012;84(3):661–7. doi: 10.1016/j.ijrobp.2011.12.086.CrossRefPubMedGoogle Scholar
  22. 22.
    Silber JR, Bobola MS, Blank A, Chamberlain MC. O(6)-methylguanine-DNA methyltransferase in glioma therapy: Promise and problems. Biochim Biophys Acta. 2012;1826(1):71–82. doi: 10.1016/j.bbcan.2011.12.004.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Gilbert MR, Wang M, Aldape KD, Stupp R, Hegi ME, Jaeckle KA, et al. Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol. 2013;31(32):4085–91. doi: 10.1200/JCO.2013.49.6968.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Norden AD, Lesser GJ, Drappatz J, Ligon KL, Hammond SN, Lee EQ, et al. Phase 2 study of dose-intense temozolomide in recurrent glioblastoma. Neuro Oncol. 2013;15(7):930–5. doi: 10.1093/neuonc/not040.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Krex D, Klink B, Hartmann C, von Deimling A, Pietsch T, Simon M, et al. Long-term survival with glioblastoma multiforme. Brain J Neurol. 2007;130(Pt 10):2596–606. doi: 10.1093/brain/awm204.CrossRefGoogle Scholar
  26. 26.
    Collins VP, Ichimura K, Di Y, Pearson D, Chan R, Thompson LC, et al. Prognostic and predictive markers in recurrent high grade glioma; results from the BR12 randomised trial. Acta Neuropathol Commun. 2014;2:68. doi: 10.1186/2051-5960-2-68.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Stancheva G, Goranova T, Laleva M, Kamenova M, Mitkova A, Velinov N, et al. IDH1/IDH2 but not TP53 mutations predict prognosis in Bulgarian glioblastoma patients. BioMed Res Int. 2014;2014:654727. doi: 10.1155/2014/654727.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Polivka J, Polivka Jr J, Rohan V, Pesta M, Repik T, Pitule P, et al. Isocitrate dehydrogenase-1 mutations as prognostic biomarker in glioblastoma multiforme patients in West Bohemia. BioMed Res Int. 2014;2014:735659. doi: 10.1155/2014/735659.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Erdem-Eraslan L, Gravendeel LA, de Rooi J, Eilers PH, Idbaih A, Spliet WG, et al. Intrinsic molecular subtypes of glioma are prognostic and predict benefit from adjuvant procarbazine, lomustine, and vincristine chemotherapy in combination with other prognostic factors in anaplastic oligodendroglial brain tumors: a report from EORTC study 26951. J Clin Oncol Off J Am Soc Clin Oncol. 2013;31(3):328–36. doi: 10.1200/jco.2012.44.1444.CrossRefGoogle Scholar
  30. 30.
    Singh VY, Chacko G, Chacko AG, Rajshekhar V. Fluorescence in situ hybridization for 1p, 19q status in a cohort of glial neoplasms. Neurol India. 2014;62(1):32–6. doi: 10.4103/0028-3886.128275.CrossRefPubMedGoogle Scholar
  31. 31.
    Minniti G, Arcella A, Scaringi C, Lanzetta G, Di Stefano D, Scarpino S, et al. Chemoradiation for anaplastic oligodendrogliomas: Clinical outcomes and prognostic value of molecular markers. J Neurooncol. 2014;116(2):275–82. doi: 10.1007/s11060-013-1288-y.CrossRefPubMedGoogle Scholar
  32. 32.
    van den Bent MJ, Carpentier AF, Brandes AA, Sanson M, Taphoorn MJ, Bernsen HJ, et al. Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III trial. J Clin Oncol Off J Am Soc Clin Oncol. 2006;24(18):2715–22. doi: 10.1200/jco.2005.04.6078.CrossRefGoogle Scholar
  33. 33.
    Kreth FW, Thon N, Simon M, Westphal M, Schackert G, Nikkhah G, et al. Gross total but not incomplete resection of glioblastoma prolongs survival in the era of radiochemotherapy. Ann Oncol Off J Eur Soc Med Oncol ESMO. 2013;24(12):3117–23. doi: 10.1093/annonc/mdt388.CrossRefGoogle Scholar
  34. 34.
    McGirt MJ, Chaichana KL, Attenello FJ, Weingart JD, Than K, Burger PC, et al. Extent of surgical resection is independently associated with survival in patients with hemispheric infiltrating low-grade gliomas. Neurosurgery. 2008;63(4):700–7. doi: 10.1227/01.NEU.0000325729.41085.73. author reply 7–8.CrossRefPubMedGoogle Scholar
  35. 35.
    Bambury RM, Morris PG. The search for novel therapeutic strategies in the treatment of recurrent glioblastoma multiforme. Exp Rev Anticancer Ther. 2014:1–10. doi: 10.1586/14737140.2014.916214.
  36. 36.
    Franceschi E, Tosoni A, Bartolini S, Mazzocchi V, Fioravanti A, Brandes AA. Treatment options for recurrent glioblastoma: Pitfalls and future trends. Expert Rev Anticancer Ther. 2009;9(5):613–9. doi: 10.1586/era.09.23.CrossRefPubMedGoogle Scholar
  37. 37.
    Zhang GB, Huang SY, Wang ZC. A meta-analysis of bevacizumab alone and in combination with irinotecan in the treatment of patients with recurrent glioblastoma multiforme. J Clin Neurosci. 2012;19(12):1636–40. doi: 10.1016/J.Jocn.2011.12.028.CrossRefPubMedGoogle Scholar
  38. 38.
    Prados M, Cloughesy T, Samant M, Fang LA, Wen PY, Mikkelsen T, et al. Response as a predictor of survival in patients with recurrent glioblastoma treated with bevacizumab. Neuro-Oncology. 2011;13(1):143–51. doi: 10.1093/Neuonc/Noq151.CrossRefPubMedGoogle Scholar
  39. 39.
    Ellingson BM, Kim HJ, Woodworth DC, Pope WB, Cloughesy JN, Harris RJ, et al. Recurrent glioblastoma treated with bevacizumab: contrast-enhanced T1-weighted subtraction maps improve tumor delineation and aid prediction of survival in a multicenter clinical trial. Radiology. 2014;271(1):200–10. doi: 10.1148/Radiol.13131305.CrossRefPubMedGoogle Scholar
  40. 40.
    Ahluwalia MS, Daw HA. Neoadjuvant therapy with trastuzumab, paclitaxel and epirubicin for HER-2-positive operable breast cancer. J Clin Oncol. 2005;23(30):7759–60. doi: 10.1200/Jco.2005.03.0213.CrossRefPubMedGoogle Scholar
  41. 41.
    Gasparini G, Longo R, Torino F, Morabito A. Therapy of breast cancer with molecular targeting agents. Ann Oncol. 2005;16:28–36. doi: 10.1093/Annonc/Mdi905.Google Scholar
  42. 42.
    Hayes DF, Thor AD, Dressler LG, Weaver D, Edgerton S, Cowan D, et al. HER2 and response to paclitaxel in node-positive breast cancer. N Engl J Med. 2007;357(15):1496–506. doi: 10.1056/Nejmoa071167.CrossRefPubMedGoogle Scholar
  43. 43.
    Lam KO, Lee VHF, Liu RKY, Leung TW, Kwong DLW. Bevacizumab-containing regimens after cetuximab failure in Kras wild-type metastatic colorectal carcinoma. Oncol Lett. 2013;5(2):637–40. doi: 10.3892/Ol.2012.1045.PubMedGoogle Scholar
  44. 44.
    Janne PA, Engelman JA, Johnson BE. Epidermal growth factor receptor mutations in non-small-cell lung cancer: Implications for treatment and tumor biology. J Clin Oncol. 2005;23(14):3227–34. doi: 10.1200/Jco.2005.09.985.CrossRefPubMedGoogle Scholar
  45. 45.
    Erlotinib (Tarceva) for advanced non-small cell lung cancer. Med Lett Drugs Ther. 2005;47(1205):25–6.Google Scholar
  46. 46.
    Shaw AT, Kim DW, Mehra R, Tan DSW, Felip E, Chow LQM, et al. The New England journal of medicine. N Engl J Med. 2014;370(13):1189–97. doi: 10.1056/Nejmoa1311107.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Kong DS, Lee JI, Kim JH, Kim ST, Kim WS, Suh YL, et al. Phase II trial of low-dose continuous (metronomic) treatment of temozolomide for recurrent glioblastoma. Neuro Oncol. 2010;12(3):289–96. doi: 10.1093/neuonc/nop030.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Omuro A, Chan TA, Abrey LE, Khasraw M, Reiner AS, Kaley TJ, et al. Phase II trial of continuous low-dose temozolomide for patients with recurrent malignant glioma. Neuro Oncol. 2013;15(2):242–50. doi: 10.1093/neuonc/nos295.CrossRefPubMedGoogle Scholar
  49. 49.
    Perry JR, Belanger K, Mason WP, Fulton D, Kavan P, Easaw J, et al. Phase II trial of continuous dose-intense temozolomide in recurrent malignant glioma: RESCUE study. J Clin Oncol Off J Am Soc Clin Oncol. 2010;28(12):2051–7. doi: 10.1200/JCO.2009.26.5520.CrossRefGoogle Scholar
  50. 50.
    Zustovich F, Landi L, Lombardi G, Porta C, Galli L, Fontana A, et al. Sorafenib plus daily low-dose temozolomide for relapsed glioblastoma: a phase II study. Anticancer Res. 2013;33(8):3487–94.PubMedGoogle Scholar
  51. 51.
    Reardon DA, Desjardins A, Peters K, Gururangan S, Sampson J, Rich JN, et al. Phase II study of metronomic chemotherapy with bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy. J Neurooncol. 2011;103(2):371–9. doi: 10.1007/s11060-010-0403-6.CrossRefPubMedGoogle Scholar
  52. 52.
    Santoni M, Paccapelo A, Burattini L, Bianconi M, Cardinali M, Fabbietti L, et al. Protracted low doses of temozolomide for the treatment of patients with recurrent glioblastoma: a phase II study. Oncol Lett. 2012;4(4):799–801. doi: 10.3892/ol.2012.788.PubMedPubMedCentralGoogle Scholar
  53. 53.
    de Groot JF, Lamborn KR, Chang SM, Gilbert MR, Cloughesy TF, Aldape K, et al. Phase II study of aflibercept in recurrent malignant glioma: a North American brain tumor consortium study. J Clin Oncol. 2011;29(19):2689–95.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Galanis E, Anderson SK, Lafky JM, Uhm JH, Giannini C, Kumar SK, et al. Phase II study of bevacizumab in combination with sorafenib in recurrent glioblastoma (N0776): a north central cancer treatment group trial. Clin Cancer Res Off J Am Assoc Cancer Res. 2013;19(17):4816–23. doi: 10.1158/1078-0432.CCR-13-0708.CrossRefGoogle Scholar
  55. 55.
    Oehler C, Frei K, Rushing EJ, McSheehy PM, Weber D, Allegrini PR, et al. Patupilone (epothilone B) for recurrent glioblastoma: Clinical outcome and translational analysis of a single-institution phase I/II trial. Oncology. 2012;83(1):1–9. doi: 10.1159/000339152.CrossRefPubMedGoogle Scholar
  56. 56.
    Mason WP, Belanger K, Nicholas G, Vallieres I, Mathieu D, Kavan P, et al. A phase II study of the Ras-MAPK signaling pathway inhibitor TLN-4601 in patients with glioblastoma at first progression. J Neurooncol. 2012;107(2):343–9. doi: 10.1007/s11060-011-0747-6.CrossRefPubMedGoogle Scholar
  57. 57.
    Wen PY, Schiff D, Cloughesy TF, Raizer JJ, Laterra J, Smitt M, et al. A phase II study evaluating the efficacy and safety of AMG 102 (rilotumumab) in patients with recurrent glioblastoma. Neuro-Oncology. 2011;13(4):437–46. doi: 10.1093/neuonc/noq198.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Batchelor TT, Duda DG, di Tomaso E, Ancukiewicz M, Plotkin SR, Gerstner E, et al. Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. J Clin Oncol Off J Am Soc Clin Oncol. 2010;28(17):2817–23. doi: 10.1200/JCO.2009.26.3988.CrossRefGoogle Scholar
  59. 59.
    Friday BB, Anderson SK, Buckner J, Yu C, Giannini C, Geoffroy F, et al. Phase II trial of vorinostat in combination with bortezomib in recurrent glioblastoma: a north central cancer treatment group study. Neuro Oncol. 2012;14(2):215–21. doi: 10.1093/neuonc/nor198.CrossRefPubMedGoogle Scholar
  60. 60.
    Iwamoto FM, Kreisl TN, Kim L, Duic JP, Butman JA, Albert PS, et al. Phase 2 trial of talampanel, a glutamate receptor inhibitor, for adults with recurrent malignant gliomas. Cancer. 2010;116(7):1776–82. doi: 10.1002/cncr.24957.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Kreisl TN, McNeill KA, Sul J, Iwamoto FM, Shih J, Fine HA. A phase I/II trial of vandetanib for patients with recurrent malignant glioma. Neuro Oncol. 2012;14(12):1519–26. doi: 10.1093/neuonc/nos265.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Moller S, Grunnet K, Hansen S, Schultz H, Holmberg M, Sorensen M, et al. A phase II trial with bevacizumab and irinotecan for patients with primary brain tumors and progression after standard therapy. Acta Oncol (Stockholm, Sweden). 2012;51(6):797–804. doi: 10.3109/0284186x.2012.681063.CrossRefGoogle Scholar
  63. 63.
    Nagane M, Nishikawa R, Narita Y, Kobayashi H, Takano S, Shinoura N, et al. Phase II study of single-agent bevacizumab in Japanese patients with recurrent malignant glioma. Jpn J Clin Oncol. 2012;42(10):887–95. doi: 10.1093/jjco/hys121.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Pan E, Yu D, Yue B, Potthast L, Chowdhary S, Smith P, et al. A prospective phase II single-institution trial of sunitinib for recurrent malignant glioma. J Neuro-Oncol. 2012;110(1):111–8.CrossRefGoogle Scholar
  65. 65.
    Raizer JJ, Abrey LE, Lassman AB, Chang SM, Lamborn KR, Kuhn JG, et al. A phase II trial of erlotinib in patients with recurrent malignant gliomas and nonprogressive glioblastoma multiforme postradiation therapy. Neuro Oncol. 2010;12(1):95–103. doi: 10.1093/neuonc/nop015.CrossRefPubMedGoogle Scholar
  66. 66.
    Raizer JJ, Grimm S, Chamberlain MC, Nicholas MK, Chandler JP, Muro K, et al. A phase 2 trial of single-agent bevacizumab given in an every-3-week schedule for patients with recurrent high-grade gliomas. Cancer. 2010;116(22):5297–305. doi: 10.1002/cncr.25462.CrossRefPubMedGoogle Scholar
  67. 67.
    Sathornsumetee S, Desjardins A, Vredenburgh JJ, McLendon RE, Marcello J, Herndon JE, et al. Phase II trial of bevacizumab and erlotinib in patients with recurrent malignant glioma. Neuro Oncol. 2010;12(12):1300–10. doi: 10.1093/neuonc/noq099.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Schafer N, Tichy J, Thanendrarajan S, Kim Y, Stuplich M, Mack F, et al. Ifosfamide, carboplatin and etoposide in recurrent malignant glioma. Oncology. 2011;80(5–6):330–2. doi: 10.1159/000330358.CrossRefPubMedGoogle Scholar
  69. 69.
    Macdonald DR, Cascino TL, Schold Jr SC, Cairncross JG. Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol. 1990;8(7):1277–80.CrossRefPubMedGoogle Scholar
  70. 70.
    Aoki T, Mizutani T, Nojima K, Takagi T, Okumura R, Yuba Y, et al. Phase II study of ifosfamide, carboplatin, and etoposide in patients with a first recurrence of glioblastoma multiforme. J Neurosurg. 2010;112(1):50–6. doi: 10.3171/2009.5.JNS081738.CrossRefPubMedGoogle Scholar
  71. 71.
    Hasselbalch B, Eriksen JG, Broholm H, Christensen IJ, Grunnet K, Horsman MR, et al. Prospective evaluation of angiogenic, hypoxic and EGFR-related biomarkers in recurrent glioblastoma multiforme treated with cetuximab, bevacizumab and irinotecan. APMIS. 2010;118(8):585–94. doi: 10.1111/j.1600-0463.2010.02631.x.PubMedGoogle Scholar
  72. 72.
    Dieci MV, Barbieri E, Piacentini F, Ficarra G, Bettelli S, Dominici M, et al. Discordance in receptor status between primary and recurrent breast cancer has a prognostic impact: a single-institution analysis. Ann Oncol Off J Eur Soc Med Oncol ESMO. 2013;24(1):101–8. doi: 10.1093/annonc/mds248.CrossRefGoogle Scholar
  73. 73.
    Johnson BE, Mazor T, Hong C, Barnes M, Aihara K, McLean CY, et al. Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Science. 2014;343(6167):189–93. doi: 10.1126/science.1239947.CrossRefPubMedGoogle Scholar
  74. 74.
    van den Bent MJ, Wefel JS, Schiff D, Taphoorn MJ, Jaeckle K, Junck L, et al. Response assessment in neuro-oncology (a report of the RANO group): Assessment of outcome in trials of diffuse low-grade gliomas. Lancet Oncol. 2011;12(6):583–93. doi: 10.1016/S1470-2045(11)70057-2.CrossRefPubMedGoogle Scholar
  75. 75.
    Wagle N, Grabiner BC, Van Allen EM, Hodis E, Jacobus S, Supko JG, et al. Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of Everolimus and Pazopanib. Cancer Discov. 2014;4(5):546–53. doi: 10.1158/2159-8290.CD-13-0353.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Voss MH, Hakimi AA, Pham CG, Brannon AR, Chen YB, Cunha LF, et al. Tumor genetic analyses of patients with metastatic renal cell carcinoma and extended benefit from mTOR inhibitor therapy. Clin Cancer Res Off J Am Assoc Cancer Res. 2014;20(7):1955–64. doi: 10.1158/1078-0432.CCR-13-2345.CrossRefGoogle Scholar
  77. 77.
    Brennan CW, Verhaak RGW, McKenna A, Campos B, Noushmehr H, Salama SR, et al. The somatic genomic landscape of glioblastoma. Cell. 2013;155(2):462–77. doi: 10.1016/J.Cell.2013.09.034.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17(1):98–110. doi: 10.1016/j.ccr.2009.12.020.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Celldex Therapeutics. ACT IV & ReACT Clinical Trials. Celldex Therapeutics. 2013. Accessed 6 August 2014.
  80. 80.
    Jaeckle KA, Ballman KV, Giannini C, Schomberg PJ, Ames MM, Reid JM, et al. Phase II NCCTG trial of RT + irinotecan and adjuvant BCNU plus irinotecan for newly diagnosed GBM. J Neurooncol. 2010;99(1):73–80.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Chamberlain MC, Johnston SK. Salvage therapy with single agent bendamustine for recurrent glioblastoma. J Neurooncol. 2011;105(3):523–30.CrossRefPubMedGoogle Scholar
  82. 82.
    Peereboom DM, Ahluwalia MS, Ye X, Supko JG, Hilderbrand SL, Phuphanich S, et al. NABTT 0502: a phase II and pharmacokinetic study of erlotinib and sorafenib for patients with progressive or recurrent glioblastoma multiforme. Neuro Oncol. 2013;15(4):490–6.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Raizer JJ, Abrey LE, Lassman AB, Chang SM, Lamborn KR, Kuhn JG, et al. A phase II trial of erlotinib in patients with recurrent malignant gliomas and nonprogressive glioblastoma multiforme postradiation therapy. Neuro Oncol. 2010;12(1):95–103.CrossRefPubMedGoogle Scholar
  84. 84.
    Reardon DA, Desjardins A, Peters K, Gururangan S, Sampson J, Rich JN, et al. Phase II study of metronomic chemotherapy with bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy. J Neurooncol. 2011;103(2):371–9.CrossRefPubMedGoogle Scholar
  85. 85.
    Reardon DA, Desjardins A, Peters KB, Gururangan S, Sampson JH, McLendon RE, et al. Phase II study of carboplatin, irinotecan, and bevacizumab for bevacizumab naive, recurrent glioblastoma. J Neurooncol. 2012;107(1):155–64.CrossRefPubMedGoogle Scholar
  86. 86.
    Thiessen B, Stewart C, Tsao M, Kamel-Reid S, Schaiquevich P, Mason W, et al. A phase I/II trial of GW572016 (lapatinib) in recurrent glioblastoma multiforme: clinical outcomes, pharmacokinetics and molecular correlation. Cancer Chemother Pharmacol. 2010;65(2):353–61.CrossRefPubMedGoogle Scholar
  87. 87.
    Kreisl TN, Smith P, Sul J, Salgado C, Iwamoto FM, Shih JH, et al. Continuous daily sunitinib for recurrent glioblastoma. J Neurooncol. 2013;111(1):41–8.CrossRefPubMedGoogle Scholar
  88. 88.
    Muhic A, Poulsen HS, Sorensen M, Grunnet K, Lassen U. Phase II open-label study of nintedanib in patients with recurrent glioblastoma multiforme. J Neuro-Oncol. 2013;111(2):205–12.CrossRefGoogle Scholar
  89. 89.
    Soffietti R, Trevisan E, Ruda R, Bertero L, Bosa C, Fabrini MG, et al. Phase II trial of bevacizumab with fotemustine in recurrent glioblastoma: Final results of a multicenter study of AINO (Italian Association of Neuro-oncology). J Clin Oncol. 2011;29 Suppl 15:2027.CrossRefGoogle Scholar
  90. 90.
    Raizer JJ, Abrey LE, Lassman AB, Chang SM, Lamborn KR, Kuhn JG, et al. A phase II trial of erlotinib in patients with recurrent malignant gliomas and nonprogressive glioblastoma multiforme postradiation therapy. Neuro Oncol. 2010;12(1):95–103.CrossRefPubMedGoogle Scholar
  91. 91.
    Dresemann G, Weller M, Rosenthal MA, Wedding U, Wagner W, Engel E, et al. Imatinib in combination with hydroxyurea versus hydroxyurea alone as oral therapy in patients with progressive pretreated glioblastoma resistant to standard dose temozolomide. J Neurooncol. 2010;96(3):393–402.CrossRefPubMedGoogle Scholar
  92. 92.
    Reardon DA, Groves MD, Wen PY, Nabors L, Mikkelsen T, Rosenfeld S, et al. A phase I/II trial of pazopanib in combination with lapatinib in adult patients with relapsed malignant glioma. Clin Cancer Res. 2013;19(4):900–8.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Toni Rose Jue
    • 1
  • Elizabeth Hovey
    • 2
  • Sara Davis
    • 1
  • Oliver Carleton
    • 1
  • Kerrie L. McDonald
    • 1
  1. 1.Cure Brain Cancer Neuro-oncology GroupPrince of Wales Clinical School, Lowy Cancer Research Centre C25, UNSWSydneyAustralia
  2. 2.Department of Medical OncologyPrince of Wales HospitalRandwickAustralia

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