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High-dose salvage re-irradiation for recurrent/progressive adult diffuse glioma: healing or hurting?

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Abstract

Purpose

To report survival outcomes and identify prognostic factors of salvage re-irradiation (re-RT) in recurrent/progressive glioma.

Methods

Medical records of patients treated with high-dose re-RT as part of multi-modality salvage therapy for recurrence/progression of adult diffuse glioma from 2010 to 2019 were analyzed retrospectively.

Results

A total of 111 patients developing recurrent/progressive high-grade glioma after adequate upfront treatment at initial diagnosis were included. The first course of radiotherapy (RT) had been delivered to a median dose of 59.4 Gy with an inter-quartile range (IQR) of 54-60 Gy. Median time to recurrence/progression was 4.3 years (IQR = 2.3–7.4 years) while the median time to re-RT was 4.8 years (IQR = 3.6–7.9 years). Re-RT was delivered with intensity-modulated radiation therapy (IMRT) using 1.8 Gy/fraction to a median dose of 54 Gy (IQR = 50.4–55.8 Gy) for a cumulative median equivalent dose in 2-Gy fractions (EQD2) of 104.3 Gy (IQR = 102.6–109.4 Gy). At a median follow-up of 14 months after re-RT, the 1-year Kaplan–Meier estimates of post-re-RT progression-free survival (PFS) and overall survival (OS) were 42.8 and 61.8%, respectively. Univariate analysis identified histological grade at recurrence/progression; histological subtype; disease-free interval (DFI) and time interval between both courses of RT; performance status at re-RT; dose at re-RT and cumulative EQD2; isocitrate dehydrogenase (IDH) mutation; and O6-methyl-guanine DNA methyl transferase (MGMT) gene promoter methylation as significant prognostic factors. Preserved performance status, longer DFI, prolonged time interval between both courses of RT, and presence of IDH mutation were associated with significantly improved PFS on multi-variate analysis. However, only performance status retained independent prognostic significance for OS on multi-variate analysis. Post-treatment changes were seen in 33 (30%) patients on follow-up imaging, with higher cumulative dose (EQD2 ≥ 104.3 Gy) being associated with increased risk of post-re-RT pseudo-progression.

Conclusion

This clinical audit reports encouraging survival outcomes and identifies key prognostic factors associated with high-dose salvage re-RT in recurrent/progressive glioma.

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References

  1. Ostrom QT, Cioffi G, Gittleman H, Patil N, Waite K, Kruchko C, et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2012–2016. Neuro Oncol. 2019;21:v1-100. https://doi.org/10.1093/neuonc/noz150.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007;114:97–109. https://doi.org/10.1007/s00401-007-0243-4.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Berrocal A, Gil M, Gallego O, Balana C, Segura PP, Garcia-Mata J, et al. SEOM guideline for the treatment of malignant glioma. Clin Transl Oncol. 2012;14:545–50. https://doi.org/10.1007/s12094-012-0839-6.

    Article  CAS  PubMed  Google Scholar 

  4. Stupp R, Brada M, van den Bent MJ, Tonn JC, Pentheroudakis G. High-grade glioma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25:93–101. https://doi.org/10.1093/annonc/mdu050.

    Article  Google Scholar 

  5. Kirkpatrick JP, Sampson JH. Recurrent Malignant Gliomas. Semin Radiat Oncol. 2014;24:289–98. https://doi.org/10.1016/j.semradonc.2014.06.006.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Niyazi M, Siefert A, Schwarz SB, Ganswindt U, Kreth F-W, Tonn J-C, et al. Therapeutic options for recurrent malignant glioma. Radiother Oncol. 2011;98:1–14. https://doi.org/10.1016/j.radonc.2010.11.006.

    Article  PubMed  Google Scholar 

  7. Birk HS, Han SJ, Butowski NA. Treatment options for recurrent high-grade gliomas. CNS Oncol. 2017;6:61–70. https://doi.org/10.2217/cns-2016-0013.

    Article  CAS  PubMed  Google Scholar 

  8. Lee J, Cho J, Chang JH, Suh CO. Re-Irradiation for recurrent gliomas: treatment outcomes and prognostic factors. Yonsei Med J. 2016;57(4):824–30. https://doi.org/10.3349/ymj.2016.57.4.824.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Klobukowski L, Falkov A, Chelimo C, Fogh SE. A retrospective review of re-irradiating patients’ recurrent high-grade gliomas. Clin Oncol. 2018;30(9):563–70. https://doi.org/10.1016/j.clon.2018.05.004.

    Article  CAS  Google Scholar 

  10. Maitre P, Gupta T, Maitre M, Goda J, Krishnatry R, Chatterjee A, et al. Prospective longitudinal assessment of quality of life and activities of daily living as patient-reported outcome measures in recurrent/rogressive glioma treated with high-dose salvage re-irradiation. Clin Oncol. 2020. https://doi.org/10.1016/j.clon.2020.08.011.

    Article  Google Scholar 

  11. Yeole U, Arimappamagan A. Role of surgery in recurrent high-grade glioma: current evidence. Int J Neurooncol. 2020;3:1–7. https://doi.org/10.4103/IJNO.IJNO_7_20.

    Article  Google Scholar 

  12. Palmer JD, Siglin J, Yamoah K, Dan T, Champ CE, Bar-Ad V, et al. Re-resection for recurrent high-grade glioma in the setting of re-irradiation: more is not always better. J Neurooncol. 2015;124(2):215–21. https://doi.org/10.1007/s11060-015-1825-y.

    Article  CAS  PubMed  Google Scholar 

  13. Wei W, Chen X, Ma X, Wang D, Guo Z. The efficacy and safety of various dose-dense regimens of temozolomide for recurrent high-grade glioma: systematic review and meta-analysis. J Neurooncol. 2015;125(2):339–49. https://doi.org/10.1007/s11060-015-1920-0.

    Article  CAS  PubMed  Google Scholar 

  14. Shi W, Scannell Bryan M, Gilbert MR, Mehta MP, Blumenthal DT, Brown PD, et al. 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. 2018;100:38–44. https://doi.org/10.1016/j.ijrobp.2017.08.038.

    Article  Google Scholar 

  15. Shanker M, Chua B, Bettington C, Foote MC, Pinkham MB. Re-irradiation for recurrent high-grade gliomas: a systematic review and analysis of treatment technique with respect to survival and risk of radionecrosis. Neuro-Oncology Pract. 2019;6:144–55. https://doi.org/10.1093/nop/npy019.

    Article  Google Scholar 

  16. Kazmi F, Soon YY, Leong YH, Koh WY, Vellayappan B. Re-irradiation for recurrent glioblastoma (GBM): a systematic review and meta-analysis. J Neurooncol. 2019;142:79–90. https://doi.org/10.1007/s11060-018-03064-0.

    Article  CAS  PubMed  Google Scholar 

  17. Ruifrok AC, van der Kogel AJ. A “reappraisal” of the LQ model for the understanding of dose-fractionation in radiotherapy. Int J Radiat Oncol Biol Phys. 1993;25:926–9. https://doi.org/10.1016/0360-3016(93)90328-s.

    Article  CAS  PubMed  Google Scholar 

  18. Krauze AV, Attia A, Braunstein S, Chan M, Combs SE, Fietkau R, et al. Expert consensus on re-irradiation for recurrent glioma. Radiat Oncol. 2017;12:194. https://doi.org/10.1186/s13014-017-0928-3.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Shen CJ, Kummerlowe MN, Redmond KJ, Martinez-Gutierrez JC, Usama SM, Holdhoff M, et al. Re-irradiation for malignant glioma: Toward patient selection and defining treatment parameters for salvage. Adv Radiat Oncol. 2018;3:582–90. https://doi.org/10.1016/j.adro.2018.06.005.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Arvold ND, Shi DD, Aizer AA, Norden AD, Reardon DA, Lee EQ, et al. Salvage re-irradiation for recurrent high-grade glioma and comparison to bevacizumab alone. J Neurooncol. 2017;135:581–91. https://doi.org/10.1007/s11060-017-2611-9.

    Article  CAS  PubMed  Google Scholar 

  21. Hundsberger T, Brugge D, Putora PM, Weder P, Weber J, Plasswilm L. Re-irradiation with and without bevacizumab as salvage therapy for recurrent or progressive high-grade gliomas. J Neurooncol. 2013;112(1):133–9. https://doi.org/10.1007/s11060-013-1044-3.

    Article  CAS  PubMed  Google Scholar 

  22. Palmer JD, Bhamidipati D, Song A, Eldredge-Hindy HB, Siglin J, Dan TD, et al. Bevacizumab and re-irradiation for recurrent high grade gliomas: does sequence matter? J Neurooncol. 2018;140:623–8. https://doi.org/10.1007/s11060-018-2989-z.

    Article  CAS  PubMed  Google Scholar 

  23. Schernberg A, Dhermain F, Ammari S, Dumont SN, Domont J, Patrikidou A, et al. Reirradiation with concurrent bevacizumab for recurrent high-grade gliomas in adult patients. Cancer. 2018;22:9–16. https://doi.org/10.1016/j.canrad.2017.06.013.

    Article  CAS  Google Scholar 

  24. Bergman D, Modh A, Schultz L, Snyder J, Mikkelsen T, Shah M, et al. Randomized prospective trial of fractionated stereotactic radiosurgery with chemotherapy versus chemotherapy alone for bevacizumab-resistant high-grade glioma. J Neurooncol. 2020;148:353–61. https://doi.org/10.1007/s11060-020-03526-4.

    Article  CAS  PubMed  Google Scholar 

  25. Tsien C, Pugh S, Dicker AP, Raizer JJ, Matuszak MM, Lallana E, et al. Randomized phase ii trial of re-irradiation and concurrent bevacizumab versus bevacizumab alone as treatment for recurrent glioblastoma (NRG Oncology/RTOG 1205): initial outcomes and RT plan quality report. Int J Radiat Oncol Biol Phys. 2019;105:S78. https://doi.org/10.1016/j.ijrobp.2019.06.539.

    Article  Google Scholar 

  26. Fleischmann DF, Jenn J, Corradini S, Ruf V, Herms J, Forbrig R, et al. Bevacizumab reduces toxicity of reirradiation in recurrent high-grade glioma. Radiother Oncol. 2019;138:99–105. https://doi.org/10.1016/j.radonc.2019.06.009.

    Article  CAS  PubMed  Google Scholar 

  27. Balana C, Etxaniz O, Buges C, Martinez A. Approval denided by European Medicines Agency (EMA) for bevacizumab in the treatment of high-grade glioma recurrence: a good idea or a grave error. Clin Transl Oncol. 2011;13:209. https://doi.org/10.1007/s12094-011-0642-9.

    Article  PubMed  Google Scholar 

  28. Back M, Gzell CE, Kastelan M, Guo L, Wheeler HR. Large volume re-irradiation with bevacizumab is a feasible salvage option for patients with refractory high-grade glioma. Neuro-Oncology Pract. 2015;2:48–53. https://doi.org/10.1093/nop/npu031.

    Article  Google Scholar 

  29. Combs SE, Edler L, Rausch R, Welzel T, Wick W, Debus J. Generation and validation of a prognostic score to predict outcome after re-irradiation of recurrent glioma. Acta Oncol. 2013;52:147–52. https://doi.org/10.3109/0284186X.2012.692882.

    Article  PubMed  Google Scholar 

  30. Kessel KA, Hesse J, Straube C, Zimmer C, Schmidt-Graf F, Schlegel J, et al. Validation of an established prognostic score after re-irradiation of recurrent glioma. Acta Oncol (Madr). 2017;56:422–6. https://doi.org/10.1080/0284186X.2016.1276621.

    Article  Google Scholar 

  31. Krauze AV, Peters C, Cheng J, Ning H, Mackey M, Rowe L, et al. Re-irradiation for recurrent glioma—the NCI experience in tumor control, OAR toxicity and proposal of a novel prognostic scoring system. Radiat Oncol. 2017;12:1–10. https://doi.org/10.1186/s13014-017-0930-9.

    Article  Google Scholar 

  32. Niyazi M, Adeberg S, Kaul D, Boulesteix AL, Bougatf N, Fleischmann DF, et al. Independent validation of a new reirradiation risk score (RRRS) for glioma patients predicting post-recurrence survival: a multicenter DKTK/ROG analysis. Radiother Oncol. 2018;127:121–7. https://doi.org/10.1016/j.radonc.2018.01.011.

    Article  PubMed  Google Scholar 

  33. Chapman CH, Hara JH, Molinaro AM, Clarke JL, Oberheim Bush NA, Taylor JW, et al. Reirradiation of recurrent high-grade glioma and development of prognostic scores for progression and survival. Neuro-Oncology Pract. 2019. https://doi.org/10.1093/nop/npz017.

    Article  Google Scholar 

  34. Molinaro AM, Taylor JW, Wiencke JK, Wrensch MR. Genetic and molecular epidemiology of adult diffuse glioma. Nat Rev Neurol. 2019;15:405–17. https://doi.org/10.1038/s41582-019-0220-2.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Delga-Lopez PD, Saiz-Lopez P, Gargini R, Sola-Vendrell E, Tejada S. A comprehensive overview of the molecular biology of humar glioma: what the clinician needs to know. Clin Transl Oncol. 2020;22:1909–22. https://doi.org/10.1007/s12094-020-02340-8.

    Article  Google Scholar 

  36. 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;2:1–15. https://doi.org/10.1186/2051-5960-2-68.

    Article  Google Scholar 

  37. Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, et al. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol. 2010;28(11):1963–72. https://doi.org/10.1200/JCO.2009.26.3541.

    Article  PubMed  Google Scholar 

  38. Mayer R, Sminia P. Re-irradiation tolerance of the human brain. Int J Radiat Oncol Biol Phys. 2008;70(5):1350–60. https://doi.org/10.1016/j.ijrobp.2007.08.015.

    Article  CAS  PubMed  Google Scholar 

  39. Sminia P, Mayer R. External beam radiotherapy of recurrent glioma: Radiation tolerance of the human brain. Cancers. 2012;4:379–99. https://doi.org/10.3390/cancers4020379.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Ho ALK, Jena R. Re-irradiation in the brain: primary gliomas. Clin Oncol. 2018;30:124–36. https://doi.org/10.1016/j.clon.2017.11.006.

    Article  CAS  Google Scholar 

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Funding

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Authors and Affiliations

  1. Department of Radiation Oncology, Advanced Centre for Treatment Research and Education in Cancer (ACTREC)/Tata Memorial Hospital (TMH), Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Kharghar, Navi Mumbai, 410210, India

    T. Gupta, M. Maitre, P. Maitre, J. S. Goda, R. Krishnatry, A. Chatterjee & R. Jalali

  2. Department of Neuro-Surgical Oncology, Advanced Centre for Treatment Research and Education in Cancer (ACTREC)/Tata Memorial Hospital (TMH), Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Kharghar, Navi Mumbai, 410210, India

    A. Moiyadi & P. Shetty

  3. Department of Pathology, Advanced Centre for Treatment Research and Education in Cancer (ACTREC)/Tata Memorial Hospital (TMH), Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Kharghar, Navi Mumbai, 410210, India

    S. Epari & A. Sahay

  4. Department of Medical Oncology, Advanced Centre for Treatment Research and Education in Cancer (ACTREC)/Tata Memorial Hospital (TMH), Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Kharghar, Navi Mumbai, 410210, India

    V. Patil

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Correspondence to T. Gupta.

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The study was duly reviewed and approved by the Institutional Ethics Committee (IEC) and waiver of consent was granted by IEC owing to the retrospective nature of the study with less than minimal risk to participants.

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Gupta, T., Maitre, M., Maitre, P. et al. High-dose salvage re-irradiation for recurrent/progressive adult diffuse glioma: healing or hurting?. Clin Transl Oncol 23, 1358–1367 (2021). https://doi.org/10.1007/s12094-020-02526-0

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