Glioblastoma

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Section editor
Seema Nagpal, MD
Stanford University
Palo Alto, CA, USA
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For placebo or observational studies in this condition, please visit this page.
Note: pediatric regimens have been moved to a dedicated page:

Last updated on 2024-09-06:
30 regimens on this page
46 variants on this page


Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

ASCO


EANO


ESMO


NCCN


First-line therapy, standard patients

Bevacizumab & RT

Bevacizumab & RT: Bevacizumab & Radiation Therapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Herrlinger et al. 2016 (GLARIUS) 2010-2012 Randomized Phase 2 (E-switch-ooc) Temozolomide & RT, then Temozolomide Superior PFS6 (primary endpoint)

Preceding treatment

Targeted therapy

Radiotherapy

8-week course

Subsequent treatment

References

  1. GLARIUS: Herrlinger U, Schäfer N, Steinbach JP, Weyerbrock A, Hau P, Goldbrunner R, Friedrich F, Rohde V, Ringel F, Schlegel U, Sabel M, Ronellenfitsch MW, Uhl M, Maciaczyk J, Grau S, Schnell O, Hänel M, Krex D, Vajkoczy P, Gerlach R, Kortmann RD, Mehdorn M, Tüttenberg J, Mayer-Steinacker R, Fietkau R, Brehmer S, Mack F, Stuplich M, Kebir S, Kohnen R, Dunkl E, Leutgeb B, Proescholdt M, Pietsch T, Urbach H, Belka C, Stummer W, Glas M. Bevacizumab plus irinotecan versus temozolomide in newly diagnosed O6-methylguanine-DNA methyltransferase nonmethylated glioblastoma: the randomized GLARIUS trial. J Clin Oncol. 2016 May 10;34(14):1611-9. Epub 2016 Mar 14. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00967330


Carmustine & RT

BCNU & RT: BCNU (Carmustine) & Radiation Therapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Eyre et al. 1986 (SWOG S7703) 1977-1981 Phase 3 (E-switch-ic) 1. DTIC & RT Not reported
2. Procarbazine & RT Superior ORR
Dinapoli et al. 1993 1985-1989 Phase 3 (C) PCNU & RT Did not meet co-primary endpoints of TTP50%/OS50%
Buckner et al. 2001 1990-1994 Phase 3 (C) BCNU, IFN alfa, RT Did not meet endpoint of OS50%
Ali et al. 2018 (RTOG 9006) 1990-1994 Phase 3 (C) BCNU & RT; hyperfractionated Did not meet primary endpoint of OS
Buckner et al. 2006 (NCCTG 93-72-52/SWOG S9503) 1994-1999 Phase 3 (C) BCNU, Cisplatin, RT Did not meet primary endpoint of OS50%
Grossman et al. 2003 (ECOG E2394) 1996-1999 Phase 3 (C) BCNU & Cisplatin, then RT Did not meet primary endpoint of OS
Blumenthal et al. 2014 (SWOG S0001) 2001-2005 Phase 3 (C) BCNU, O⁶-benzylguanine, RT Did not meet primary endpoint of OS
Median OS: 10 vs 11 mo
(HR 1.30, 95% CI 0.85-1.96)

Preceding treatment

Chemotherapy

42-day cycle for up to 7 cycles

Radiotherapy

  • External beam radiotherapy 5 days per week for 5040 cGy in 28 fractions, with boost volume treated for an additional 1080 cGy in 6 fractions (cumulative dose of 6120 cGy)

References

  1. BTSG 69-01: Walker MD, Alexander E Jr, Hunt WE, MacCarty CS, Mahaley MS Jr, Mealey J Jr, Norrell HA, Owens G, Ransohoff J, Wilson CB, Gehan EA, Strike TA. Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas: a cooperative clinical trial. J Neurosurg. 1978 Sep;49(3):333-43. link to original article PubMed
  2. BTSG 72-01: Walker MD, Green SB, Byar DP, Alexander E Jr, Batzdorf U, Brooks WH, Hunt WE, MacCarty CS, Mahaley MS Jr, Mealey J Jr, Owens G, Ransohoff J 2nd, Robertson JT, Shapiro WR, Smith KR Jr, Wilson CB, Strike TA. Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N Engl J Med. 1980 Dec 4;303(23):1323-9. link to original article PubMed
  3. SWOG S7703: Eyre HJ, Eltringham JR, Gehan EA, Vogel FS, Al-Sarraf M, Talley RW, Costanzi JJ, Athens JW, Oishi N, Fletcher WS. Randomized comparisons of radiotherapy and carmustine versus procarbazine versus dacarbazine for the treatment of malignant gliomas following surgery: a Southwest Oncology Group Study. Cancer Treat Rep. 1986 Sep;70(9):1085-90. PubMed
  4. Dinapoli RP, Brown LD, Arusell RM, Earle JD, O'Fallon JR, Buckner JC, Scheithauer BW, Krook JE, Tschetter LK, Maier JA, Pfeifle DM, Gesme DH. Phase III comparative evaluation of PCNU and carmustine combined with radiation therapy for high-grade glioma. J Clin Oncol. 1993 Jul;11(7):1316-21. link to original article PubMed
  5. Buckner JC, Schomberg PJ, McGinnis WL, Cascino TL, Scheithauer BW, O'Fallon JR, Morton RF, Kuross SA, Mailliard JA, Hatfield AK, Cole JT, Steen PD, Bernath AM. A phase III study of radiation therapy plus carmustine with or without recombinant interferon-alpha in the treatment of patients with newly diagnosed high-grade glioma. Cancer. 2001 Jul 15;92(2):420-33. link to original article PubMed
  6. ECOG E2394: Grossman SA, O'Neill A, Grunnet M, Mehta M, Pearlman JL, Wagner H, Gilbert M, Newton HB, Hellman R; ECOG. Phase III study comparing three cycles of infusional carmustine and cisplatin followed by radiation therapy with radiation therapy and concurrent carmustine in patients with newly diagnosed supratentorial glioblastoma multiforme: Eastern Cooperative Oncology Group Trial 2394. J Clin Oncol. 2003 Apr 15;21(8):1485-91. link to original article PubMed
  7. NCCTG 93-72-52/SWOG S9503: Buckner JC, Ballman KV, Michalak JC, Burton GV, Cascino TL, Schomberg PJ, Hawkins RB, Scheithauer BW, Sandler HM, Marks RS, O'Fallon JR; North Central Cancer Treatment Group; SWOG. Phase III trial of carmustine and cisplatin compared with carmustine alone and standard radiation therapy or accelerated radiation therapy in patients with glioblastoma multiforme: North Central Cancer Treatment Group 93-72-52 and Southwest Oncology Group 9503 Trials. J Clin Oncol. 2006 Aug 20;24(24):3871-9. link to original article PubMed
  8. SWOG S0001: Blumenthal DT, Rankin C, Stelzer KJ, Spence AM, Sloan AE, Moore DF Jr, Padula GD, Schulman SB, Wade ML, Rushing EJ. A Phase III study of radiation therapy (RT) and O⁶-benzylguanine + BCNU versus RT and BCNU alone and methylation status in newly diagnosed glioblastoma and gliosarcoma: Southwest Oncology Group (SWOG) study S0001. Int J Clin Oncol. 2015 Aug;20(4):650-8. Epub 2014 Nov 19. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00017147
  9. RTOG 9006: Ali AN, Zhang P, Yung WKA, Chen Y, Movsas B, Urtasun RC, Jones CU, Choi KN, Michalski JM, Fischbach AJ, Markoe AM, Schultz CJ, Penas-Prado M, Garg MK, Hartford AC, Kim HE, Won M, Curran WJ Jr. NRG oncology RTOG 9006: a phase III randomized trial of hyperfractionated radiotherapy (RT) and BCNU versus standard RT and BCNU for malignant glioma patients. J Neurooncol. 2018 Mar;137(1):39-47. Epub 2018 Feb 5. link to original article link to PMC article PubMed


Lomustine, Temozolomide, RT

Lomustine, Temozolomide, RT: Lomustine, Temozolomide, Radiation Therapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Herrlinger et al. 2019 (CeTeG/NOA-09) 2011-2014 Phase 3 (E-esc) Temozolomide & RT Might have superior OS (primary endpoint)
Median OS: 48.1 vs 31.4 mo
(HR 0.60, 95% CI 0.35-1.03)

Note: see paper for dose adjustments to temozolomide after cycle 1.

Preceding treatment

Chemotherapy

42-day cycle for up to 6 cycles

Radiotherapy

6- to 7-week course

References

  1. CeTeG/NOA-09: Herrlinger U, Tzaridis T, Mack F, Steinbach JP, Schlegel U, Sabel M, Hau P, Kortmann RD, Krex D, Grauer O, Goldbrunner R, Schnell O, Bähr O, Uhl M, Seidel C, Tabatabai G, Kowalski T, Ringel F, Schmidt-Graf F, Suchorska B, Brehmer S, Weyerbrock A, Renovanz M, Bullinger L, Galldiks N, Vajkoczy P, Misch M, Vatter H, Stuplich M, Schäfer N, Kebir S, Weller J, Schaub C, Stummer W, Tonn JC, Simon M, Keil VC, Nelles M, Urbach H, Coenen M, Wick W, Weller M, Fimmers R, Schmid M, Hattingen E, Pietsch T, Coch C, Glas M; Neurooncology Working Group of the German Cancer Society. Lomustine-temozolomide combination therapy versus standard temozolomide therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter (CeTeG/NOA-09): a randomised, open-label, phase 3 trial. Lancet. 2019 Feb 16;393(10172):678-688. Epub 2019 Feb 14. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01149109


Nimustine & RT

Nimustine & RT: Nimustine & Radiation Therapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Shibui et al. 2012 (JCOG 0305) 2004-2006 Phase 3 (C) Nimustine, Procarbazine, RT Did not meet primary endpoint of OS
Median OS: 27.4 vs 22.4 mo

Note: this is of historic interest; ACNU is not generally available outside of Japan.

Preceding treatment

Chemotherapy

Radiotherapy

One course

References

  1. JCOG 0305: Shibui S, Narita Y, Mizusawa J, Beppu T, Ogasawara K, Sawamura Y, Kobayashi H, Nishikawa R, Mishima K, Muragaki Y, Maruyama T, Kuratsu J, Nakamura H, Kochi M, Minamida Y, Yamaki T, Kumabe T, Tominaga T, Kayama T, Sakurada K, Nagane M, Kobayashi K, Nakamura H, Ito T, Yazaki T, Sasaki H, Tanaka K, Takahashi H, Asai A, Todo T, Wakabayashi T, Takahashi J, Takano S, Fujimaki T, Sumi M, Miyakita Y, Nakazato Y, Sato A, Fukuda H, Nomura K. 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. 2013 Feb;71(2):511-21. Epub 2012 Dec 11. link to original article dosing details in manuscript have been reviewed by our editors PubMed UMIN C000000108


PCV

PCV: Procarbazine, CCNU (Lomustine), Vincristine

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Levin et al. 2000 1992-1998 Phase 3 (C) DFMO-PCV Did not meet co-primary endpoints of TTP/OS

Chemotherapy

42-day cycle for 7 cycles

References

  1. Levin VA, Uhm JH, Jaeckle KA, Choucair A, Flynn PJ, Yung WKA, Prados MD, Bruner JM, Chang SM, Kyritsis AP, Gleason MJ, Hess KR. Phase III randomized study of postradiotherapy chemotherapy with alpha-difluoromethylornithine-procarbazine, N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosurea, vincristine (DFMO-PCV) versus PCV for glioblastoma multiforme. Clin Cancer Res. 2000 Oct;6(10):3878-84. link to original article PubMed


Radiation therapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Walker et al. 1978 (BTSG 69-01) 1969-1972 Phase 3 (E-esc) 1. Best supportive care Seems to have superior OS
2. Carmustine Might have superior OS
3. Carmustine & RT Did not meet primary endpoint of OS50%
Walker et al. 1980 (BTSG 72-01) 1972-1975 Phase 3 (C) 1. Carmustine & RT
2. Semustine & RT 		Did not meet primary endpoint of OS
3. Semustine Seems to have superior OS
Urtasun et al. 1976 1974 to not reported Randomized (C) Metronidazole & RT Seems to have inferior OS
Stupp et al. 2005 (EORTC 22981/26981; NCIC-CTG CE.3) 2000-2002 Phase 3 (C) Temozolomide & RT, then Temozolomide Inferior OS (primary endpoint)

Adjuvant radiotherapy alone.

Preceding treatment

Radiotherapy

References

  1. Urtasun R, Band P, Chapman JD, Feldstein ML, Mielke B, Fryer C. Radiation and high-dose metronidazole in supratentorial glioblastomas. N Engl J Med. 1976 Jun 17;294(25):1364-7. link to original article PubMed
  2. BTSG 69-01: Walker MD, Alexander E Jr, Hunt WE, MacCarty CS, Mahaley MS Jr, Mealey J Jr, Norrell HA, Owens G, Ransohoff J, Wilson CB, Gehan EA, Strike TA. Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas: a cooperative clinical trial. J Neurosurg. 1978 Sep;49(3):333-43. link to original article PubMed
  3. BTSG 72-01: Walker MD, Green SB, Byar DP, Alexander E Jr, Batzdorf U, Brooks WH, Hunt WE, MacCarty CS, Mahaley MS Jr, Mealey J Jr, Owens G, Ransohoff J 2nd, Robertson JT, Shapiro WR, Smith KR Jr, Wilson CB, Strike TA. Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N Engl J Med. 1980 Dec 4;303(23):1323-9. link to original article PubMed
  4. EORTC 22981/26981; NCIC-CTG CE.3: Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; EORTC Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987-96. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00006353
    1. Biomarker analysis: Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005 Mar 10;352(10):997-1003. link to original article PubMed
    2. Update: Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO; EORTC Brain Tumour and Radiation Oncology Groups; National Cancer Institute of Canada Clinical Trials Group. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009 May;10(5):459-66. Epub 2009 Mar 9. link to original article PubMed


RT, then Carmustine

Regimen variant #1, WBRT

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Shapiro et al. 1989 (BTCG 8001) 1980-1983 Phase 3 (C) 1. Carmustine/Procarbazine & RT Did not meet primary endpoint of OS
2. Carmustine & Hydrea/Procarbazine, VM-26, RT Did not meet primary endpoint of OS

Note: Pulmonary function tests (PFTs) were checked before start of therapy, and then when cumulative dose of Carmustine (BCNU) reaches 800 mg/m2 and 1200 mg/m2.

Preceding treatment

Radiotherapy

  • Whole-brain External beam radiotherapy: 172 cGy (rads) per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33, 36 to 40 (35 fractions for a total dose of 6020 cGy [6020 rads/~1700 rets])

Chemotherapy

  • Carmustine (BCNU) as follows:
    • Cycles 2 up to 19: 80 mg/m2 IV over 30 to 60 minutes once per day on days 1 to 3

7-week course, then 8-week cycle for up to 18 cycles (a maximum cumulative carmustine dose of 1500 mg/m2)


Regimen variant #2, WBRT with cone-down

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Shapiro et al. 1989 (BTCG 8001) 1980-1983 Phase 3 (C) 1. Carmustine/Procarbazine & RT Did not meet primary endpoint of OS
2. Carmustine & Hydrea/Procarbazine, VM-26, RT Did not meet primary endpoint of OS

Note: Pulmonary function tests (PFTs) were checked before start of therapy, and then when cumulative dose of Carmustine (BCNU) reaches 800 mg/m2 and 1200 mg/m2.

Preceding treatment

Radiotherapy

  • Whole-brain External beam radiotherapy, 172 cGy (rads) fractions x 25 fractions, given over 5 weeks for a total dose of 4300 cGy (4300 rads), then coned-down boost of 172 cGy (rads) fractions x 10 fractions, given over 2 weeks for a dose of 1720 cGy (rads), and a total cumulative dose of 6020 cGy (rads)

7-week course, followed by:

Chemotherapy

8-week cycle for up to 18 cycles (a maximum cumulative carmustine dose of 1500 mg/m2)

References

  1. BTCG 8001: Shapiro WR, Green SB, Burger PC, Mahaley MS Jr, Selker RG, VanGilder JC, Robertson JT, Ransohoff J, Mealey J Jr, Strike TA, Pistenmaa DA. Randomized trial of three chemotherapy regimens and two radiotherapy regimens and two radiotherapy regimens in postoperative treatment of malignant glioma: Brain Tumor Cooperative Group Trial 8001. J Neurosurg. 1989 Jul;71(1):1-9. link to original article dosing details in manuscript have been reviewed by our editors PubMed


Temozolomide & RT

Temozolomide & RT: Temozolomide & Radiation Therapy

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Stupp et al. 2002 Not reported Phase 2
Stupp et al. 2005 (EORTC 22981/26981; NCIC-CTG CE.3) 2000-2002 Phase 3 (E-RT-esc) See link See link
Gilbert et al. 2013 (RTOG 0525) 2006-2008 Non-randomized part of phase 3 RCT
Westphal et al. 2015 (OSAG 101-BSA-05) 2007-2010 Phase 3 (C) Temozolomide, Nimotuzumab, RT Did not meet co-primary endpoints of PFS12/PFS
PFS12: 20.3% vs 25.6%
Stupp et al. 2014 (CENTRIC) 2008-2011 Phase 3 (C) Cilengitide, Temozolomide, RT Did not meet primary endpoint of OS
Median OS: 26.3 vs 26.3 mo
(HR 0.98, 95% CI 0.78-1.23)
Kong et al. 2016 (IcmLCBT 301) 2008-2012 Phase 3 (C) Temozolomide & RT with CIK cells Seems to have inferior PFS
Gilbert et al. 2014 (RTOG 0825) 2009-2011 Phase 3 (C) See link See link
Chinot et al. 2014 (AVAglio) 2009-2011 Phase 3 (C) See link See link
Lassman et al. 2022 (INTELLANCE-1) 2015-09-11 to 2018-03-31 Phase 3 (C) Depatuxizumab mafodotin, Temozolomide, RT Did not meet primary endpoint of OS
Median OS: 18.7 vs 18.9 mo
(HR 0.98, 95% CI 0.79-1.22)
Omuro et al. 2022 (CheckMate 498) 2016-2018 Phase 3 (C) Nivolumab & RT Superior OS
Median OS: 14.9 vs 13.4 mo
(HR 0.76, 95% CI 0.63-0.92)
Lim et al. 2022 (CheckMate 548) 2016-2019 Phase 3 (C) Temozolomide, Nivolumab, RT Did not meet co-primary endpoint of PFS
Median PFS: 10.3 vs 10.6 mo
(HR 0.91, 95% CI 0.77-1.11)

Did not meet co-primary endpoint of OS
Median OS: 32.1 vs 28.9 mo
(HR 0.91, 95% CI 0.77-1.11)
Roth et al. 2024 (MIRAGE) 2018-07 to 2020-09 Phase 3 (C) Temozolomide, Marizomib, RT Did not meet primary endpoint of OS
Median OS: 17 vs 16.5 mo
(HR 0.96, 95% CI 0.79-1.16)

Biomarker eligibility criteria

Preceding treatment

Chemotherapy

  • Temozolomide (Temodar) 75 mg/m2 PO or IV once per day, used starting the first day of radiation therapy until the last day of radiation therapy, and no longer than 49 days

Supportive therapy

Radiotherapy

  • Concurrent radiation therapy, 200 cGy fractions x 30 fractions, for a total dose of 6000 cGy, five days per week

6-week course

Subsequent treatment

References

  1. Stupp R, Dietrich PY, Ostermann Kraljevic S, Pica A, Maillard I, Maeder P, Meuli R, Janzer R, Pizzolato G, Miralbell R, Porchet F, Regli L, de Tribolet N, Mirimanoff RO, Leyvraz S. Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide. J Clin Oncol. 2002 Mar 1;20(5):1375-82. link to original article PubMed
  2. EORTC 22981/26981; NCIC-CTG CE.3: Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; EORTC Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987-96. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00006353
    1. Biomarker analysis: Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005 Mar 10;352(10):997-1003. link to original article PubMed
    2. Update: Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO; EORTC Brain Tumour and Radiation Oncology Groups; National Cancer Institute of Canada Clinical Trials Group. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009 May;10(5):459-66. Epub 2009 Mar 9. link to original article PubMed
  3. RTOG 0525: Gilbert MR, Wang M, Aldape KD, Stupp R, Hegi ME, Jaeckle KA, Armstrong TS, Wefel JS, Won M, Blumenthal DT, Mahajan A, Schultz CJ, Erridge S, Baumert B, Hopkins KI, Tzuk-Shina T, Brown PD, Chakravarti A, Curran WJ Jr, Mehta MP. Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol. 2013 Nov 10;31(32):4085-91. Epub 2013 Oct 7. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00304031
  4. RTOG 0825: Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, Colman H, Chakravarti A, Pugh S, Won M, Jeraj R, Brown PD, Jaeckle KA, Schiff D, Stieber VW, Brachman DG, Werner-Wasik M, Tremont-Lukats IW, Sulman EP, Aldape KD, Curran WJ Jr, Mehta MP. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014 Feb 20;370(8):699-708. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00884741
  5. AVAglio: Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, Carpentier AF, Hoang-Xuan K, Kavan P, Cernea D, Brandes AA, Hilton M, Abrey L, Cloughesy T. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014 Feb 20;370(8):709-22. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00943826
  6. CENTRIC: Stupp R, Hegi ME, Gorlia T, Erridge SC, Perry J, Hong YK, Aldape KD, Lhermitte B, Pietsch T, Grujicic D, Steinbach JP, Wick W, Tarnawski R, Nam DH, Hau P, Weyerbrock A, Taphoorn MJ, Shen CC, Rao N, Thurzo L, Herrlinger U, Gupta T, Kortmann RD, Adamska K, McBain C, Brandes AA, Tonn JC, Schnell O, Wiegel T, Kim CY, Nabors LB, Reardon DA, van den Bent MJ, Hicking C, Markivskyy A, Picard M, Weller M; EORTC; Canadian Brain Tumor Consortium; CENTRIC study team. Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Sep;15(10):1100-8. Epub 2014 Aug 19. link to original article PubMed NCT00689221
  7. OSAG 101-BSA-05: Westphal M, Heese O, Steinbach JP, Schnell O, Schackert G, Mehdorn M, Schulz D, Simon M, Schlegel U, Senft C, Geletneky K, Braun C, Hartung JG, Reuter D, Metz MW, Bach F, Pietsch T. A randomised, open label phase III trial with nimotuzumab, an anti-epidermal growth factor receptor monoclonal antibody in the treatment of newly diagnosed adult glioblastoma. Eur J Cancer. 2015 Mar;51(4):522-32. Epub 2015 Jan 20. link to original article PubMed NCT00753246
  8. GLARIUS: Herrlinger U, Schäfer N, Steinbach JP, Weyerbrock A, Hau P, Goldbrunner R, Friedrich F, Rohde V, Ringel F, Schlegel U, Sabel M, Ronellenfitsch MW, Uhl M, Maciaczyk J, Grau S, Schnell O, Hänel M, Krex D, Vajkoczy P, Gerlach R, Kortmann RD, Mehdorn M, Tüttenberg J, Mayer-Steinacker R, Fietkau R, Brehmer S, Mack F, Stuplich M, Kebir S, Kohnen R, Dunkl E, Leutgeb B, Proescholdt M, Pietsch T, Urbach H, Belka C, Stummer W, Glas M. Bevacizumab plus irinotecan versus temozolomide in newly diagnosed O6-methylguanine-DNA methyltransferase nonmethylated glioblastoma: the randomized GLARIUS trial. J Clin Oncol. 2016 May 10;34(14):1611-9. Epub 2016 Mar 14. link to original article PubMed NCT00967330
  9. IcmLCBT 301: Kong DS, Nam DH, Kang SH, Lee JW, Chang JH, Kim JH, Lim YJ, Koh YC, Chung YG, Kim JM, Kim CH. Phase III randomized trial of autologous cytokine-induced killer cell immunotherapy for newly diagnosed glioblastoma in Korea. Oncotarget. 2017 Jan 24;8(4):7003-7013. Epub 2016 Sep 27. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00807027
  10. CheckMate 548: Lim M, Weller M, Idbaih A, Steinbach J, Finocchiaro G, Raval RR, Ansstas G, Baehring J, Taylor JW, Honnorat J, Petrecca K, De Vos F, Wick A, Sumrall A, Sahebjam S, Mellinghoff IK, Kinoshita M, Roberts M, Slepetis R, Warad D, Leung D, Lee M, Reardon DA, Omuro A. Phase III trial of chemoradiotherapy with temozolomide plus nivolumab or placebo for newly diagnosed glioblastoma with methylated MGMT promoter. Neuro Oncol. 2022 Nov 2;24(11):1935-1949. Epub 2022 May 2. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT02667587
  11. CheckMate 498: Omuro A, Brandes AA, Carpentier AF, Idbaih A, Reardon DA, Cloughesy T, Sumrall A, Baehring J, van den Bent M, Bähr O, Lombardi G, Mulholland P, Tabatabai G, Lassen U, Sepulveda JM, Khasraw M, Vauleon E, Muragaki Y, Di Giacomo AM, Butowski N, Roth P, Qian X, Fu AZ, Liu Y, Potter V, Chalamandaris AG, Tatsuoka K, Lim M, Weller M. Radiotherapy combined with nivolumab or temozolomide for newly diagnosed glioblastoma with unmethylated MGMT promoter: An international randomized phase III trial. Neuro Oncol. 2023 Jan 5;25(1):123-134. Epub 2022 Apr 14. link to original article link to PMC article PubMed NCT02617589
  12. INTELLANCE-1: Lassman AB, Pugh SL, Wang TJC, Aldape K, Gan HK, Preusser M, Vogelbaum MA, Sulman EP, Won M, Zhang P, Moazami G, Macsai MS, Gilbert MR, Bain EE, Blot V, Ansell PJ, Samanta S, Kundu MG, Armstrong TS, Wefel JS, Seidel C, de Vos FY, Hsu S, Cardona AF, Lombardi G, Bentsion D, Peterson RA, Gedye C, Bourg V, Wick A, Curran WJ, Mehta MP. Depatuxizumab mafodotin in EGFR-amplified newly diagnosed glioblastoma: A phase III randomized clinical trial. Neuro Oncol. 2023 Feb 14;25(2):339-350. Epub 2022 Jul 15. link to original article link to PMC article PubMed NCT02573324
  13. MIRAGE: Roth P, Gorlia T, Reijneveld JC, de Vos F, Idbaih A, Frenel JS, Le Rhun E, Sepulveda JM, Perry J, Masucci GL, Freres P, Hirte H, Seidel C, Walenkamp A, Lukacova S, Meijnders P, Blais A, Ducray F, Verschaeve V, Nicholas G, Balana C, Bota DA, Preusser M, Nuyens S, Dhermain F, van den Bent M, O'Callaghan CJ, Vanlancker M, Mason W, Weller M. Marizomib for patients with newly diagnosed glioblastoma: A randomized phase 3 trial. Neuro Oncol. 2024 Sep 5;26(9):1670-1682. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT03345095


First-line therapy, elderly or poor performance status patients

Radiation therapy

Regimen variant #1, hypofractionated (3400 cGy)

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Malmström et al. 2012 2000-2009 Phase 3 (E-switch-ic) 1. RT; standard Did not meet primary endpoint of OS
2. Temozolomide Did not meet primary endpoint of OS

Preceding treatment

Radiotherapy

2-week course


Regimen variant #2, abbreviated course (4000 cGy)

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Roa et al. 2004 1996-2001 Randomized Phase 2 (E-switch-de-esc) RT; standard (6000 cGy) Did not meet primary endpoint of OS
Perry et al. 2017 (NCIC-CTG CE.6) 2007-2013 Phase 3 (C) Temozolomide & LDRT Inferior OS

Note: Roa et al. 2004 was closed early due to poor accrual.

Preceding treatment

Radiotherapy

3-week course


Regimen variant #3, standard course (5040 cGy)

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Keime-Guibert et al. 2007 2001-2005 Phase 3 (E-esc) Best supportive care Superior OS (primary endpoint)
Median OS: 29.1 vs 16.9 wk
(HR 0.47, 95% CI 0.29-0.76)

Preceding treatment

Radiotherapy

5.5-week course


Regimen variant #4, standard course (6000 cGy)

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Roa et al. 2004 1996-2001 Randomized Phase 2 (C) RT; abbreviated (4000 cGy) Did not meet primary endpoint of OS
Malmström et al. 2012 2000-2009 Phase 3 (C) 1. RT; hypofractionated Did not meet primary endpoint of OS
2. Temozolomide Inferior OS

Note: Roa et al. 2004 was closed early due to poor accrual.

Preceding treatment

Radiotherapy

6-week course

References

  1. Roa W, Brasher PM, Bauman G, Anthes M, Bruera E, Chan A, Fisher B, Fulton D, Gulavita S, Hao C, Husain S, Murtha A, Petruk K, Stewart D, Tai P, Urtasun R, Cairncross JG, Forsyth P. Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: a prospective randomized clinical trial. J Clin Oncol. 2004 May 1;22(9):1583-8. Epub 2004 Mar 29. link to original article dosing details in abstract have been reviewed by our editors PubMed
  2. Keime-Guibert F, Chinot O, Taillandier L, Cartalat-Carel S, Frenay M, Kantor G, Guillamo JS, Jadaud E, Colin P, Bondiau PY, Meneï P, Loiseau H, Bernier V, Honnorat J, Barrié M, Mokhtari K, Mazeron JJ, Bissery A, Delattre JY; Association of French-Speaking Neuro-Oncologists. Radiotherapy for glioblastoma in the elderly. N Engl J Med. 2007 Apr 12;356(15):1527-35. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT00430911
  3. Malmström A, Grønberg BH, Marosi C, Stupp R, Frappaz D, Schultz H, Abacioglu U, Tavelin B, Lhermitte B, Hegi ME, Rosell J, Henriksson R; Nordic Clinical Brain Tumour Study Group. Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncol. 2012 Sep;13(9):916-26. Epub 2012 Aug 8. link to original article dosing details in manuscript have been reviewed by our editors PubMed ISRCTN81470623
  4. NCIC-CTG CE.6: Perry JR, Laperriere N, O'Callaghan CJ, Brandes AA, Menten J, Phillips C, Fay M, Nishikawa R, Cairncross JG, Roa W, Osoba D, Rossiter JP, Sahgal A, Hirte H, Laigle-Donadey F, Franceschi E, Chinot O, Golfinopoulos V, Fariselli L, Wick A, Feuvret L, Back M, Tills M, Winch C, Baumert BG, Wick W, Ding K, Mason WP; Trial Investigators. Short-course radiation plus temozolomide in elderly patients with glioblastoma. N Engl J Med. 2017 Mar 16;376(11):1027-1037. link to original article PubMed NCT00482677
  5. JCOG1910: jRCTs031200099


Temozolomide monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Malmström et al. 2012 2000-2009 Phase 3 (E-switch-ooc) 1. Hypofractionated RT Did not meet primary endpoint of OS
2. Standard RT Superior OS (primary endpoint)

Preceding treatment

Chemotherapy

28-day cycle for up to 6 cycles

References

  1. Malmström A, Grønberg BH, Marosi C, Stupp R, Frappaz D, Schultz H, Abacioglu U, Tavelin B, Lhermitte B, Hegi ME, Rosell J, Henriksson R; Nordic Clinical Brain Tumour Study Group. Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncol. 2012 Sep;13(9):916-26. Epub 2012 Aug 8. link to original article dosing details in manuscript have been reviewed by our editors PubMed ISRCTN81470623


Temozolomide & low-dose RT

Temozolomide & LDRT: Temozolomide & Low-Dose Radiation Therapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Perry et al. 2017 (NCIC-CTG CE.6) 2007-2013 Phase 3 (E-esc) Radiotherapy Superior OS (primary endpoint)
Median OS: 9.3 vs 7.6 mo
(HR 0.67, 95% CI 0.56-0.80)

Preceding treatment

Chemotherapy

  • Temozolomide (Temodar) 75 mg/m2 PO once per day, starting the first day of radiation therapy until the last day of radiation therapy, and no longer than 21 days

Radiotherapy

  • Concurrent radiation therapy, 267 cGy fractions x 15 fractions, for a total dose of 4005 cGy

3-week course

Subsequent treatment

References

  1. NCIC-CTG CE.6: Perry JR, Laperriere N, O'Callaghan CJ, Brandes AA, Menten J, Phillips C, Fay M, Nishikawa R, Cairncross JG, Roa W, Osoba D, Rossiter JP, Sahgal A, Hirte H, Laigle-Donadey F, Franceschi E, Chinot O, Golfinopoulos V, Fariselli L, Wick A, Feuvret L, Back M, Tills M, Winch C, Baumert BG, Wick W, Ding K, Mason WP; Trial Investigators. Short-course radiation plus temozolomide in elderly patients with glioblastoma. N Engl J Med. 2017 Mar 16;376(11):1027-1037. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00482677


Maintenance after first-line therapy

Irinotecan & Bevacizumab

Regimen

Study Dates of enrollment Evidence
Herrlinger et al. 2016 (GLARIUS) 2010-2012 Non-randomized part of phase 2 RCT

Preceding treatment

Chemotherapy

  • Irinotecan (Camptosar) by the following exposure-based criteria:
    • No concomitant EIAED: 125 mg/m2 IV once on day 1
    • Concomitant EIAED: 340 mg/m2 IV once on day 1

Targeted therapy

14-day cycles

References

  1. GLARIUS: Herrlinger U, Schäfer N, Steinbach JP, Weyerbrock A, Hau P, Goldbrunner R, Friedrich F, Rohde V, Ringel F, Schlegel U, Sabel M, Ronellenfitsch MW, Uhl M, Maciaczyk J, Grau S, Schnell O, Hänel M, Krex D, Vajkoczy P, Gerlach R, Kortmann RD, Mehdorn M, Tüttenberg J, Mayer-Steinacker R, Fietkau R, Brehmer S, Mack F, Stuplich M, Kebir S, Kohnen R, Dunkl E, Leutgeb B, Proescholdt M, Pietsch T, Urbach H, Belka C, Stummer W, Glas M. Bevacizumab plus irinotecan versus temozolomide in newly diagnosed O6-methylguanine-DNA methyltransferase nonmethylated glioblastoma: the randomized GLARIUS trial. J Clin Oncol. 2016 May 10;34(14):1611-9. Epub 2016 Mar 14. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00967330


Temozolomide monotherapy

Regimen variant #1, 6 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Stupp et al. 2005 (EORTC 22981/26981; NCIC-CTG CE.3) 2000-2002 Phase 3 (E-RT-esc) See link See link
Liau et al. 2018 2007-2015 Phase 3 (C) Temozolomide & DCVax-L Not reported1
Kong et al. 2016 (IcmLCBT 301) 2008-2012 Non-randomized part of phase 3 RCT
Gilbert et al. 2014 (RTOG 0825) 2009-2011 Phase 3 (C) See link See link
Chinot et al. 2014 (AVAglio) 2009-2011 Phase 3 (C) See link See link
Stupp et al. 2015 (EF-14) 2009-2014 Phase 3 (C) Temozolomide & NovoTTF-100A Inferior OS

1The only publication thus far reports OS, which was not the primary endpoint of this study.
Note: The total duration of temozolomide in Liau et al. 2018 is unclear. Patients in RTOG 0825 could extend maintenance to 12 cycles if no major adverse events and evidence of ongoing benefit. Temozolomide dose is increased only if prior dose was tolerated.

Preceding treatment

Chemotherapy

  • Temozolomide (Temodar) as follows:
    • Cycle 1: 150 mg/m2 PO once per day on days 1 to 5
    • Cycles 2 to 6: 200 mg/m2 PO once per day on days 1 to 5

Supportive therapy

28-day cycle for 6 cycles


Regimen variant #2, 12 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gilbert et al. 2013 (RTOG 0525) 2006-2008 Phase 3 (C) Temozolomide; dose-dense Did not meet primary endpoint of OS
Perry et al. 2017 (NCIC-CTG CE.6) 2007-2013 Non-randomized part of phase 3 RCT
Weller et al. 2017 (ACT IV) 2012-2014 Phase 3 (C) Rindopepimut & Temozolomide Did not meet primary endpoint of OS
Median OS: 20 vs 20.1 mo
(HR 0.99, 95% CI 0.77-1.27)
Guo et al. 2023 (CSNO2012001) 2012-05-01 to 2016-03-30 Phase 3 (C) Temozolomide & Interferon alfa Inferior OS

Note: treatment in ACT IV was given for a minimum of 6 cycles.

Preceding treatment

Chemotherapy

28-day cycle for up to 12 cycles

References

  1. EORTC 22981/26981; NCIC-CTG CE.3: Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; EORTC Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987-96. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00006353
    1. Biomarker analysis: Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005 Mar 10;352(10):997-1003. link to original article PubMed
    2. Update: Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO; EORTC Brain Tumour and Radiation Oncology Groups; National Cancer Institute of Canada Clinical Trials Group. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009 May;10(5):459-66. Epub 2009 Mar 9. link to original article PubMed
  2. RTOG 0525: Gilbert MR, Wang M, Aldape KD, Stupp R, Hegi ME, Jaeckle KA, Armstrong TS, Wefel JS, Won M, Blumenthal DT, Mahajan A, Schultz CJ, Erridge S, Baumert B, Hopkins KI, Tzuk-Shina T, Brown PD, Chakravarti A, Curran WJ Jr, Mehta MP. Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol. 2013 Nov 10;31(32):4085-91. Epub 2013 Oct 7. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00304031
  3. RTOG 0825: Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, Colman H, Chakravarti A, Pugh S, Won M, Jeraj R, Brown PD, Jaeckle KA, Schiff D, Stieber VW, Brachman DG, Werner-Wasik M, Tremont-Lukats IW, Sulman EP, Aldape KD, Curran WJ Jr, Mehta MP. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014 Feb 20;370(8):699-708. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00884741
  4. AVAglio: Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, Carpentier AF, Hoang-Xuan K, Kavan P, Cernea D, Brandes AA, Hilton M, Abrey L, Cloughesy T. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014 Feb 20;370(8):709-22. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00943826
  5. EF-14: Stupp R, Taillibert S, Kanner AA, Kesari S, Steinberg DM, Toms SA, Taylor LP, Lieberman F, Silvani A, Fink KL, Barnett GH, Zhu JJ, Henson JW, Engelhard HH, Chen TC, Tran DD, Sroubek J, Tran ND, Hottinger AF, Landolfi J, Desai R, Caroli M, Kew Y, Honnorat J, Idbaih A, Kirson ED, Weinberg U, Palti Y, Hegi ME, Ram Z. Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma: a randomized clinical trial. JAMA. 2015 Dec 15;314(23):2535-43. link to original article contains partial dosing details; refers to Stupp et al. 2005 PubMed NCT00916409
    1. Update: Stupp R, Taillibert S, Kanner A, Read W, Steinberg DM, Lhermitte B, Toms S, Idbaih A, Ahluwalia MS, Fink K, Di Meco F, Lieberman F, Zhu JJ, Stragliotto G, Tran DD, Brem S, Hottinger AF, Kirson ED, Lavy-Shahaf G, Weinberg U, Kim CY, Paek SH, Nicholas G, Bruna J, Hirte H, Weller M, Palti Y, Hegi ME, Ram Z. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial. JAMA. 2017 Dec 19;318(23):2306-2316. link to original article link to PMC article PubMed
  6. GLARIUS: Herrlinger U, Schäfer N, Steinbach JP, Weyerbrock A, Hau P, Goldbrunner R, Friedrich F, Rohde V, Ringel F, Schlegel U, Sabel M, Ronellenfitsch MW, Uhl M, Maciaczyk J, Grau S, Schnell O, Hänel M, Krex D, Vajkoczy P, Gerlach R, Kortmann RD, Mehdorn M, Tüttenberg J, Mayer-Steinacker R, Fietkau R, Brehmer S, Mack F, Stuplich M, Kebir S, Kohnen R, Dunkl E, Leutgeb B, Proescholdt M, Pietsch T, Urbach H, Belka C, Stummer W, Glas M. Bevacizumab plus irinotecan versus temozolomide in newly diagnosed O6-methylguanine-DNA methyltransferase nonmethylated glioblastoma: the randomized GLARIUS trial. J Clin Oncol. 2016 May 10;34(14):1611-9. Epub 2016 Mar 14. link to original article PubMed NCT00967330
  7. IcmLCBT 301: Kong DS, Nam DH, Kang SH, Lee JW, Chang JH, Kim JH, Lim YJ, Koh YC, Chung YG, Kim JM, Kim CH. Phase III randomized trial of autologous cytokine-induced killer cell immunotherapy for newly diagnosed glioblastoma in Korea. Oncotarget. 2017 Jan 24;8(4):7003-7013. Epub 2016 Sep 27. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00807027
  8. NCIC-CTG CE.6: Perry JR, Laperriere N, O'Callaghan CJ, Brandes AA, Menten J, Phillips C, Fay M, Nishikawa R, Cairncross JG, Roa W, Osoba D, Rossiter JP, Sahgal A, Hirte H, Laigle-Donadey F, Franceschi E, Chinot O, Golfinopoulos V, Fariselli L, Wick A, Feuvret L, Back M, Tills M, Winch C, Baumert BG, Wick W, Ding K, Mason WP; Trial Investigators. Short-course radiation plus temozolomide in elderly patients with glioblastoma. N Engl J Med. 2017 Mar 16;376(11):1027-1037. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00482677
  9. ACT IV: Weller M, Butowski N, Tran DD, Recht LD, Lim M, Hirte H, Ashby L, Mechtler L, Goldlust SA, Iwamoto F, Drappatz J, O'Rourke DM, Wong M, Hamilton MG, Finocchiaro G, Perry J, Wick W, Green J, He Y, Turner CD, Yellin MJ, Keler T, Davis TA, Stupp R, Sampson JH; ACT IV trial investigators. Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial. Lancet Oncol. 2017 Oct;18(10):1373-1385. Epub 2017 Aug 23. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT01480479
  10. Liau LM, Ashkan K, Tran DD, Campian JL, Trusheim JE, Cobbs CS, Heth JA, Salacz M, Taylor S, D'Andre SD, Iwamoto FM, Dropcho EJ, Moshel YA, Walter KA, Pillainayagam CP, Aiken R, Chaudhary R, Goldlust SA, Bota DA, Duic P, Grewal J, Elinzano H, Toms SA, Lillehei KO, Mikkelsen T, Walbert T, Abram SR, Brenner AJ, Brem S, Ewend MG, Khagi S, Portnow J, Kim LJ, Loudon WG, Thompson RC, Avigan DE, Fink KL, Geoffroy FJ, Lindhorst S, Lutzky J, Sloan AE, Schackert G, Krex D, Meisel HJ, Wu J, Davis RP, Duma C, Etame AB, Mathieu D, Kesari S, Piccioni D, Westphal M, Baskin DS, New PZ, Lacroix M, May SA, Pluard TJ, Tse V, Green RM, Villano JL, Pearlman M, Petrecca K, Schulder M, Taylor LP, Maida AE, Prins RM, Cloughesy TF, Mulholland P, Bosch ML. First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma. J Transl Med. 2018 May 29;16(1):142. Erratum in: J Transl Med. 2018 Jun 29;16(1):179. link to original article link to PMC article PubMed NCT00045968
  11. CSNO2012001: Guo C, Yang Q, Xu P, Deng M, Jiang T, Cai L, Li J, Sai K, Xi S, Ouyang H, Liu M, Li X, Li Z, Ni X, Cao X, Li C, Wu S, Du X, Su J, Xue X, Wang Y, Li G, Qin Z, Yang H, Zhou T, Liu J, Hu X, Wang J, Jiang X, Lin F, Zhang X, Ke C, Lv X, Lv Y, Hu W, Zeng J, Chen Z, Zhong S, Wang H, Chen Y, Zhang J, Li D, Mou Y, Chen Z. Adjuvant Temozolomide Chemotherapy With or Without Interferon Alfa Among Patients With Newly Diagnosed High-grade Gliomas: A Randomized Clinical Trial. JAMA Netw Open. 2023 Jan 3;6(1):e2253285. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01765088
  12. CALGB A071102: NCT02152982


Temozolomide & NovoTTF-100A

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Stupp et al. 2015 (EF-14) 2009-2014 Phase 3 (E-esc) Temozolomide Superior PFS (primary endpoint)
Median PFS: 7.1 vs 4 mo
(HR 0.62, 98.7% CI 0.43-0.89)

Superior OS1 (secondary endpoint)
Median OS: 20.9 vs 16 mo
(HR 0.63, 95% CI 0.53-0.76)

1Reported efficacy is based on the 2017 update.
Note: Temozolomide dose is increased only if prior dose was tolerated.

Preceding treatment

Chemotherapy

  • Temozolomide (Temodar) as follows:
    • Cycle 1: 150 mg/m2 PO once per day on days 1 to 5
    • Cycles 2 to 6: 200 mg/m2 PO once per day on days 1 to 5

28-day cycle for 6 to 12 cycles

Tumor treating fields, CNS

Up to to 24-month course

References

  1. EF-14: Stupp R, Taillibert S, Kanner AA, Kesari S, Steinberg DM, Toms SA, Taylor LP, Lieberman F, Silvani A, Fink KL, Barnett GH, Zhu JJ, Henson JW, Engelhard HH, Chen TC, Tran DD, Sroubek J, Tran ND, Hottinger AF, Landolfi J, Desai R, Caroli M, Kew Y, Honnorat J, Idbaih A, Kirson ED, Weinberg U, Palti Y, Hegi ME, Ram Z. Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma: a randomized clinical trial. JAMA. 2015 Dec 15;314(23):2535-43. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT00916409
    1. Update: Stupp R, Taillibert S, Kanner A, Read W, Steinberg DM, Lhermitte B, Toms S, Idbaih A, Ahluwalia MS, Fink K, Di Meco F, Lieberman F, Zhu JJ, Stragliotto G, Tran DD, Brem S, Hottinger AF, Kirson ED, Lavy-Shahaf G, Weinberg U, Kim CY, Paek SH, Nicholas G, Bruna J, Hirte H, Weller M, Palti Y, Hegi ME, Ram Z. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial. JAMA. 2017 Dec 19;318(23):2306-2316. link to original article link to PMC article PubMed


Recurrent disease, non-curative therapy, randomized data

Bevacizumab monotherapy

Regimen variant #1, limited duration

Study Dates of enrollment Evidence
Friedman et al. 2009 (AVF3708g) 2006-2007 Phase 2 (RT)

Targeted therapy

14-day cycle for up to 52 cycles (2 years)


Regimen variant #2, indefinite

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kreisl et al. 2008 (NCI 06-C-0064E) 2006-2007 Phase 2 (RT)
Reardon et al. 2020 (CheckMate 143) 2014-09 to 2015-05 Phase 3 (C) Nivolumab Did not meet primary endpoint of OS
Median OS: 10 vs 9.8 mo
(HR 0.96, 95% CI 0.77-1.20)
Cloughesy et al. 2020 (GLOBE) 2015-2017 Phase 3 (C) Ofranergene obadenovec & Bevacizumab Did not meet primary endpoint of OS
Median OS: 7.9 vs 6.8 mo
(HR 0.83, 95% CI 0.63-1.10)

Targeted therapy

14-day cycles

Subsequent treatment

References

  1. NCI 06-C-0064E: Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, Garren N, Mackey M, Butman JA, Camphausen K, Park J, Albert PS, Fine HA. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009 Feb 10;27(5):740-5. Epub 2008 Dec 29. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed
  2. AVF3708g: Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, Yung WK, Paleologos N, Nicholas MK, Jensen R, Vredenburgh J, Huang J, Zheng M, Cloughesy T. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009 Oct 1;27(28):4733-40. Epub 2009 Aug 31. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00345163
  3. BELOB: Taal W, Oosterkamp HM, Walenkamp AM, Dubbink HJ, Beerepoot LV, Hanse MC, Buter J, Honkoop AH, Boerman D, de Vos FY, Dinjens WN, Enting RH, Taphoorn MJ, van den Berkmortel FW, Jansen RL, Brandsma D, Bromberg JE, van Heuvel I, Vernhout RM, van der Holt B, van den Bent MJ. 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 Aug;15(9):943-53. Epub 2014 Jul 15. link to original article PubMed NTR1929
    1. HRQoL analysis: Dirven L, van den Bent MJ, Bottomley A, van der Meer N, van der Holt B, Vos MJ, Walenkamp AM, Beerepoot LV, Hanse MC, Reijneveld JC, Otten A, de Vos FY, Smits M, Bromberg JE, Taal W, Taphoorn MJ; Dutch Neuro-Oncology Group. The impact of bevacizumab on health-related quality of life in patients treated for recurrent glioblastoma: results of the randomised controlled phase 2 BELOB trial. Eur J Cancer. 2015 Jul;51(10):1321-30. Epub 2015 Apr 17. link to original article PubMed
  4. GLOBE: Cloughesy TF, Brenner A, de Groot JF, Butowski NA, Zach L, Campian JL, Ellingson BM, Freedman LS, Cohen YC, Lowenton-Spier N, Rachmilewitz Minei T, Fain Shmueli S; GLOBE Study Investigators, Wen PY. A randomized controlled phase III study of VB-111 combined with bevacizumab vs bevacizumab monotherapy in patients with recurrent glioblastoma (GLOBE). Neuro Oncol. 2020 May 15;22(5):705-717. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT02511405
  5. CheckMate 143: Reardon DA, Brandes AA, Omuro A, Mulholland P, Lim M, Wick A, Baehring J, Ahluwalia MS, Roth P, Bähr O, Phuphanich S, Sepulveda JM, De Souza P, Sahebjam S, Carleton M, Tatsuoka K, Taitt C, Zwirtes R, Sampson J, Weller M. Effect of Nivolumab vs Bevacizumab in Patients With Recurrent Glioblastoma: The CheckMate 143 Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020 Jul 1;6(7):1003-1010. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT02017717


Carmustine monotherapy

Regimen

Study Dates of enrollment Evidence
Fewer et al. 1972 1968-12 to 1970-08-01 Retrospective
Brandes et al. 2004a 2002-06 to 2003-10 Phase 2

Chemotherapy

Supportive therapy

8-week cycle for up to 6 cycles

References

  1. Retrospective: Fewer D, Wilson CB, Boldrey EB, Enot KJ, Powell MR. The chemotherapy of brain tumors: clinical experience with carmustine (BCNU) and vincristine. JAMA. 1972 Oct 30;222(5):549-52. link to original article PubMed
  2. Brandes AA, Tosoni A, Amistà P, Nicolardi L, Grosso D, Berti F, Ermani M. How effective is BCNU in recurrent glioblastoma in the modern era? A phase II trial. Neurology. 2004 Oct 12;63(7):1281-4. link to original article dosing details in manuscript have been reviewed by our editors PubMed


Gliadel wafer monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Brem et al. 1995 1989-1992 Phase 3 (E-esc) Placebo wafer Superior OS
Westphal et al. 2003 1997-1999 Phase 3 (E-esc) Placebo wafer Seems to have superior OS
Kunwar et al. 2010 (PRECISE) 2004-03 to 2005-12 Phase 3 (C) Cintredekin besudotox Did not meet primary endpoint of OS
Median OS: 8.8 vs 9.1 mo

Local therapy

References

  1. Brem H, Piantadosi S, Burger PC, Walker M, Selker R, Vick NA, Black K, Sisti M, Brem S, Mohr G, Muller P, Morawetz R, Schold SC; Polymer-Brain Tumor Treatment Group. Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. Lancet. 1995 Apr 22;345(8956):1008-12. link to original article PubMed
  2. Westphal M, Hilt DC, Bortey E, Delavault P, Olivares R, Warnke PC, Whittle IR, Jääskeläinen J, Ram Z. A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neuro Oncol. 2003 Apr;5(2):79-88. link to original article link to PMC article PubMed
  3. PRECISE: Kunwar S, Chang S, Westphal M, Vogelbaum M, Sampson J, Barnett G, Shaffrey M, Ram Z, Piepmeier J, Prados M, Croteau D, Pedain C, Leland P, Husain SR, Joshi BH, Puri RK; PRECISE Study Group. Phase III randomized trial of CED of IL13-PE38QQR vs Gliadel wafers for recurrent glioblastoma. Neuro Oncol. 2010 Aug;12(8):871-81. Epub 2010 Feb 4. link to original article link to PMC article PubMed NCT00076986


Hydroxyurea monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Dresemann et al. 2009 (CSTI571BDE40) 2004-2006 Phase 3 (C) Hydroxyurea & Imatinib Did not meet primary endpoint of PFS

Chemotherapy

42-day cycles

References

  1. CSTI571BDE40: Dresemann G, Weller M, Rosenthal MA, Wedding U, Wagner W, Engel E, Heinrich B, Mayer-Steinacker R, Karup-Hansen A, Fluge O, Nowak A, Mehdorn M, Schleyer E, Krex D, Olver IN, Steinbach JP, Hosius C, Sieder C, Sorenson G, Parker R, Nikolova Z. 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 Feb;96(3):393-402. Epub 2009 Aug 18. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00154375


Hydroxyurea & Imatinib

Regimen variant #1, imatinib 400 mg/day

Study Dates of enrollment Evidence
Dresemann 2005 Not reported Non-randomized

Note: this combination did not succeed in the randomized phase 3 trial.

Chemotherapy

Targeted therapy

Continued indefinitely


Regimen variant #2, imatinib 600 mg/day

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Dresemann et al. 2009 (CSTI571BDE40) 2004-2006 Phase 3 (E-esc) Hydroxyurea Did not meet primary endpoint of PFS

Note: this combination did not succeed in the randomized phase 3 trial.

Chemotherapy

Targeted therapy

Continued indefinitely

References

  1. Dresemann G. Imatinib and hydroxyurea in pretreated progressive glioblastoma multiforme: a patient series. Ann Oncol. 2005 Oct;16(10):1702-8. Epub 2005 Jul 20. link to original article dosing details in manuscript have been reviewed by our editors PubMed
  2. CSTI571BDE40: Dresemann G, Weller M, Rosenthal MA, Wedding U, Wagner W, Engel E, Heinrich B, Mayer-Steinacker R, Karup-Hansen A, Fluge O, Nowak A, Mehdorn M, Schleyer E, Krex D, Olver IN, Steinbach JP, Hosius C, Sieder C, Sorenson G, Parker R, Nikolova Z. 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 Feb;96(3):393-402. Epub 2009 Aug 18. link to original article PubMed NCT00154375


Lomustine monotherapy

Regimen variant #1, 100 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Wick et al. 2010 (JCBF) 2006-03 to 2007-08 Phase 3 (C) Enzastaurin Might have superior PFS
Median PFS: 1.6 vs 1.5 mo
(HR 0.78, 95% CI 0.59-1.03)

Note: this was the lower bound of the range specified in the trial.

Chemotherapy

Supportive therapy

  • Enzyme-inducing antiepileptic drugs (EIAEDs) needed to be discontinued 14 days before enrolling in the trial

42-day cycles


Regimen variant #2, 110 mg/m2, uncapped

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Batchelor et al. 2013 (REGAL) 2008-10 to 2009-09 Phase 3 (C) 1. Cediranib
2. Cediranib & Lomustine 		Did not meet primary endpoint of PFS

Chemotherapy

42-day cycles


Regimen variant #3, 110 mg/m2, capped

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Taal et al. 2014 (BELOB) 2009-12-11 to 2011-11-10 Randomized Phase 2 (C) Lomustine & Bevacizumab Not reported
Wick et al. 2017 (EORTC 26101) 2011-2014 Phase 3 (C) Lomustine & Bevacizumab Did not meet primary endpoint of OS

Chemotherapy

42-day cycle for varying durations: 6 cycles (BELOB); indefinitely (EORTC 26101)


Regimen variant #4, 130 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bleehen et al. 1989 1983-1986 Randomized (C) Benznidazole & Lomustine Did not meet endpoint
Wick et al. 2010 (JCBF) 2006-03 to 2007-08 Phase 3 (C) Enzastaurin Might have superior PFS
Median PFS: 1.6 vs 1.5 mo
(HR 0.78, 95% CI 0.59-1.03)

Note: this was the upper bound of the range specified in JCBF.

Chemotherapy

Supportive therapy

  • Enzyme-inducing antiepileptic drugs (EIAEDs) needed to be discontinued 14 days before enrolling in JCBF

42-day cycle for varying durations: 6 cycles (Bleehen et al. 1989); indefinitely (JCBF)

References

  1. Bleehen NM, Freedman LS, Stenning SP. A randomized study of CCNU with and without benznidazole in the treatment of recurrent grades 3 and 4 astrocytoma: report to the Medical Research Council by the Brain Tumor Working Party. Int J Radiat Oncol Biol Phys. 1989 Apr;16(4):1077-81. link to original article PubMed
  2. JCBF: Wick W, Puduvalli VK, Chamberlain MC, van den Bent MJ, Carpentier AF, Cher LM, Mason W, Weller M, Hong S, Musib L, Liepa AM, Thornton DE, Fine HA. Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma. J Clin Oncol. 2010 Mar 1;28(7):1168-74. Epub 2010 Feb 1. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00295815
  3. REGAL: Batchelor TT, Mulholland P, Neyns B, Nabors LB, Campone M, Wick A, Mason W, Mikkelsen T, Phuphanich S, Ashby LS, de Groot J, Gattamaneni R, Cher L, Rosenthal M, Payer F, Jürgensmeier JM, Jain RK, Sorensen AG, Xu J, Liu Q, van den Bent M. 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 Sep 10;31(26):3212-8. Epub 2013 Aug 12. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00777153
  4. BELOB: Taal W, Oosterkamp HM, Walenkamp AM, Dubbink HJ, Beerepoot LV, Hanse MC, Buter J, Honkoop AH, Boerman D, de Vos FY, Dinjens WN, Enting RH, Taphoorn MJ, van den Berkmortel FW, Jansen RL, Brandsma D, Bromberg JE, van Heuvel I, Vernhout RM, van der Holt B, van den Bent MJ. 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 Aug;15(9):943-53. Epub 2014 Jul 15. link to original article dosing details in manuscript have been reviewed by our editors PubMed NTR1929
    1. HRQoL analysis: Dirven L, van den Bent MJ, Bottomley A, van der Meer N, van der Holt B, Vos MJ, Walenkamp AM, Beerepoot LV, Hanse MC, Reijneveld JC, Otten A, de Vos FY, Smits M, Bromberg JE, Taal W, Taphoorn MJ; Dutch Neuro-Oncology Group. The impact of bevacizumab on health-related quality of life in patients treated for recurrent glioblastoma: results of the randomised controlled phase 2 BELOB trial. Eur J Cancer. 2015 Jul;51(10):1321-30. Epub 2015 Apr 17. link to original article PubMed
  5. EORTC 26101: Wick W, Gorlia T, Bendszus M, Taphoorn M, Sahm F, Harting I, Brandes AA, Taal W, Domont J, Idbaih A, Campone M, Clement PM, Stupp R, Fabbro M, Le Rhun E, Dubois F, Weller M, von Deimling A, Golfinopoulos V, Bromberg JC, Platten M, Klein M, van den Bent MJ. Lomustine and bevacizumab in progressive glioblastoma. N Engl J Med. 2017 Nov 16;377(20):1954-1963. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01290939


Lomustine & Bevacizumab

Regimen variant #1

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Taal et al. 2014 (BELOB) 2009-12-11 to 2011-11-10 Randomized Phase 2 (E-esc) Lomustine Not reported

Chemotherapy

Targeted therapy

42-day cycles


Regimen variant #2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Wick et al. 2017 (EORTC 26101) 2011-2014 Phase 3 (E-RT-esc) Lomustine Did not meet primary endpoint of OS

Chemotherapy

  • Lomustine (CCNU) as follows:
    • Cycle 1: 90 mg/m2 (maximum dose of 160 mg) IV once on day 1
    • Cycle 2 onwards: 110 mg/m2 (maximum dose of 200 mg) IV once on day 1

Targeted therapy

42-day cycles

References

  1. BELOB: Taal W, Oosterkamp HM, Walenkamp AM, Dubbink HJ, Beerepoot LV, Hanse MC, Buter J, Honkoop AH, Boerman D, de Vos FY, Dinjens WN, Enting RH, Taphoorn MJ, van den Berkmortel FW, Jansen RL, Brandsma D, Bromberg JE, van Heuvel I, Vernhout RM, van der Holt B, van den Bent MJ. 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 Aug;15(9):943-53. Epub 2014 Jul 15. link to original article dosing details in abstract have been reviewed by our editors PubMed NTR1929
    1. HRQoL analysis: Dirven L, van den Bent MJ, Bottomley A, van der Meer N, van der Holt B, Vos MJ, Walenkamp AM, Beerepoot LV, Hanse MC, Reijneveld JC, Otten A, de Vos FY, Smits M, Bromberg JE, Taal W, Taphoorn MJ; Dutch Neuro-Oncology Group. The impact of bevacizumab on health-related quality of life in patients treated for recurrent glioblastoma: results of the randomised controlled phase 2 BELOB trial. Eur J Cancer. 2015 Jul;51(10):1321-30. Epub 2015 Apr 17. link to original article PubMed
  2. EORTC 26101: Wick W, Gorlia T, Bendszus M, Taphoorn M, Sahm F, Harting I, Brandes AA, Taal W, Domont J, Idbaih A, Campone M, Clement PM, Stupp R, Fabbro M, Le Rhun E, Dubois F, Weller M, von Deimling A, Golfinopoulos V, Bromberg JC, Platten M, Klein M, van den Bent MJ. Lomustine and bevacizumab in progressive glioblastoma. N Engl J Med. 2017 Nov 16;377(20):1954-1963. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01290939


NovoTTF-100A monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Stupp et al. 2012 (EF-11) 2006-2009 Phase 3 (E-switch-ooc) Investigator's choice of chemotherapy Did not meet primary endpoint of OS

Tumor treating fields, CNS

References

  1. EF-11: Stupp R, Wong ET, Kanner AA, Steinberg D, Engelhard H, Heidecke V, Kirson ED, Taillibert S, Liebermann F, Dbalý V, Ram Z, Villano JL, Rainov N, Weinberg U, Schiff D, Kunschner L, Raizer J, Honnorat J, Sloan A, Malkin M, Landolfi JC, Payer F, Mehdorn M, Weil RJ, Pannullo SC, Westphal M, Smrcka M, Chin L, Kostron H, Hofer S, Bruce J, Cosgrove R, Paleologous N, Palti Y, Gutin PH. NovoTTF-100A versus physician's choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality. Eur J Cancer. 2012 Sep;48(14):2192-202. Epub 2012 May 18. link to original article PubMed NCT00379470


PCV

PCV: Procarbazine, CCNU (Lomustine), Vincristine

Regimen variant #1, 60/110/1.4

Study Evidence
Levin et al. 1980 Non-randomized

Chemotherapy

42-day cycles


Regimen variant #2, 100/100/1.5

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Brada et al. 2010 (MRC BR12) 2003-2008 Phase 3 (C) Temozolomide Did not meet co-primary endpoints of PFS3/OS

Chemotherapy

42-day cycle for up to 6 cycles

References

  1. Levin VA, Edwards MS, Wright DC, Seager ML, Schimberg TP, Townsend JJ, Wilson CB. Modified procarbazine, CCNU, and vincristine (PCV 3) combination chemotherapy in the treatment of malignant brain tumors. Cancer Treat Rep. 1980 Feb-Mar;64(2-3):237-44. dosing details in abstract have been reviewed by our editors PubMed
  2. MRC BR12: Brada M, Stenning S, Gabe R, Thompson LC, Levy D, Rampling R, Erridge S, Saran F, Gattamaneni R, Hopkins K, Beall S, Collins VP, Lee SM. Temozolomide versus procarbazine, lomustine, and vincristine in recurrent high-grade glioma. J Clin Oncol. 2010 Oct 20;28(30):4601-8. Epub 2010 Sep 20. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00052455


Recurrent disease, non-curative therapy, non-randomized or retrospective data

Carboplatin & Bevacizumab

Regimen variant #1, q2wk bevacizumab

Study Dates of enrollment Evidence
Norden et al. 2008 2005-06 to 2007-03 Retrospective

Chemotherapy

Targeted therapy

14-day cycles


Regimen variant #2, q4wk bevacizumab

Study Dates of enrollment Evidence
Thompson et al. 2010 2006-2008 Retrospective

Chemotherapy

Targeted therapy

28-day cycles

References

  1. Retrospective: Norden AD, Young GS, Setayesh K, Muzikansky A, Klufas R, Ross GL, Ciampa AS, Ebbeling LG, Levy B, Drappatz J, Kesari S, Wen PY. Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence. Neurology. 2008 Mar 4;70(10):779-87. link to original article PubMed
  2. Retrospective: Thompson EM, Dosa E, Kraemer DF, Neuwelt EA. Treatment with bevacizumab plus carboplatin for recurrent malignant glioma. Neurosurgery. 2010 Jul;67(1):87-93. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed


CART-EGFRvIII monotherapy

Regimen

Study Dates of enrollment Evidence
O'Rourke et al. 2017 (UPCC 35313) Not reported Phase 1

Immunotherapy

One treatment

References

  1. UPCC 35313: O'Rourke DM, Nasrallah MP, Desai A, Melenhorst JJ, Mansfield K, Morrissette JJD, Martinez-Lage M, Brem S, Maloney E, Shen A, Isaacs R, Mohan S, Plesa G, Lacey SF, Navenot JM, Zheng Z, Levine BL, Okada H, June CH, Brogdon JL, Maus MV. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci Transl Med. 2017 Jul 19;9(399). link to original article link to PMC article PubMed NCT02209376


Cyclophosphamide monotherapy

Regimen

Study Dates of enrollment Evidence
Chamberlain & Tsao-Wei 2004 1999-11 to 2003-01 Phase 2

Prior treatment criteria

  • Temozolomide exposure, with refractory disease

Chemotherapy

Supportive therapy

28-day cycles

References

  1. Chamberlain MC, Tsao-Wei DD. Salvage chemotherapy with cyclophosphamide for recurrent, temozolomide-refractory glioblastoma multiforme. Cancer. 2004 Mar 15;100(6):1213-20. link to original article dosing details in manuscript have been reviewed by our editors PubMed


Irinotecan monotherapy

Regimen

Study Evidence
Friedman et al. 1999 Phase 2

Chemotherapy

Supportive therapy

  • Steroids at lowest dose necessary
  • Avoid laxatives and magnesium-containing antacids due to potential for diarrhea

42-day cycles

Dose and schedule modifications

  • If tolerated, irinotecan dose could be increased to 150 mg/m2 IV once per day on days 1, 8, 15, 22

References

  1. Friedman HS, Petros WP, Friedman AH, Schaaf LJ, Kerby T, Lawyer J, Parry M, Houghton PJ, Lovell S, Rasheed K, Cloughsey T, Stewart ES, Colvin OM, Provenzale JM, McLendon RE, Bigner DD, Cokgor I, Haglund M, Rich J, Ashley D, Malczyn J, Elfring GL, Miller LL. Irinotecan therapy in adults with recurrent or progressive malignant glioma. J Clin Oncol. 1999 May;17(5):1516-25. link to original article dosing details in manuscript have been reviewed by our editors PubMed


Irinotecan & Bevacizumab

Regimen variant #1, q2wk bev

Study Dates of enrollment Evidence
Chen et al. 2007 2005-06 to 2006-02 Pilot, >20 pts
Vredenburgh et al. 2007 Not reported Phase 2
Norden et al. 2008 2005-06 to 2007-03 Retrospective
Kreisl et al. 2008 (NCI 06-C-0064E) 2006-2007 Phase 2
Friedman et al. 2009 (AVF3708g) 2006-2007 Phase 2

Note: AVF3708g described 6-week cycles in which treatment was every 2 weeks, given up to 104 weeks, and was otherwise identical, so its entry was consolidated with the other ones here.

Chemotherapy

  • Irinotecan (Camptosar) 125 mg/m2 IV over 90 minutes once on day 1, given first
    • Patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) are treated with a higher dose: 340 mg/m2 (NCI 06-C-0064E) or 350 mg/m2 (Chen et al. 2007) IV over 90 minutes once on day 1, given first

Targeted therapy

  • Bevacizumab (Avastin) 10 mg/kg IV once on day 1, given second, 90 minutes after the start of irinotecan
    • Infusion times for bevacizumab are 90 minutes for the first dose, then if tolerated, 60 minutes for the second dose, and 30 minutes for the third dose and later

Supportive therapy

  • Steroids were generally maintained at the same dose

14-day cycles


Regimen variant #2, q3wk bev

Study Dates of enrollment Evidence
Vredenburgh et al. 2007 Not reported Phase 2, fewer than 20 pts

Chemotherapy

  • Irinotecan (Camptosar) 125 mg/m2 IV over 90 minutes once per day on days 1, 8, 22, 29, given first
    • Patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) are treated with a higher dose: 350 mg/m2 IV over 90 minutes once per day on days 1, 8, 22, 29, given first

Targeted therapy

  • Bevacizumab (Avastin) 15 mg/kg IV once per day on days 1 & 22, given second, 90 minutes after the start of irinotecan
    • Infusion time is 90 minutes for the first dose, then if tolerated, 60 minutes for the second dose, and 30 minutes for the third dose and later

Supportive therapy

  • Steroids were generally maintained at the same dose

42-day cycles

References

  1. Chen W, Delaloye S, Silverman DH, Geist C, Czernin J, Sayre J, Satyamurthy N, Pope W, Lai A, Phelps ME, Cloughesy T. Predicting treatment response of malignant gliomas to bevacizumab and irinotecan by imaging proliferation with [18F] fluorothymidine positron emission tomography: a pilot study. J Clin Oncol. 2007 Oct 20;25(30):4714-21. link to original article dosing details in manuscript have been reviewed by our editors PubMed
  2. Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Dowell JM, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Wagner M, Bigner DD, Friedman AH, Friedman HS. Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res. 2007 Feb 15;13(4):1253-9. link to original article dosing details in manuscript have been reviewed by our editors PubMed
    1. Update: Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Marcello J, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Sampson J, Wagner M, Bailey L, Bigner DD, Friedman AH, Friedman HS. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol. 2007 Oct 20;25(30):4722-9. link to original article dosing details in manuscript have been reviewed by our editors PubMed
  3. Norden AD, Young GS, Setayesh K, Muzikansky A, Klufas R, Ross GL, Ciampa AS, Ebbeling LG, Levy B, Drappatz J, Kesari S, Wen PY. Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence. Neurology. 2008 Mar 4;70(10):779-87. link to original article dosing details in manuscript have been reviewed by our editors PubMed
  4. NCI 06-C-0064E: Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, Garren N, Mackey M, Butman JA, Camphausen K, Park J, Albert PS, Fine HA. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009 Feb 10;27(5):740-5. Epub 2008 Dec 29. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed
  5. AVF3708g: Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, Yung WK, Paleologos N, Nicholas MK, Jensen R, Vredenburgh J, Huang J, Zheng M, Cloughesy T. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009 Oct 1;27(28):4733-40. Epub 2009 Aug 31. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00345163


Procarbazine monotherapy

Regimen

Study Dates of enrollment Evidence
Yung et al. 2000 1995-01-05 to 1997-10-28 Phase 2

Chemotherapy

  • Procarbazine (Matulane) by the following exposure-based criteria:
    • No prior exposure to chemotherapy: 150 mg/m2 PO once per day on days 1 to 28
    • Patients who previously received chemotherapy: 125 mg/m2 PO once per day on days 1 to 28

Supportive therapy

8-week cycle for up to 13 cycles (2 years)

References

  1. Yung WK, Albright RE, Olson J, Fredericks R, Fink K, Prados MD, Brada M, Spence A, Hohl RJ, Shapiro W, Glantz M, Greenberg H, Selker RG, Vick NA, Rampling R, Friedman H, Phillips P, Bruner J, Yue N, Osoba D, Zaknoen S, Levin VA. A phase II study of temozolomide vs procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer. 2000 Sep;83(5):588-93. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed


Temozolomide monotherapy

Regimen variant #1, continuous ramped dose

Study Dates of enrollment Evidence
Bower et al. 1997 Not reported Phase 2

Chemotherapy

  • Temozolomide (Temodar) as follows:
    • Cycle 1: 150 mg/m2 PO once per day on days 1 to 5
    • Cycle 2 onwards: 200 mg/m2 PO once per day on days 1 to 5

28-day cycles


Regimen variant #2, continuous low-dose

Study Dates of enrollment Evidence
Perry et al. 2008 (RESCUE) 2001-01 to 2005-07 Retrospective

Note: See paper for details of when this regimen is used.

Chemotherapy

Continued indefinitely


Regimen variant #3, 2 years

Study Dates of enrollment Evidence
Yung et al. 2000 1995-01-05 to 1997-10-28 Phase 2

Chemotherapy

  • Temozolomide (Temodar) by the following exposure-based criteria:
    • Patients who had never previously received chemotherapy: 200 mg/m2 PO once per day on days 1 to 5
    • Patients who previously received chemotherapy: 150 mg/m2 PO once per day on days 1 to 5

28-day cycle for up to 26 cycles (2 years)

References

  1. Bower M, Newlands ES, Bleehen NM, Brada M, Begent RJ, Calvert H, Colquhoun I, Lewis P, Brampton MH. Multicentre CRC phase II trial of temozolomide in recurrent or progressive high-grade glioma. Cancer Chemother Pharmacol. 1997;40(6):484-8. link to original article PubMed
  2. Yung WK, Albright RE, Olson J, Fredericks R, Fink K, Prados MD, Brada M, Spence A, Hohl RJ, Shapiro W, Glantz M, Greenberg H, Selker RG, Vick NA, Rampling R, Friedman H, Phillips P, Bruner J, Yue N, Osoba D, Zaknoen S, Levin VA. A phase II study of temozolomide vs procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer. 2000 Sep;83(5):588-93. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed
  3. RESCUE: Perry JR, Rizek P, Cashman R, Morrison M, Morrison T. Temozolomide rechallenge in recurrent malignant glioma by using a continuous temozolomide schedule: the "rescue" approach. Cancer. 2008 Oct 15;113(8):2152-7. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00392171
    1. Update: Perry JR, Bélanger K, Mason WP, Fulton D, Kavan P, Easaw J, Shields C, Kirby S, Macdonald DR, Eisenstat DD, Thiessen B, Forsyth P, Pouliot JF. Phase II trial of continuous dose-intense temozolomide in recurrent malignant glioma: RESCUE study. J Clin Oncol. 2010 Apr 20;28(12):2051-7. Epub 2010 Mar 22. link to original article dosing details in manuscript have been reviewed by our editors PubMed


Response criteria

Response Assessment in Neuro-Oncology Working Group


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