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Congress of neurological surgeons systematic review and evidence-based guidelines update on the role of chemotherapeutic management and antiangiogenic treatment of newly diagnosed glioblastoma in adults

Journal of Neuro-Oncology volume 150, pages 165–213 (2020)Cite this article

Abstract

Question

What is the role of temozolomide in the management of adult patients (aged 65 and under) with newly diagnosed glioblastoma?

Target population

These recommendations apply to adult patients diagnosed with newly diagnosed glioblastoma.

Recommendation

Level I: Concurrent and post-irradiation Temozolomide (TMZ) in combination with radiotherapy and post-radiotherapy as described by Stupp et al. is recommended to improve both PFS and OS in adult patients with newly diagnosed GBM. There is no evidence that alterations in the dosing regimen have additional beneficial effect.

Question

Is there benefit to adjuvant temozolomide treatment in elderly patients (> 65 years old?).

Target population

These recommendations apply to adult patients diagnosed with newly diagnosed glioblastoma.

Recommendation

Level III: Adjuvant TMZ treatment is suggested as a treatment option to improve PFS and OS in adult patients (over 70 years of age) with newly diagnosed GBM.

Question

What is the role of local regional chemotherapy with BCNU biodegradable polymeric wafers in adult patients with newly diagnosed glioblastoma?

Target population

These recommendations apply to adult patients diagnosed with newly diagnosed glioblastoma.

Recommendation

Level III: There is insufficient evidence for the use of BCNU wafers following resection in patients with newly diagnosed glioblastoma who undergo the Stupp protocol after surgery. Further studies of higher quality are suggested to understand the role of BCNU wafer and other locoregional therapy in the setting of Stupp Protocol.

Question

What is the role of bevacizumab in the adult patient with newly diagnosed glioblastoma?

Target population

These recommendations apply to adult patients diagnosed with newly diagnosed glioblastoma.

Recommendation

Level I: Bevacizumab in general is not recommended in the initial treatment of adult patients with newly diagnosed GBM. It continues to be strongly recommended that patients with newly diagnosed GBM be enrolled in properly designed clinical trials to assess the benefit of novel chemotherapeutic agents compared to standard therapy.

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References

  1. Fadul CE, Wen PY, Kim L, Olson JJ (2008) Cytotoxic chemotherapeutic management of newly diagnosed glioblastoma multiforme. J Neurooncol 89:339–357. https://doi.org/10.1007/s11060-008-9615-4

    CAS  Article  PubMed  Google Scholar 

  2. Stupp R, Mason WP, van den Bent MJ et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996. https://doi.org/10.1056/NEJMoa043330

    CAS  Article  Google Scholar 

  3. Karacetin D, Okten B, Yalcin B, Incekara O (2011) Concomitant temozolomide and radiotherapy versus radiotherapy alone for treatment of newly diagnosed glioblastoma multiforme. J BUON 16:133–137

    CAS  PubMed  Google Scholar 

  4. Park CK, Lee SH, Kim TM et al (2013) The value of temozolomide in combination with radiotherapy during standard treatment for newly diagnosed glioblastoma. J Neurooncol 112:277–283. https://doi.org/10.1007/s11060-013-1060-3

    CAS  Article  PubMed  Google Scholar 

  5. Barbagallo GMV, Paratore S, Caltabiano R et al (2014) Long-term therapy with temozolomide is a feasible option for newly diagnosed glioblastoma: a single-institution experience with as many as 101 temozolomide cycles. Neurosurg Focus 37:E4. https://doi.org/10.3171/2014.9.FOCUS14502

    Article  PubMed  Google Scholar 

  6. Gilbert MR, Wang M, Aldape KD et al (2013) Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol 31:4085–4091. https://doi.org/10.1200/JCO.2013.49.6968

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. Pérez-Larraya JG, Ducray F, Chinot O et al (2011) Temozolomide in elderly patients with newly diagnosed glioblastoma and poor performance status: an ANOCEF phase II trial. J Clin Oncol 29:3050–3055. https://doi.org/10.1200/JCO.2011.34.8086

    CAS  Article  Google Scholar 

  8. Gilbert MR, Dignam JJ, Armstrong TSTS et al (2014) A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 370:699–708. https://doi.org/10.1056/NEJMoa1308573

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. Weiler M, Hartmann C, Wiewrodt D et al (2010) Chemoradiotherapy of newly diagnosed glioblastoma with intensified temozolomide. Int J Radiat Oncol Biol Phys 77:670–676. https://doi.org/10.1016/j.ijrobp.2009.05.031

    CAS  Article  PubMed  Google Scholar 

  10. Behm T, Horowski A, Schneider S et al (2013) Concomitant and adjuvant temozolomide of newly diagnosed glioblastoma in elderly patients. Clin Neurol Neurosurg 115:2142–2146. https://doi.org/10.1016/j.clineuro.2013.08.002

    Article  PubMed  Google Scholar 

  11. Brandes AA, Vastola F, Basso U et al (2003) A prospective study on glioblastoma in the elderly. Cancer 97:657–662. https://doi.org/10.1002/cncr.11097

    Article  PubMed  Google Scholar 

  12. Glantz M, Chamberlain M, Liu Q et al (2003) Temozolomide as an alternative to irradiation for elderly patients with newly diagnosed malignant gliomas. Cancer 97:2262–2266. https://doi.org/10.1002/cncr.11323

    CAS  Article  PubMed  Google Scholar 

  13. Chinot OL, Barrle M, Frauger E et al (2004) Phase II study of temozolomide without radiotherapy in newly diagnosed glioblastoma multiforme in an elderly populations. Cancer 100:2208–2214. https://doi.org/10.1002/cncr.20224

    CAS  Article  PubMed  Google Scholar 

  14. Keime-Guibert F, Chinot O, Taillandier L et al (2007) Radiotherapy for glioblastoma in the elderly. N Engl J Med 356:1527–1535. https://doi.org/10.1056/NEJMoa065901

    CAS  Article  PubMed  Google Scholar 

  15. Han SJ, Rutledge WC, Molinaro AM et al (2015) The effect of timing of concurrent chemoradiation in patients with newly diagnosed glioblastoma. Neurosurgery 77:248–253. https://doi.org/10.1227/NEU.0000000000000766

    Article  PubMed  PubMed Central  Google Scholar 

  16. Sun MZ, Oh T, Ivan ME et al (2015) Survival impact of time to initiation of chemoradiotherapy after resection of newly diagnosed glioblastoma. J Neurosurg 122:1144–1150. https://doi.org/10.3171/2014.9.JNS14193

    Article  PubMed  Google Scholar 

  17. Blumenthal DT, Won M, Mehta MP et al (2009) Short delay in initiation of radiotherapy may not affect outcome of patients with glioblastoma: a secondary analysis from the radiation therapy oncology group database. J Clin Oncol 27:733–739. https://doi.org/10.1200/jco.2008.18.9035

    Article  PubMed  Google Scholar 

  18. Seidlitz A, Siepmann T, Löck S et al (2015) Impact of waiting time after surgery and overall time of postoperative radiochemotherapy on treatment outcome in glioblastoma multiforme. Radiat Oncol 10:172. https://doi.org/10.1186/s13014-015-0478-5

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. Noel G, Huchet A, Feuvret L et al (2012) Waiting times before initiation of radiotherapy might not affect outcomes for patients with glioblastoma: a French retrospective analysis of patients treated in the era of concomitant temozolomide and radiotherapy. J Neurooncol 109:167–175. https://doi.org/10.1007/s11060-012-0883-7

    Article  PubMed  Google Scholar 

  20. Bhandari M, Gandhi AK, Devnani B, et al (2017) Comparative study of adjuvant temozolomide six cycles versus extended 12 cycles in newly diagnosed glioblastoma multiforme. J Clin Diagn Res 11:XC04–XC08. https://doi.org/10.7860/JCDR/2017/27611.9945

  21. Roldán Urgoiti GB, Singh AD, Easaw JC (2012) Extended adjuvant temozolomide for treatment of newly diagnosed glioblastoma multiforme. J Neurooncol 108:173–177. https://doi.org/10.1007/s11060-012-0826-3

    CAS  Article  PubMed  Google Scholar 

  22. Blumenthal DT, Gorlia T, Gilbert MR et al (2017) Is more better? The impact of extended adjuvant temozolomide in newly diagnosed glioblastoma: a secondary analysis of EORTC and NRG Oncology/RTOG. Neuro Oncol 19:1119–1126. https://doi.org/10.1093/neuonc/nox025

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. Skardelly M, Dangel E, Gohde J et al (2017) Prolonged temozolomide maintenance therapy in newly diagnosed glioblastoma. Oncologist 22:570–575. https://doi.org/10.1634/theoncologist.2016-0347

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. Gramatzki D, Kickingereder P, Hentschel B et al (2017) Limited role for extended maintenance temozolomide for newly diagnosed glioblastoma. Neurology 88:1422–1430. https://doi.org/10.1212/WNL.0000000000003809

    CAS  Article  PubMed  Google Scholar 

  25. Clarke JL, Iwamoto FM, Sul J et al (2009) Randomized phase II trial of chemoradiotherapy followed by either dose-dense or metronomic temozolomide for newly diagnosed glioblastoma. J Clin Oncol 27:3861–3867. https://doi.org/10.1200/JCO.2008.20.7944

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. Sher DJ, Henson JW, Avutu B et al (2008) The added value of concurrently administered temozolomide versus adjuvant temozolomide alone in newly diagnosed glioblastoma. J Neurooncol 88:43–50. https://doi.org/10.1007/s11060-008-9530-8

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. Lou AM, Heery CR, Herndon JE et al (2009) Overall survival of newly diagnosed glioblastoma patients receiving carmustine wafers followed by radiation and concurrent temozolomide plus rotational multiagent chemotherapy. Cancer 115:3501–3511. https://doi.org/10.1002/cncr.24398

    CAS  Article  Google Scholar 

  28. De Bonis P, Anile C, Pompucci A et al (2012) Safety and efficacy of gliadel wafers for newly diagnosed and recurrent glioblastoma. Acta Neurochir (Wien) 154:1371–1378. https://doi.org/10.1007/s00701-012-1413-2

    Article  Google Scholar 

  29. Salmaggi A, Milanesi I, Silvani A et al (2013) Prospective study of carmustine wafers in combination with 6-month metronomic temozolomide and radiation therapy in newly diagnosed glioblastoma: preliminary results. J Neurosurg 118:821–829. https://doi.org/10.3171/2012.12.JNS111893

    CAS  Article  PubMed  Google Scholar 

  30. Chaichana KL, Zaidi H, Pendleton C et al (2011) The efficacy of carmustine wafers for older patients with glioblastoma multiforme: prolonging survival. Neurol Res 33:759–764. https://doi.org/10.1179/1743132811Y.0000000006

    Article  PubMed  PubMed Central  Google Scholar 

  31. Noël G, Schott R, Froelich S et al (2012) Retrospective comparison of chemoradiotherapy followed by adjuvant chemotherapy, with or without prior Gliadel implantation (Carmustine) after initial surgery in patients with newly diagnosed high-grade gliomas. Int J Radiat Oncol Biol Phys 82:749–755. https://doi.org/10.1016/j.ijrobp.2010.11.073

    Article  PubMed  Google Scholar 

  32. Akiyama Y, Kimura Y, Enatsu R et al (2018) Advantages and disadvantages of combined chemotherapy with carmustine wafer and bevacizumab in patients with newly diagnosed glioblastoma: a single-institutional experience. World Neurosurg 113:e508–e514. https://doi.org/10.1016/j.wneu.2018.02.070

    Article  PubMed  Google Scholar 

  33. Roux A, Peeters S, Zanello M et al (2017) Extent of resection and Carmustine wafer implantation safely improve survival in patients with a newly diagnosed glioblastoma: a single center experience of the current practice. J Neurooncol 135:83–92. https://doi.org/10.1007/s11060-017-2551-4

    Article  PubMed  Google Scholar 

  34. Westphal M, Hilt DC, Bortey E et al (2003) A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neuro Oncol 5:79–88. https://doi.org/10.1215/S1522-8517-02-00023-6

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. Valtonen S, Timonen U, Toivanen P, et al (1997) Interstitial chemotherapy with carmustine-loaded polymers for high-grade gliomas: a randomized double-blind study. Neurosurgery 41:44–8; discussion 48–9

  36. Chinot OL, Wick W, Mason W et al (2014) Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med 370:709–722. https://doi.org/10.1056/NEJMoa1308345

    CAS  Article  PubMed  Google Scholar 

  37. Carlson JA, Reddy K, Gaspar LE et al (2015) Hypofractionated-intensity modulated radiotherapy (hypo-IMRT) and temozolomide (TMZ) with or without bevacizumab (BEV) for newly diagnosed glioblastoma multiforme (GBM): a comparison of two prospective phase II trials. J Neurooncol 123:251–257. https://doi.org/10.1007/s11060-015-1791-4

    CAS  Article  PubMed  Google Scholar 

  38. Lai A, Filka E, McGibbon B et al (2008) Phase II pilot study of bevacizumab in combination with temozolomide and regional radiation therapy for up-front treatment of patients with newly diagnosed glioblastoma multiforme: interim analysis of safety and tolerability. Int J Radiat Oncol Biol Phys 71:1372–1380. https://doi.org/10.1016/j.ijrobp.2007.11.068

    CAS  Article  PubMed  Google Scholar 

  39. Lai A, Tran A, Nghiemphu PL et al (2011) Phase II study of bevacizumab plus temozolomide during and after radiation therapy for patients with newly diagnosed glioblastoma multiforme. J Clin Oncol 29:142–148. https://doi.org/10.1200/JCO.2010.30.2729

    CAS  Article  PubMed  Google Scholar 

  40. Van Linde ME, Verhoeff JJ, Richel DJ et al (2015) Bevacizumab in combination with radiotherapy and temozolomide for patientswith newly diagnosed glioblastomamultiforme. Oncologist 20:107–108. https://doi.org/10.1634/theoncologist.2014-0418

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. Narayana A, Gruber D, Kunnakkat S et al (2012) A clinical trial of bevacizumab, temozolomide, and radiation for newly diagnosed glioblastoma. J Neurosurg 116:341–345. https://doi.org/10.3171/2011.9.JNS11656

    CAS  Article  PubMed  Google Scholar 

  42. Omuro A, Beal K, Gutin P et al (2014) Phase II study of bevacizumab, temozolomide, and hypofractionated stereotactic radiotherapy for newly diagnosed glioblastoma. Clin Cancer Res 20:5023–5031. https://doi.org/10.1158/1078-0432.CCR-14-0822

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. Vredenburgh JJ, Desjardins A, Reardon DA et al (2011) The addition of bevacizumab to standard radiation therapy and temozolomide followed by bevacizumab, temozolomide, and irinotecan for newly diagnosed glioblastoma. Clin Cancer Res 17:4119–4124. https://doi.org/10.1158/1078-0432.CCR-11-0120

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. Reyes-Botero G, Cartalat-Carel S, Chinot OL et al (2018) Temozolomide plus bevacizumab in elderly patients with newly diagnosed glioblastoma and poor performance status: an ANOCEF phase II trial (ATAG). Oncologist 23:524–e44. https://doi.org/10.1634/theoncologist.2017-0689

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. Hata N, Yoshimoto K, Hatae R et al (2017) Add-on bevacizumab can prevent early clinical deterioration and prolong survival in newly diagnosed partially resected glioblastoma patients with a poor performance status. Onco Targets Ther 10:429–437. https://doi.org/10.2147/OTT.S125587

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. Hofland KF, Hansen S, Sorensen M et al (2014) Neoadjuvant bevacizumab and irinotecan versus bevacizumab and temozolomide followed by concomitant chemoradiotherapy in newly diagnosed glioblastoma multiforme: a randomized phase II study. Acta Oncol (Madr). https://doi.org/10.3109/0284186X.2013.879607

    Article  Google Scholar 

  47. Jaeckle KA, Ballman KV, Giannini C et al (2010) Phase II NCCTG trial of RT + irinotecan and adjuvant BCNU plus irinotecan for newly diagnosed GBM. J Neurooncol 99:73–80. https://doi.org/10.1007/s11060-009-0103-2

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. Quinn JA, Jiang SX, Reardon DA et al (2009) Phase II trial of temozolomide (TMZ) plus irinotecan (CPT-11) in adults with newly diagnosed glioblastoma multiforme before radiotherapy. J Neurooncol 95:393–400. https://doi.org/10.1007/s11060-009-9937-x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. Kim IH, Park CK, Heo DS et al (2011) Radiotherapy followed by adjuvant temozolomide with or without neoadjuvant ACNU-CDDP chemotherapy in newly diagnosed glioblastomas: a prospective randomized controlled multicenter phase III trial. J Neurooncol 103:595–602. https://doi.org/10.1007/s11060-010-0427-y

    CAS  Article  PubMed  Google Scholar 

  50. Shibui S, Narita Y, Mizusawa J et al (2013) Randomized trial of chemoradiotherapy and adjuvant chemotherapy with nimustine (ACNU) versus nimustine plus procarbazine for newly diagnosed anaplastic astrocytoma and glioblastoma (JCOG0305). Cancer Chemother Pharmacol 71:511–521. https://doi.org/10.1007/s00280-012-2041-5

    CAS  Article  PubMed  Google Scholar 

  51. Vinjamuri M, Adumala RR, Altaha R et al (2009) Comparative analysis of temozolomide (TMZ) versus 1,3-bis (2-chloroethyl)-1 nitrosourea (BCNU) in newly diagnosed glioblastoma multiforme (GBM) patients. J Neurooncol 91:221–225. https://doi.org/10.1007/s11060-008-9702-6

    CAS  Article  PubMed  Google Scholar 

  52. Wang Y, Chen X, Zhang Z et al (2014) Comparison of the clinical efficacy of temozolomide (TMZ) versus nimustine (ACNU)-based chemotherapy in newly diagnosed glioblastoma. Neurosurg Rev 37:73–78. https://doi.org/10.1007/s10143-013-0490-x

    Article  PubMed  Google Scholar 

  53. Metro G, Fabi A, Mirri MA et al (2010) Phase II study of fixed dose rate gemcitabine as radiosensitizer for newly diagnosed glioblastoma multiforme. Cancer Chemother Pharmacol 65:391–397. https://doi.org/10.1007/s00280-009-1155-x

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

We would like to acknowledge the significant contributions of Mary Bodach, Trish Rehring and the AANS/CNS Joint Guidelines Committee (JGC) for their review, comments and suggestions, as well as Martha Stone and Lisa Philpotts, for their valuable input as Medical Research Librarians. We also acknowledge the following individual peer reviewers their contributions to the development process: John O’Toole, MD, David Bauer, MD, Kimon Bekelis, MD, Andrew Carlson, MD, Isabelle Germano, MD, Catherine McClung Smith, MD, Jonathan Sherman, MD.

Disclaimer of liability

This clinical systematic review and evidence-based guideline was developed by a multidisciplinary physician volunteer task force and serves as an educational tool designed to provide an accurate review of the subject matter covered. These guidelines are disseminated with the understanding that the recommendations by the authors and consultants who have collaborated in their development are not meant to replace the individualized care and treatment advice from a patient's physician(s). If medical advice or assistance is required, the services of a competent physician should be sought. The proposals contained in these guidelines may not be suitable for use in all circumstances. The choice to implement any particular recommendation contained in these guidelines must be made by a managing physician in light of the situation in each particular patient and on the basis of existing resources.

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Author notes

  1. Navid Redjal and Brian V. Nahed have contributed equally as co-first authors.

Affiliations

  1. Department of Neurosurgery, Capital Health Institute for Neurosciences, Capital Health Institute for Neurosciences, Two Capital Way, Pennington, NJ, 08534, USA

    Navid Redjal

  2. Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA

    Brian V. Nahed

  3. Department of Neurology, Massachusetts General Hospital, Boston, MA, USA

    Jorg Dietrich

  4. Department of Neurosurgery, Henry Ford Health System, Detroit, MI, USA

    Steven N. Kalkanis

  5. Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, USA

    Jeffrey J. Olson

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  1. Navid Redjal
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  3. Jorg Dietrich
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  4. Steven N. Kalkanis
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  5. Jeffrey J. Olson
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Corresponding author

Correspondence to Navid Redjal.

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Conflict of interest

The Update on Newly Diagnosed Glioblastoma Task Force members were required to report all possible COIs prior to beginning work on the guideline, using the COI disclosure form of the AANS/CNS Joint Guidelines Committee, including potential COIs that are unrelated to the topic of the guideline. The CNS Guidelines Committee and Guideline Task Force Chair reviewed the disclosures and either approved or disapproved the nomination. The CNS Guidelines Committee and Guideline Task Force Chair are given latitude to approve nominations of Task Force Members with possible conflicts and address this by restricting the writing and reviewing privileges of that person to topics unrelated to the possible COIs.

Author Conflicts
Navid Redjal None
Brian Nahed Research Funding: NIH, American Cancer Society
Co-founder and consultant React Neuro
Jorg Dietrich Consulting: Blue Earth Diagnostics, Unum Therapeutics
Royalties: Wolters Kluwer
Jeffrey J. Olson American Cancer Society, Editorial Consultant

Disclosures

These guidelines were funded exclusively by the CNS Guidelines Committee and the AANS/CNS Joint Tumor Section Executive Committee with no funding from any outside commercial sources to support the development of this document.

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Redjal, N., Nahed, B.V., Dietrich, J. et al. Congress of neurological surgeons systematic review and evidence-based guidelines update on the role of chemotherapeutic management and antiangiogenic treatment of newly diagnosed glioblastoma in adults. J Neurooncol 150, 165–213 (2020). https://doi.org/10.1007/s11060-020-03601-w

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Keywords

  • GBM
  • Chemotherapy
  • Brain tumors
  • Bevacizumab
  • Temozolomide
  • Gliomas