Re-irradiation for recurrent glioblastoma (GBM): a systematic review and meta-analysis

Abstract

Purpose

To determine the efficacy and toxicity of re-irradiation for patients with recurrent GBM.

Materials and methods

We searched various biomedical databases from 1998 to 2018, for eligible studies where patients were treated with re-irradiation for recurrent GBM. Outcomes of interest were 6 and 12-month overall survival (OS-6, OS-12), 6 and 12-month progression free survival (PFS-6, PFS-12) and serious (Grade 3 +) adverse events (AE). We used the random effects model to pool outcomes across studies and compared pre-defined subgroups using interaction test. Methodological quality of each study was assessed using the Newcastle-Ottawa scoring system.

Results

We found 50 eligible non-comparative studies including 2095 patients. Of these, 42% were of good or fair quality. The pooled results were as follows: OS-6 rate 73% (95% confidence interval (CI) 69–77%), OS-12 rate 36% (95% CI 32–40%), PFS-6 rate 43% (95% CI 35–50%), PFS-12 rate 17% (95% CI 13–20%), and Grade 3 + AE rate 7% (95% CI 4–10%). Subgroup analysis showed that prospective studies reported higher toxicity rates, and studies which utilized brachytherapy to have a longer OS-12. Within the external beam radiotherapy group, there was no dose–response [above or below 36 Gy in 2 Gy equivalent doses (EQD2)]. However, a short fractionation regimen (≤ 5 fractions) seemed to provide superior PFS-6.

Conclusion

The available evidence, albeit mostly level III, suggests that re-irradiation provides encouraging disease control and survival rates. Toxicity was not uniformly reported, but seemed to be low from the included studies. Randomized controlled trials (RCT) are needed to establish the optimal management strategy for recurrent GBM.

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References

  1. 1.

    Louis DN et al (2016) The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 131(6):803–820

    Article  PubMed  Google Scholar 

  2. 2.

    Stupp R et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–996

    CAS  Article  Google Scholar 

  3. 3.

    Wallner KE et al (1989) Patterns of failure following treatment for glioblastoma multiforme and anaplastic astrocytoma. Int J Radiat Oncol Biol Phys 16(6):1405–1409

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Easaw JC et al (2011) Canadian recommendations for the treatment of recurrent or progressive glioblastoma multiforme. Curr Oncol 18(3):e126

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  5. 5.

    Krauze AV et al (2017) Expert consensus on re-irradiation for recurrent glioma. Radiat Oncol 12:194. https://doi.org/10.1186/s13014-017-0928-3

    PubMed Central  Article  PubMed  Google Scholar 

  6. 6.

    Dirks P et al (1993) The value of reoperation for recurrent glioblastoma. Can J Surg 36(3):271–275

    CAS  PubMed  Google Scholar 

  7. 7.

    Perry JR et al (2010) Phase II trial of continuous dose-intense temozolomide in recurrent malignant glioma: RESCUE study. J Clin Oncol 28(12):2051–2057

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Chinot OL et al (2014) Bevacizumab plus radiotherapy–temozolomide for newly diagnosed glioblastoma. N Engl J Med 370(8):709–722

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Taal W et al (2013) A randomized phase II study of bevacizumab versus bevacizumab plus lomustine versus lomustine single agent in recurrent glioblastoma: the Dutch BELOB study 2013:2001–2001

  10. 10.

    Weller M, Butowski N, Tran D, Recht L, Lim M, Hirte H, Ashby L, Mechtler L, Goldlust S, Iwamoto F, Drappatz J, O’Rourke D, Wong M, Finocchiaro G, Perry J, Wick W, He Y, Davis T, Stupp R, Sampson J (2016) ATIM-03. ACT IV: an international, double-blind, phase 3 trial of rindopepimut in newly diagnosed, EGFRvIII-expressing glioblastoma. Neuro Oncol 18(suppl_6):vi17–vi18

    Article  Google Scholar 

  11. 11.

    Stang A (2010) Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 25(9):603–605

    Article  Google Scholar 

  12. 12.

    Brown LD, Tony Cai T, DasGupta A (2001) Interval estimation for a binomial proportion. Stat Sci 2001:101–117

    Google Scholar 

  13. 13.

    DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177–188

    CAS  Article  Google Scholar 

  14. 14.

    Higgins JPT et al (2003) Measuring inconsistency in meta-analyses. BMJ 327(7414):557

    PubMed Central  Article  PubMed  Google Scholar 

  15. 15.

    Miyatake S-I et al (2009) Survival benefit of boron neutron capture therapy for recurrent malignant gliomas. J Neuro-Oncol 91(2):199

    Article  Google Scholar 

  16. 16.

    Pellettieri L et al (2008) An investigation of boron neutron capture therapy for recurrent glioblastoma multiforme. Acta Neurol Scand 117(3):191–197

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Shrieve DC, Alexander E, 3rd, Wen PY, Fine HA, Kooy HM, Black PM, Loeffler JS (1995) Comparison of stereotactic radiosurgery and brachytherapy in the treatment of recurrent glioblastoma multiforme. Neurosurgery 36(2):275-282; discussion 282–274

    Article  Google Scholar 

  18. 18.

    Hall WA, Djalilian HR, Sperduto PW, Cho KH, Gerbi BJ, Gibbons JP et al (1995) Stereotactic radiosurgery for recurrent malignant gliomas. J Clin Oncol 13(7):1642–1648

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Lederman G, Wronski M, Arbit E, Odaimi M, Wertheim S, Lombardi E et al (2000) Treatment of recurrent glioblastoma multiforme using fractionated stereotactic radiosurgery and concurrent paclitaxel. Am J Clin Oncol 23(2):155–159

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Mahajan A, McCutcheon IE, Suki D, Chang EL, Hassenbusch SJ, Weinberg JS et al (2005) Case-control study of stereotactic radiosurgery for recurrent glioblastoma multiforme. J Neurosurg 103(2):210–217

    Article  PubMed  Google Scholar 

  21. 21.

    Combs SE, Thilmann C, Edler L, Debus J, Schulz-Ertner D (2005) Efficacy of fractionated stereotactic reirradiation in recurrent gliomas: long-term results in 172 patients treated in a single institution. J Clin Oncol 23(34):8863–8869

    Article  PubMed  Google Scholar 

  22. 22.

    Vordermark D, Ruprecht K, Rieckmann P, Roggendorf W, Vince GH, Warmuth-Metz M et al (2006) Glioblastoma multiforme with oligodendroglial component (GBMO): favorable outcome after post-operative radiotherapy and chemotherapy with nimustine (ACNU) and teniposide (VM26). BMC Cancer 6:247

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  23. 23.

    Kohshi K, Yamamoto H, Nakahara A, Katoh T, Takagi M (2007) Fractionated stereotactic radiotherapy using gamma unit after hyperbaric oxygenation on recurrent high-grade gliomas. J Neuro-Oncol 82(3):297–303

    Article  Google Scholar 

  24. 24.

    Kong DS, Lee JI, Park K, Kim JH, Lim DH, Nam DH (2008) Efficacy of stereotactic radiosurgery as a salvage treatment for recurrent malignant gliomas. Cancer 112(9):2046–2051

    Article  PubMed  Google Scholar 

  25. 25.

    Gutin PH, Iwamoto FM, Beal K, Mohile NA, Karimi S, Hou BL et al (2009) Safety and efficacy of bevacizumab with hypofractionated stereotactic irradiation for recurrent malignant gliomas. Int J Radiat Oncol Biol Phys 75(1):156–163

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  26. 26.

    Fokas E, Wacker U, Gross MW, Henzel M, Encheva E, Engenhart-Cabillic R (2009) Hypofractionated stereotactic reirradiation of recurrent glioblastomas: a beneficial treatment option after high-dose radiotherapy? Strahlenther Onkol 185(4):235–240

    Article  PubMed  Google Scholar 

  27. 27.

    Elliott RE, Parker EC, Rush SC, Kalhorn SP, Moshel YA, Narayana A, Donahue B, Golfinos JG (2011) Efficacy of gamma knife radiosurgery for small-volume recurrent malignant gliomas after initial radical resection. World neurosurgery 76(1-2):128-140; discussion 161–122. https://doi.org/10.1016/j.wneu.2010.12.053

    Article  PubMed  Google Scholar 

  28. 28.

    Minniti G, Armosini V, Salvati M, Lanzetta G, Caporello P, Mei M et al (2011) Fractionated stereotactic reirradiation and concurrent temozolomide in patients with recurrent glioblastoma. J Neuro-Oncol 103(3):683–691

    CAS  Article  Google Scholar 

  29. 29.

    Torok JA, Wegner RE, Mintz AH, Heron DE, Burton SA (2011) Re-irradiation with radiosurgery for recurrent glioblastoma multiforme. Technol Cancer Res Treat 10(3):253–258

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Koga T et al (2012) Extended field stereotactic radiosurgery for recurrent glioblastoma. Cancer 118(17):4193–4200

    Article  PubMed  Google Scholar 

  31. 31.

    Maranzano E, Anselmo P, Casale M, Trippa F, Carletti S, Principi M et al (2011) Treatment of recurrent glioblastoma with stereotactic radiotherapy: long-term results of a mono-institutional trial. Tumori J 97(1):56–61

    Article  Google Scholar 

  32. 32.

    Skeie BS et al (2012) Gamma knife surgery versus reoperation for recurrent glioblastoma multiforme. World Neurosurg 78(6):658–669

    Article  PubMed  Google Scholar 

  33. 33.

    Conti A, Pontoriero A, Arpa D, Siragusa C, Tomasello C, Romanelli P et al (2012) Efficacy and toxicity of CyberKnife re-irradiation and “dose dense” temozolomide for recurrent gliomas. Acta Neurochir 154(2):203–209

    Article  PubMed  Google Scholar 

  34. 34.

    Park KJ, Kano H, Iyer A, Liu X, Niranjan A, Flickinger JC et al (2012) Salvage gamma knife stereotactic radiosurgery followed by bevacizumab for recurrent glioblastoma multiforme: a case-control study. J Neuro-Oncol 107(2):323–333

    CAS  Article  Google Scholar 

  35. 35.

    Combs SE, Edler L, Rausch R, Welzel T, Wick W, Debus J (2013) Generation and validation of a prognostic score to predict outcome after re-irradiation of recurrent glioma. Acta Oncol 52(1):147–152

    Article  PubMed  Google Scholar 

  36. 36.

    Ciammella P, Galeandro M, D’Abbiero N, Podgornii A, Pisanello A, Botti A et al (2013) Hypo-fractionated IMRT for patients with newly diagnosed glioblastoma multiforme: a 6 year single institutional experience. Clin Neurol Neurosurg 115(9):16

    Article  Google Scholar 

  37. 37.

    Miwa K, Matsuo M, Ogawa S, Shinoda J, Asano Y, Ito T et al (2014) Hypofractionated high-dose irradiation with positron emission tomography data for the treatment of glioblastoma multiforme. BioMed Res Int 2014:407026

    PubMed Central  Article  PubMed  Google Scholar 

  38. 38.

    Magnuson W, Robins HI, Mohindra P, Howard S (2014) Large volume reirradiation as salvage therapy for glioblastoma after progression on bevacizumab. J Neuro-Oncol 117(1):133–139

    CAS  Article  Google Scholar 

  39. 39.

    Clarke J, Neil E, Terziev R, Gutin P, Barani I, Kaley T et al (2017) Multicenter, phase 1, dose escalation study of hypofractionated stereotactic radiation therapy with bevacizumab for recurrent glioblastoma and anaplastic astrocytoma. Int J Radiat Oncol Biol Phys 99(4):797–804

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  40. 40.

    Wick W, Debus J, Bendszus M, Kobyakov G, Martens T, Heese O et al (2013) A phase II, randomized, open-label, multi-center study of weekly APG101 + reirradiation versus reirradiation in the treatment of patients with recurrent glioblastoma. Eur J Cancer 49:S776

    Google Scholar 

  41. 41.

    Balducci M et al (2014) Low-dose fractionated radiotherapy and concomitant chemotherapy for recurrent or progressive glioblastoma. Strahlenther Onkol 190(4):370

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Ertas G et al (2014) Survival following stereotactic radiotherapy for recurrent high grade gliomas. Int J Hematol Oncol 27(4):233–238

    Google Scholar 

  43. 43.

    Greenspoon JN, Sharieff W, Hirte H, Overholt A, Devillers R, Gunnarsson T et al (2014) Fractionated stereotactic radiosurgery with concurrent temozolomide chemotherapy for locally recurrent glioblastoma multiforme: a prospective cohort study. OncoTargets Ther 7:485–490

    CAS  Article  Google Scholar 

  44. 44.

    Hasan S, Chen E, Lanciano R, Yang J, Hanlon A, Lamond J et al (2015) Salvage fractionated stereotactic radiotherapy with or without chemotherapy and immunotherapy for recurrent glioblastoma multiforme: a single institution experience. Front Oncol 5:106

    PubMed Central  Article  PubMed  Google Scholar 

  45. 45.

    Dincoglan F, Beyzadeoglu M, Sager O, Demiral S, Gamsiz H, Uysal B et al (2015) Management of patients with recurrent glioblastoma using hypofractionated stereotactic radiotherapy. Tumor J 101(2):179–184

    CAS  Article  Google Scholar 

  46. 46.

    Bir SC, Connor DE Jr, Ambekar S, Wilden JA, Nanda A (2015) Factors predictive of improved overall survival following stereotactic radiosurgery for recurrent glioblastoma. Neurosurg Rev 38(4):705–713

    Article  PubMed  Google Scholar 

  47. 47.

    Holt DE, Bernard ME, Quan K, Clump DA, Engh JA, Burton SA et al (2016) Salvage stereotactic radiosurgery for recurrent glioblastoma multiforme with prior radiation therapy. J Cancer Res Ther 12(4):1243–1248

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Kim H, Rye et al (2015) Outcome of salvage treatment for recurrent glioblastoma. J Clin Neurosci 22(3):468–473

    Article  PubMed  Google Scholar 

  49. 49.

    Shi W et al (2018) Salvage fractionated stereotactic re-irradiation (FSRT) for patients with recurrent high grade gliomas progressed after bevacizumab treatment. J Neuro-Oncol 137(1):171–177

    CAS  Article  Google Scholar 

  50. 50.

    Scharfen CO, Sneed PK, Wara WM, Larson DA, Phillips TL, Prados MD et al (1992) High activity iodine-125 interstitial implant for gliomas. Int J Radiat Oncol Biol Phys 24(4):583–591

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    Leibel SA, Gutin PH, Wara WM, Silver PS, Larson DA, Edwards MS et al (1989) Survival and quality of life after interstitial implantation of removable high-activity iodine-125 sources for the treatment of patients with recurrent malignant gliomas. Int J Radiat Oncol Biol Phys 17(6):1129–1139

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    Larson GL, Wilbanks JH, Dennis WS, Permenter WD, Easley JD (1990) Interstitial radiogold implantation for the treatment of recurrent high-grade gliomas. Cancer 66(1):27–29

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    Patel S, Breneman JC, Warnick RE, Albright RE Jr, Tobler WD, van Loveren HR, Tew JM Jr (2000) Permanent iodine-125 interstitial implants for the treatment of recurrent glioblastoma multiforme. Neurosurgery 46(5):1123–1128; discussion 1128–1130

    CAS  Article  PubMed  Google Scholar 

  54. 54.

    Simon JM, Cornu P, Boisserie G, Hasboun D, Tep B, Hardiman C et al (2002) Brachytherapy of glioblastoma recurring in previously irradiated territory: predictive value of tumor volume. Int J Radiat Oncol Biol Phys 53(1):67–74

    Article  PubMed  Google Scholar 

  55. 55.

    Larson DA, Suplica JM, Chang SM, Lamborn KR, McDermott MW, Sneed PK et al (2004) Permanent iodine 125 brachytherapy in patients with progressive or recurrent glioblastoma multiforme. Neuro-oncology 6(2):119–126

    PubMed Central  Article  PubMed  Google Scholar 

  56. 56.

    Chan TA, Weingart JD, Parisi M, Hughes MA, Olivi A, Borzillary S et al (2005) Treatment of recurrent glioblastoma multiforme with GliaSite brachytherapy. Int J Radiat Oncol Biol Phys 62(4):1133–1139

    Article  PubMed  Google Scholar 

  57. 57.

    Gabayan AJ, Green SB, Sanan A, Jenrette J, Schultz C, Papagikos M et al (2006) GliaSite brachytherapy for treatment of recurrent malignant gliomas: a retrospective multi-institutional analysis. Neurosurgery 58(4):701–709

    Article  PubMed  Google Scholar 

  58. 58.

    Darakchiev BJ, Albright RE, Breneman JC, Warnick RE (2008) Safety and efficacy of permanent iodine-125 seed implants and carmustine wafers in patients with recurrent glioblastoma multiforme. J Neurosurg 108(2):236–242

    Article  PubMed  Google Scholar 

  59. 59.

    Lebioda A, Zyromska A, Makarewicz R, Furtak J (2008) Tumour surface area as a prognostic factor in primary and recurrent glioblastoma irradiated with 192Ir implantation. Rep Pract Oncol Radiother 13(1):15–22

    Article  Google Scholar 

  60. 60.

    Fabrini MG, Perrone F, De Franco L, Pasqualetti F, Grespi S, Vannozzi R et al (2009) Perioperative high-dose-rate brachytherapy in the treatment of recurrent malignant gliomas. Strahlenther Onkol 185(8):524–966

    Article  PubMed  Google Scholar 

  61. 61.

    Kickingereder P, Hamisch C, Suchorska B, Galldiks N, Visser-Vandewalle V, Goldbrunner R et al (2014) Low-dose rate stereotactic iodine-125 brachytherapy for the treatment of inoperable primary and recurrent glioblastoma: single-center experience with 201 cases. J Neuro-Oncol 120(3):615–623

    CAS  Article  Google Scholar 

  62. 62.

    Archavlis E, Tselis N, Birn G, Ulrich P, Zamboglou N (2014) Salvage therapy for recurrent glioblastoma multiforme: a multimodal approach combining fluorescence-guided resurgery, interstitial irradiation, and chemotherapy. Neurol Res 36(12):1047–1055

    CAS  Article  PubMed  Google Scholar 

  63. 63.

    Schwartz C et al (2015) Outcome and toxicity profile of salvage low-dose-rate iodine-125 stereotactic brachytherapy in recurrent high-grade gliomas. Acta Neurochir 157(10):1757–1764

    Article  PubMed  Google Scholar 

  64. 64.

    Shi W, Scannell Bryan M, Gilbert MR, Mehta MP, Blumenthal DT, Brown PD et al (2018) Investigating the effect of reirradiation or systemic therapy in patients with glioblastoma after tumor progression: a secondary analysis of NRG oncology/radiation therapy oncology group trial 0525. Int J Radiat Oncol Biol Phys 100(1):38–44

    Article  PubMed  Google Scholar 

  65. 65.

    van Linde ME et al (2017) Treatment outcome of patients with recurrent glioblastoma multiforme: a retrospective multicenter analysis. J Neuro-Oncol 135(1):183–192

    Article  CAS  Google Scholar 

  66. 66.

    Stupp R et al (2010) High-grade malignant glioma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 21(suppl_5):v190–v193

    Article  PubMed  Google Scholar 

  67. 67.

    Stupp R, Wong ET, Kanner AA et al (2012) NovoTTF-100A versus physician’s choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality. Eur J Cancer 48:2192–2202

    Article  PubMed  Google Scholar 

  68. 68.

    Galle JO et al (2015) Reirradiation with proton therapy for recurrent gliomas. Int J Part Ther 2(1):11–18

    Article  Google Scholar 

  69. 69.

    Scoccianti S et al (2018) Re-irradiation as salvage treatment in recurrent glioblastoma: a comprehensive literature review to provide practical answers to frequently asked questions. Crit Rev Oncol Hematol 126:80–91

    Article  Google Scholar 

  70. 70.

    Cabrera AR et al (2016) Radiation therapy for glioblastoma: executive summary of an American society for radiation oncology evidence-based clinical practice guideline. Pract Radiat Oncol 6(4):217–225

    Article  PubMed  Google Scholar 

  71. 71.

    Azoulay M et al (2017) Benefit of re-operation and salvage therapies for recurrent glioblastoma multiforme: results from a single institution. J Neuro-Oncol 132(3):419–426

    CAS  Article  Google Scholar 

  72. 72.

    Wann A et al (2018) Outcomes after second surgery for recurrent glioblastoma: a retrospective case–control study. J Neuro-Oncol 137(2):409–415

    Article  Google Scholar 

  73. 73.

    Wen PY et al (2010) Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 28(11):1963–1972

    Article  PubMed  Google Scholar 

  74. 74.

    Martínez-Carrillo M, Tovar-Martín I, Zurita-Herrera M, Del Moral-Ávila R, Guerrero-Tejada R, Saura-Rojas E, Osorio-Ceballos JL, Arrebola-Moreno JP, Expósito-Hernández J (2014) Salvage radiosurgery for selected patients with recurrent malignant gliomas. BioMed Res Int 2014:1–10

    Article  Google Scholar 

  75. 75.

    Henke G, Paulsen F, Steinbach JP, Ganswindt U, Isijanov H, Kortmann RD, Bamberg M, Belka C (2009) Hypofractionated reirradiation for recurrent malignant glioma. Strahlentherapie und Onkologie: Organ der Deutschen Rontgengesellschaft [et al] 185(2):113–119. https://doi.org/10.1007/s00066-009-1969-9

    Article  Google Scholar 

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Acknowledgements

We thank Senior Librarian (National University of Singapore, Medical Library), Ms Annelissa Chin, for assisting with the literature review and search strategy.

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Correspondence to Balamurugan Vellayappan.

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Kazmi, F., Soon, Y.Y., Leong, Y.H. et al. Re-irradiation for recurrent glioblastoma (GBM): a systematic review and meta-analysis. J Neurooncol 142, 79–90 (2019). https://doi.org/10.1007/s11060-018-03064-0

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Keywords

  • Recurrence
  • Glioblastoma multiforme
  • Re-irradiation
  • Stereotactic radiosurgery
  • Brachytherapy