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Relapsed Glioblastoma: Treatment Strategies for Initial and Subsequent Recurrences

  • Neuro-oncology (GJ Lesser, Section Editor)
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion Statement

At the time of glioblastoma (GBM) recurrence, a sharp analysis of prognostic factors, disease characteristics, response to adjuvant treatment, and clinical conditions should be performed. A prognostic assessment could allow a careful selection between patients that could be proposed to intensified approaches or palliative setting. Participation in clinical trials aims to improve outcome, and should be encouraged due to dismal prognosis of GBM patients after recurrence. Reoperation should be proposed if the tumor is amenable to a complete resection and if prognostic factors suggest that patient could benefit from a second surgery. Second-line chemotherapy should be chosen based on MGMT status, time to disease recurrence, and toxicity profile. If enrollment into a clinical trial is not possible, a nitrosourea-based regimen is the preferred choice, carefully evaluating any previous temozolomide (TMZ)-related toxicity. In MGMT-methylated patients relapsing after TMZ completion, a rechallenge could be proposed. After second progression, the clinical advantage of subsequent lines of chemotherapy still needs to be clarified. However, based on performance status, patients’ preference, and disease behavior, a third-line treatment could be considered. Available treatments include nitrosoureas, bevacizumab, or carboplatin plus etoposide. However, more effective therapeutic options are needed.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  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.

    Article  CAS  PubMed  Google Scholar 

  2. Carson KA, Grossman SA, Fisher JD, Shaw EG. Prognostic factors for survival in adult patients with recurrent glioma enrolled onto the new approaches to brain tumor therapy CNS consortium phase I and II clinical trials. J Clin Oncol. 2007;25(18):2601–6.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Wu W, Lamborn KR, Buckner JC, Novotny PJ, Chang SM, O’Fallon JR, et al. Joint NCCTG and NABTC prognostic factors analysis for high-grade recurrent glioma. Neuro-Oncology. 2010;12(2):164–72. doi:10.1093/neuonc/nop019.

    Article  CAS  PubMed  Google Scholar 

  4. Gorlia T, Stupp R, Brandes AA, Rampling RR, Fumoleau P, Dittrich C, et al. New prognostic factors and calculators for outcome prediction in patients with recurrent glioblastoma: a pooled analysis of EORTC Brain Tumour Group phase I and II clinical trials. Eur J Cancer. 2012;48(8):1176–84. doi:10.1016/j.ejca.2012.02.004 .These three studies analized the role of prognostic factors in large series of GBM recurrent patients

    Article  PubMed  Google Scholar 

  5. Lacroix M, Abi-Said D, Fourney DR, Gokaslan ZL, Shi W, DeMonte F, et al. A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg. 2001;95(2):190–8.

    Article  CAS  PubMed  Google Scholar 

  6. Sanai N, Polley MY, McDermott MW, Parsa AT, Berger MS. An extent of resection threshold for newly diagnosed glioblastomas. J Neurosurg. 2011;115(1):3–8. doi:10.3171/2011.2.JNS10998.

    Article  PubMed  Google Scholar 

  7. Chang SM, Parney IF, McDermott M, Barker 2nd FG, Schmidt MH, Huang W, et al. Perioperative complications and neurological outcomes of first and second craniotomies among patients enrolled in the Glioma Outcome Project. J Neurosurg. 2003;98(6):1175–81. doi:10.3171/jns.2003.98.6.1175.

    Article  PubMed  Google Scholar 

  8. Park JK, Hodges T, Arko L, Shen M, Dello Iacono D, McNabb A, et al. Scale to predict survival after surgery for recurrent glioblastoma multiforme. J Clin Oncol Off J Am Soc Clin Oncol. 2010;28(24):3838–43. doi:10.1200/JCO.2010.30.0582.

    Article  Google Scholar 

  9. Park CK, Kim JH, Nam DH, Kim CY, Chung SB, Kim YH, et al. A practical scoring system to determine whether to proceed with surgical resection in recurrent glioblastoma. Neuro-Oncology. 2013;15(8):1096–101. doi:10.1093/neuonc/not069.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Nava F, Tramacere I, Fittipaldo A, Bruzzone MG, Dimeco F, Fariselli L, et al. Survival effect of first- and second-line treatments for patients with primary glioblastoma: a cohort study from a prospective registry, 1997-2010. Neuro-Oncology. 2014;16(5):719–27. doi:10.1093/neuonc/not316.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Brandes AA, Bartolotti M, Tosoni A, Poggi R, Bartolini S, Paccapelo A, et al. Patient outcomes following second surgery for recurrent glioblastoma. Future Oncol. 2016;12(8):1039–44. doi:10.2217/fon.16.9 .This study conducted in a large series of GBM patients reoperated at recurrence demonstrated that extent of resection and MGMT methylation status were correlated with survival

    Article  CAS  PubMed  Google Scholar 

  12. Ringel F, Pape H, Sabel M, Krex D, Bock HC, Misch M, et al. Clinical benefit from resection of recurrent glioblastomas: results of a multicenter study including 503 patients with recurrent glioblastomas undergoing surgical resection. Neuro-Oncology. 2016;18(1):96–104. doi:10.1093/neuonc/nov145.

    Article  PubMed  Google Scholar 

  13. Clarke JL, Ennis MM, Yung WK, Chang SM, Wen PY, Cloughesy TF, et al. Is surgery at progression a prognostic marker for improved 6-month progression-free survival or overall survival for patients with recurrent glioblastoma? Neuro-Oncology. 2011;13(10):1118–24. doi:10.1093/neuonc/nor110.

    Article  PubMed  Google Scholar 

  14. Hervey-Jumper SL, Berger MS. Reoperation for recurrent high-grade glioma: a current perspective of the literature. Neurosurgery. 2014;75(5):491–9 . doi:10.1227/NEU.0000000000000486.discussion 8-9

    Article  PubMed  Google Scholar 

  15. Suchorska B, Weller M, Tabatabai G, Senft C, Hau P, Sabel MC, et al. Complete resection of contrast-enhancing tumor volume is associated with improved survival in recurrent glioblastoma-results from the DIRECTOR trial. Neuro-Oncology. 2016;18(4):549–56. doi:10.1093/neuonc/nov326 .The study demonstrated that complete resection was associated with improved survival in GBM reoperated patients

    Article  PubMed  Google Scholar 

  16. Brandes AA, Bartolotti M, Tosoni A, Franceschi E. Nitrosoureas in the Management of Malignant Gliomas. Curr Neurol Neurosci Rep. 2016;16(2):13. doi:10.1007/s11910-015-0611-8.

    Article  PubMed  Google Scholar 

  17. Wick W, Puduvalli VK, Chamberlain MC, van den Bent MJ, Carpentier AF, Cher LM, et al. Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma. J Clin Oncol. 2010;28(7):1168–74. doi:10.1200/JCO.2009.23.2595.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Brandes AA, Carpentier AF, Kesari S, Sepulveda-Sanchez JM, Wheeler HR, Chinot O, et al. A phase II randomized study of galunisertib monotherapy or galunisertib plus lomustine compared with lomustine monotherapy in patients with recurrent glioblastoma. Neuro-Oncology. 2016. doi:10.1093/neuonc/now009.

    Google Scholar 

  19. Batchelor TT, Mulholland P, Neyns B, Nabors LB, Campone M, Wick A, et al. Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. J Clin Oncol. 2013;31(26):3212–8. doi:10.1200/JCO.2012.47.2464.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Taal W, Oosterkamp HM, Walenkamp AM, Dubbink HJ, Beerepoot LV, Hanse MC, et al. Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial. Lancet Oncol. 2014;15(9):943–53. doi:10.1016/S1470-2045(14)70314-6.

    Article  CAS  PubMed  Google Scholar 

  21. Brandes AA, Tosoni A, Franceschi E, Blatt V, Santoro A, Faedi M, et al. Fotemustine as second-line treatment for recurrent or progressive glioblastoma after concomitant and/or adjuvant temozolomide: a phase II trial of Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO). Cancer Chemother Pharmacol. 2009;64(4):769–75. doi:10.1007/s00280-009-0926-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Brandes AA, Finocchiaro G, Zagonel V, Reni M, Caserta C, Fabi A, et al. AVAREG: a phase 2, randomized, noncomparative study of fotemustine or bevacizumab for patients with recurrent glioblastoma. Neuro-Oncology. 2016. doi:10.1093/neuonc/now035.

    Google Scholar 

  23. van den Bent MJ, Taal W. Are we done with dose-intense temozolomide in recurrent glioblastoma? Neuro-Oncology. 2014;16(9):1161–3. doi:10.1093/neuonc/nou157 .This review evaluated the role of intensified temozolomide schedules in recurrent GBM

    Article  PubMed  PubMed Central  Google Scholar 

  24. Weller M, Tabatabai G, Kastner B, Felsberg J, Steinbach JP, Wick A, et al. MGMT promoter methylation is a strong prognostic biomarker for benefit from dose-intensified temozolomide rechallenge in progressive glioblastoma: the DIRECTOR trial. Clin Cancer Res. 2015;21(9):2057–64. doi:10.1158/1078-0432.CCR-14-2737 .This study provides the evidence for temozolomide rechallange in MGMT methylated patients in recurrence after temozolomide interruption

    Article  CAS  PubMed  Google Scholar 

  25. Reardon DA, Wen PY, Mellinghoff IK. Targeted molecular therapies against epidermal growth factor receptor: past experiences and challenges. Neuro-Oncology. 2014;16(Suppl 8):viii7–13. doi:10.1093/neuonc/nou232.

    Article  PubMed  PubMed Central  Google Scholar 

  26. van den Bent MJ, Brandes AA, Rampling R, Kouwenhoven MC, Kros JM, Carpentier AF, et al. Randomized phase II trial of erlotinib versus temozolomide or carmustine in recurrent glioblastoma: EORTC brain tumor group study 26034. J Clin Oncol. 2009;27(8):1268–74. doi:10.1200/JCO.2008.17.5984.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Vredenburgh JJ, Desjardins A, Herndon 2nd JE, Dowell JM, Reardon DA, Quinn JA, et al. Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res. 2007;13(4):1253–9.

    Article  CAS  PubMed  Google Scholar 

  28. Vredenburgh JJ, Desjardins A, Herndon 2nd JE, Marcello J, Reardon DA, Quinn JA, et al. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol. 2007;25(30):4722–9. doi:10.1200/JCO.2007.12.2440.

    Article  CAS  PubMed  Google Scholar 

  29. Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009;27(5):740–5.

    Article  CAS  PubMed  Google Scholar 

  30. Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009;27(28):4733–40. doi:10.1200/JCO.2008.19.8721.

    Article  CAS  PubMed  Google Scholar 

  31. Field KM, Jordan JT, Wen PY, Rosenthal MA, Reardon DA. Bevacizumab and glioblastoma: scientific review, newly reported updates, and ongoing controversies. Cancer. 2015;121(7):997–1007. doi:10.1002/cncr.28935.

    Article  CAS  PubMed  Google Scholar 

  32. Wick W, Brandes A, Gorlia T, Bendszus M, Sahm F, Taal W et al. Phase III trial exploring the combination of bevacizumab and lomustine in patients with first recurrence of glioblastoma: the EORTC 26101 trial. Neuro Oncol. 2015;(17). This phase III study randomized recurrent GBM patients to bevacizumab in combination with CCNU or CCNU alone demonstrating a significant increase in PFS not translating in a survival advantage.

  33. Khasraw M, Ameratunga M, Grommes C. Bevacizumab for the treatment of high-grade glioma: an update after phase III trials. Expert Opin Biol Ther. 2014;14(5):729–40. doi:10.1517/14712598.2014.898060.

    Article  CAS  PubMed  Google Scholar 

  34. Lu-Emerson C, Duda DG, Emblem KE, Taylor JW, Gerstner ER, Loeffler JS, et al. Lessons from anti-vascular endothelial growth factor and anti-vascular endothelial growth factor receptor trials in patients with glioblastoma. J Clin Oncol. 2015;33(10):1197–213. doi:10.1200/JCO.2014.55.9575.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Piccioni DE, Lai A. Deferred use of bevacizumab for recurrent glioblastoma is not associated with diminished efficacy. Neuro-Oncology. 2014;16(10):1427–8. doi:10.1093/neuonc/nou214.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Levin VA, Mendelssohn ND, Chan J, Stovall MC, Peak SJ, Yee JL, et al. Impact of bevacizumab administered dose on overall survival of patients with progressive glioblastoma. J Neuro-Oncol. 2015;122(1):145–50. doi:10.1007/s11060-014-1693-x.

    Article  CAS  Google Scholar 

  37. Wong ET, Gautam S, Malchow C, Lun M, Pan E, Brem S. Bevacizumab for recurrent glioblastoma multiforme: a meta-analysis. J Natl Compr Cancer Netw. 2011;9(4):403–7.

    CAS  Google Scholar 

  38. Franceschi E, Bartolotti M, Brandes AA. Bevacizumab in recurrent glioblastoma: open issues. Future Oncol. 2015;11.

  39. Franceschi E, Brandes AA. The role of bevacizumab in recurrent glioblastoma: new insights from randomized trials. CNS Oncol. 2015;4(3):117–9. doi:10.2217/cns.15.7.

    Article  CAS  PubMed  Google Scholar 

  40. Sandmann T, Bourgon R, Garcia J, Li C, Cloughesy T, Chinot OL, et al. Patients with proneural glioblastoma may derive overall survival benefit from the addition of bevacizumab to first-line radiotherapy and temozolomide: retrospective analysis of the AVAglio trial. J Clin Oncol. 2015;33(25):2735–44. doi:10.1200/JCO.2015.61.5005.

    Article  CAS  PubMed  Google Scholar 

  41. Sulman EP, Won M, Blumenthal A, Vogelbaum M, Colman H, Jenkins RB et al. Molecular predictors of outcome and response to bevacizumab (BEV) based on analysis of RTOG 0825, a phase III randomized trial comparing chemoradiation with or without BEV in patients with newly diagnosed glioblastoma (GBM) J Clin Oncol. 2013;31:suppl;abstr.

  42. Erdem-Eraslan L, van den Bent MJ, Hoogstrate Y, Naz-Khan H, Stubbs A, van der Spek P, et al. Identification of patients with recurrent glioblastoma who may benefit from combined bevacizumab and CCNU therapy: a report from the BELOB trial. Cancer Res. 2016;76(3):525–34. doi:10.1158/0008-5472.CAN-15-0776.

    Article  CAS  PubMed  Google Scholar 

  43. Fecci PE, Heimberger AB, Sampson JH. Immunotherapy for primary brain tumors: no longer a matter of privilege. Clin Cancer Res. 2014;20(22):5620–9. doi:10.1158/1078-0432.CCR-14-0832.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Sampson J, Vlahovic G, Sahebjam S, Omuro A, Baehring J, Hafler D, et al. Preliminary safety and activity of nivolumab and its combination with ipilimumab in recurrent glioblastoma (GBM): CHECKMATE-143. J Clin Oncol. 2015;33(No 15_suppl (May 20 Supplement)):3010.

    Google Scholar 

  45. Sampson JH, Mitchell DA. Vaccination strategies for neuro-oncology. Neuro-Oncology. 2015;17(Suppl 7):vii15–25. doi:10.1093/neuonc/nov159.

    Article  PubMed  Google Scholar 

  46. Reardon D, Desjardins A, Schuster J, Tran D, Fink KL, Nabors BL, et al. ReACT: long-term survival from a randomized phase ii study of rindopepimut (CDX-110) plus bevacizumab in relapsed glioblastoma. Neuro-Oncology. 2015;17:v107–12.

    Article  Google Scholar 

  47. Crane CA, Han SJ, Ahn B, Oehlke J, Kivett V, Fedoroff A, et al. Individual patient-specific immunity against high-grade glioma after vaccination with autologous tumor derived peptides bound to the 96 KD chaperone protein. Clin Cancer Res. 2013;19(1):205–14. doi:10.1158/1078-0432.CCR-11-3358.

    Article  CAS  PubMed  Google Scholar 

  48. Bloch O, Parsa AT. Heat shock protein peptide complex-96 (HSPPC-96) vaccination for recurrent glioblastoma: a phase II, single arm trial. Neuro-Oncology. 2014;16(5):758–9. doi:10.1093/neuonc/nou054.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Tonder M, Weller M, Eisele G, Roth P. Carboplatin and etoposide in heavily pretreated patients with progressive high-grade glioma. Chemotherapy. 2014;60(5–6):375–8. doi:10.1159/000440678.

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Medical Oncology, Bellaria Hospital, Azienda USL—IRCCS Institute of Neurological Sciences, Via Altura 4, Bologna, Italy

    Alicia Tosoni MD, Enrico Franceschi MD, Rosalba Poggi MD & Alba A. Brandes MD

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  1. Alicia Tosoni MD
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  2. Enrico Franceschi MD
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  3. Rosalba Poggi MD
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  4. Alba A. Brandes MD
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Correspondence to Alba A. Brandes MD.

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Tosoni, A., Franceschi, E., Poggi, R. et al. Relapsed Glioblastoma: Treatment Strategies for Initial and Subsequent Recurrences. Curr. Treat. Options in Oncol. 17, 49 (2016). https://doi.org/10.1007/s11864-016-0422-4

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