Glioblastoma

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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:
*Pediatric high-grade glioma
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==
*2016: Radiation therapy for glioblastoma: American Society of Clinical Oncology Clinical Practice Guideline endorsement of the American Society for Radiation Oncology Guideline EuroPMC
==EANO==
*2017: European Association for Neuro-Oncology (EANO) guidelines for palliative care in adults with glioma EuroPMC
*2014: EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma EuroPMC
==ESMO==
*2014: Stupp et al. High-grade glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2010: Stupp et al. High-grade malignant glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2009: Stupp & Roila. Malignant glioma: ESMO clinical recommendations for diagnosis, treatment and follow-up EuroPMC
**2008: Stupp & Roila. Malignant glioma: ESMO clinical recommendations for diagnosis, treatment and follow-up EuroPMC
**2007: Stupp. Malignant glioma: ESMO clinical recommendations for diagnosis, treatment and follow-up EuroPMC
**2005: Stupp et al. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of malignant glioma EuroPMC
==NCCN==
*NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - Central Nervous System Cancers.
=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	Higher PFS6 (primary endpoint)
====Preceding treatment====
*Surgery
====Targeted therapy====
*Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1, 15, 29, 43
====Radiotherapy====
*External beam radiotherapy 200 cGy per fraction, 5 days per week for 6 weeks (total of 6000 cGy)
8-week course
====Subsequent treatment====
*Irinotecan & bevacizumab maintenance
===References===
#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 EuroPMC 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
Eyre et al. 1986 (SWOG S7703) 	1977-1981 	Phase 3 (E-switch-ic)	2. Procarbazine & RT 	Higher 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 OSMedian OS: 10 vs 11 mo(HR 1.30, 95% CI 0.85-1.96)
====Preceding treatment====
*Surgery
====Chemotherapy====
*Carmustine (BCNU) 200 mg/m2 IV over 60 minutes once on day 1
42-day cycle for up to 7 cycles
====Radiotherapy====
*External beam radiotherapy, 180 cGy given 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===
#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 EuroPMC
#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 EuroPMC
#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. EuroPMC
#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 EuroPMC
#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 EuroPMC
#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 EuroPMC
#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 EuroPMC
#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 EuroPMC NCT00017147
#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 EuroPMC
==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 longer 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====
*Surgery
====Chemotherapy====
*Lomustine (CCNU) 100 mg/m2 PO once on day 1
*Temozolomide (Temodar) 100 mg/m2 PO once per day on days 2 to 6
42-day cycle for up to 6 cycles
====Radiotherapy====
*External beam radiotherapy 5900 to 6000 cGy in 30 to 33 fractions
6- to 7-week course
===References===
#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 EuroPMC NCT01149109
##HRQoL analysis: Weller J, Tzaridis T, Mack F, Steinbach JP, Schlegel U, Hau P, Krex D, Grauer O, Goldbrunner R, Bähr O, Uhl M, Seidel C, Tabatabai G, Brehmer S, Bullinger L, Galldiks N, Schaub C, Kebir S, Stummer W, Simon M, Fimmers R, Coch C, Glas M, Herrlinger U, Schäfer N. Health-related quality of life and neurocognitive functioning with lomustine-temozolomide versus temozolomide in patients with newly diagnosed, MGMT-methylated glioblastoma (CeTeG/NOA-09): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2019 Oct;20(10):1444-1453. Epub 2019 Sep 2. link to original article EuroPMC
==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 OSMedian OS: 27.4 vs 22.4 mo
Note: this is of historic interest; ACNU is not generally available outside of Japan.
====Preceding treatment====
*Surgery
====Chemotherapy====
*Nimustine (ACNU) 80 mg/m2 IV once per day on days 1 & 36
====Radiotherapy====
*External beam radiotherapy 6000 cGy
One course
===References===
#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 EuroPMC 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====
*Procarbazine (Matulane) 60 mg/m2 PO once per day on days 8 to 21
*Lomustine (CCNU) 100 mg/m2 PO once on day 1
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once per day on days 8 & 29
42-day cycle for 7 cycles
===References===
#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 EuroPMC
==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 longer OS
Walker et al. 1978 (BTSG 69-01) 	1969-1972 	Phase 3 (E-esc)	2. Carmustine 	Might have longer OS
Walker et al. 1978 (BTSG 69-01) 	1969-1972 	Phase 3 (E-esc)	3. Carmustine & RT 	Did not meet primary endpoint of OS50%
Walker et al. 1980 (BTSG 72-01) 	1972-1975 	Phase 3 (C) 	1. Carmustine & RT2. Semustine & RT 	Did not meet primary endpoint of OS
Walker et al. 1980 (BTSG 72-01) 	1972-1975 	Phase 3 (C) 	3. Semustine 	Seems to have longer OS
Urtasun et al. 1976 	1974 to not reported	Randomized (C) 	Metronidazole & RT 	Seems to have shorter OS
Stupp et al. 2005 (EORTC 22981/26981; NCIC-CTG CE.3)	2000-2002 	Phase 3 (C) 	Temozolomide & RT, then Temozolomide	Shorter OS (primary endpoint)
Adjuvant radiotherapy alone.
====Preceding treatment====
*Surgery
====Radiotherapy====
*External beam radiotherapy
===References===
#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 EuroPMC
#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 EuroPMC
#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 EuroPMC
#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 EuroPMC NCT00006353
##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 EuroPMC
##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 EuroPMC
==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
Shapiro et al. 1989 (BTCG 8001)	1980-1983 	Phase 3 (C)	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====
*Surgery, within 3 weeks
====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
Shapiro et al. 1989 (BTCG 8001)	1980-1983 	Phase 3 (C)	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====
*Surgery, within 3 weeks
====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====
*Carmustine (BCNU) 80 mg/m2 IV over 30 to 60 minutes once per day on days 1 to 3
8-week cycle for up to 18 cycles (a maximum cumulative carmustine dose of 1500 mg/m2)
===References===
#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 EuroPMC
==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/PFSPFS12: 20.3% vs 25.6%
Stupp et al. 2014 (CENTRIC) 	2008-2011 	Phase 3 (C) 	Cilengitide, Temozolomide, RT 	Did not meet primary endpoint of OSMedian 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 shorter 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 OSMedian 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 	Longer OSMedian 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 PFSMedian PFS: 10.3 vs 10.6 mo(HR 0.91, 95% CI 0.77-1.11)Did not meet co-primary endpoint of OSMedian 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 OSMedian OS: 17 vs 16.5 mo(HR 0.96, 95% CI 0.79-1.16)
====Biomarker eligibility criteria====
*CENTRIC & CheckMate 548:methylated Biomarkers#MGMT promoter.
*INTELLANCE-1: EGFR amplification
====Preceding treatment====
*Surgical biopsy, partial resection, or total resection
====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====
*PCP prophylaxis with ONE of the following:
**Trimethoprim/Sulfamethoxazole (Bactrim)
**Pentamidine (Nebupent) 300 mg nebulized inhaled
*Metoclopramide (Reglan) or 5-HT3 antagonist recommended before the initial doses of radiation therapy & temozolomide
====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====
*Stupp et al. 2002: Temozolomide maintenance, 4 weeks after completion of radiation therapy
*RTOG 0525: Temozolomide versus temozolomide; dose-dense maintenance
===References===
#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 EuroPMC
#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 EuroPMC NCT00006353
##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 EuroPMC
##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 EuroPMC
#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 EuroPMC NCT00304031
#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 EuroPMC NCT00884741
##HRQoL analysis: Wefel JS, Armstrong TS, Pugh SL, Gilbert MR, Wendland MM, Brachman DG, Roof KS, Brown PD, Crocker IR, Robins HI, Hunter G, Won M, Mehta MP. Neurocognitive, symptom, and health-related quality of life outcomes of a randomized trial of bevacizumab for newly diagnosed glioblastoma (NRG/RTOG 0825). Neuro Oncol. 2021 Jul;23(7):1125-1138. link to original article link to EuroPMC
#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 EuroPMC NCT00943826
#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 EuroPMC NCT00689221
#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 EuroPMC NCT00753246
#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 EuroPMC NCT00967330
#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 EuroPMC NCT00807027
#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 EuroPMC NCT02667587
#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 EuroPMC NCT02617589
#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 EuroPMC NCT02573324
#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 EuroPMC 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
Malmström et al. 2012	2000-2009 	Phase 3 (E-switch-ic)	2. Temozolomide	Did not meet primary endpoint of OS
====Preceding treatment====
*Surgery
====Radiotherapy====
*External beam radiotherapy 10 x 340 cGy fractions, five days per week, for a total dose of 3400 cGy
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 	Shorter OSMedian OS: 7.6 vs 9.3 mo(HR 1.49, 95% CI 1.25-1.79)
Note: Roa et al. 2004 was closed early due to poor accrual.
====Preceding treatment====
*Surgery
====Radiotherapy====
*External beam radiotherapy 15 x 267 cGy fractions, five days per week, for a total dose of 4005 cGy
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	Longer OS (primary endpoint)Median OS: 29.1 vs 16.9 wk(HR 0.47, 95% CI 0.29-0.76)
====Preceding treatment====
*Surgery
====Radiotherapy====
*External beam radiotherapy 28 x 180 cGy fractions, five days per week, for a total dose of 5040 cGy
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
Malmström et al. 2012	2000-2009 	Phase 3 (C) 	2. Temozolomide 	Shorter OS
Note: Roa et al. 2004 was closed early due to poor accrual.
====Preceding treatment====
*Surgery
====Radiotherapy====
*External beam radiotherapy 30 x 200 cGy fractions, five days per week, for a total dose of 6000 cGy
6-week course
===References===
#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 EuroPMC
#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 EuroPMC NCT00430911
#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 EuroPMC ISRCTN81470623
#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 EuroPMC NCT00482677
#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
Malmström et al. 2012	2000-2009 	Phase 3 (E-switch-ooc)	2. Standard RT 	Longer OS (primary endpoint)
====Preceding treatment====
*Surgery
====Chemotherapy====
*Temozolomide (Temodar) 200 mg/m2 PO once per day on days 1 to 5
28-day cycle for up to 6 cycles
===References===
#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 EuroPMC 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	Longer OS (primary endpoint)Median OS: 9.3 vs 7.6 mo(HR 0.67, 95% CI 0.56-0.80)
====Preceding treatment====
*Surgery
====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====
*Temozolomide maintenance
===References===
#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 EuroPMC 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====
*First-line Bevacizumab & RT
====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====
*Bevacizumab (Avastin) 10 mg/kg IV once on day 1
14-day cycles
===References===
#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 EuroPMC 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	Shorter OS
Sarkaria et al. 2024 (CALGB A071102) 	2017-11-08 to 2018-05-18	Phase 2/3 (C) 	Temozolomide & Veliparib 	Did not meet primary endpoint of OSMedian OS: 24.8 vs 28.1 mo(aHR 1.08, 95% CI 0.89-1.28)
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.
====Biomarker eligibility criteria====
*CALGB A071102: MGMT promoter hypermethylation
====Preceding treatment====
*First-line Temozolomide & RT
*IcmLCBT 301: First-line Temozolomide & RT versus CIK cells, Temozolomide, RT
====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====
*Metoclopramide (Reglan) or 5-HT3 antagonist required
28-day cycle for 6 cycles
====Dose and schedule modifications====
*Temozolomide dose is increased only if prior dose was tolerated.
===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 OSMedian 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	Shorter OS
Note: treatment in ACT IV was given for a minimum of 6 cycles.
====Preceding treatment====
*RTOG 0525 & CSNO2012001: Surgery, then adjuvant temozolomide & RT
*NCIC-CTG CE.6: Surgery, then adjuvant temozolomide & low-dose RT versus RT
*ACT IV: Resection
====Chemotherapy====
*Temozolomide (Temodar) 150 to 200 mg/m2 PO once per day on days 1 to 5
28-day cycle for up to 12 cycles
===References===
#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 EuroPMC NCT00006353
##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 EuroPMC
##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 EuroPMC
#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 EuroPMC NCT00304031
#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 EuroPMC NCT00884741
##HRQoL analysis: Wefel JS, Armstrong TS, Pugh SL, Gilbert MR, Wendland MM, Brachman DG, Roof KS, Brown PD, Crocker IR, Robins HI, Hunter G, Won M, Mehta MP. Neurocognitive, symptom, and health-related quality of life outcomes of a randomized trial of bevacizumab for newly diagnosed glioblastoma (NRG/RTOG 0825). Neuro Oncol. 2021 Jul;23(7):1125-1138. link to original article link to EuroPMC
#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 EuroPMC NCT00943826
#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 EuroPMC NCT00916409
##HRQoL analysis: Zhu JJ, Demireva P, Kanner AA, Pannullo S, Mehdorn M, Avgeropoulos N, Salmaggi A, Silvani A, Goldlust S, David C, Benouaich-Amiel A; Zvi Ram on behalf of the EF-14 Trial Investigators. Health-related quality of life, cognitive screening, and functional status in a randomized phase III trial (EF-14) of tumor treating fields with temozolomide compared to temozolomide alone in newly diagnosed glioblastoma. J Neurooncol. 2017 Dec;135(3):545-552. link to original article link to EuroPMC
##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 EuroPMC
##HRQoL analysis: Taphoorn MJB, Dirven L, Kanner AA, Lavy-Shahaf G, Weinberg U, Taillibert S, Toms SA, Honnorat J, Chen TC, Sroubek J, David C, Idbaih A, Easaw JC, Kim CY, Bruna J, Hottinger AF, Kew Y, Roth P, Desai R, Villano JL, Kirson ED, Ram Z, Stupp R. Influence of Treatment With Tumor-Treating Fields on Health-Related Quality of Life of Patients With Newly Diagnosed Glioblastoma: A Secondary Analysis of a Randomized Clinical Trial. JAMA Oncol. 2018 Apr 1;4(4):495-504. Epub 2018 Feb 1. link to original article link to PMC article EuroPMC
#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 EuroPMC NCT00967330
#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 EuroPMC NCT00807027
#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 EuroPMC NCT00482677
#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 EuroPMC NCT01480479
#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 EuroPMC NCT00045968
#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 EuroPMC NCT01765088
#CALGB A071102: Sarkaria JN, Ballman KV, Kizilbash SH, Sulman EP, Giannini C, Friday BB, Butowski NA, Mohile NA, Piccioni DE, Battiste JD, Drappatz J, Campian JL, Mashru S, Jaeckle KA, O'Brien BJ, Dixon JG, Kabat BF, Laack NL, Hu LS, Kaufmann T, Kumthekar P, Ellingson BM, Anderson SK, Galanis E. Efficacy of Adding Veliparib to Temozolomide for Patients With MGMT-Methylated Glioblastoma: A Randomized Clinical Trial. JAMA Oncol. 2024 Dec 1;10(12):1637-1644. Erratum in: JAMA Oncol. 2024 Dec 1;10(12):1736. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC 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	Longer PFS (primary endpoint)Median PFS: 7.1 vs 4 mo(HR 0.62, 98.7% CI 0.43-0.89)Longer 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====
*Adjuvant Temozolomide & RT
====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====
*NovoTTF-100A system (Optune) for at least 18 hours per day
Up to to 24-month course
===References===
#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 EuroPMC NCT00916409
##HRQoL analysis: Zhu JJ, Demireva P, Kanner AA, Pannullo S, Mehdorn M, Avgeropoulos N, Salmaggi A, Silvani A, Goldlust S, David C, Benouaich-Amiel A; Zvi Ram on behalf of the EF-14 Trial Investigators. Health-related quality of life, cognitive screening, and functional status in a randomized phase III trial (EF-14) of tumor treating fields with temozolomide compared to temozolomide alone in newly diagnosed glioblastoma. J Neurooncol. 2017 Dec;135(3):545-552. link to original article link to EuroPMC
##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 EuroPMC
##HRQoL analysis: Taphoorn MJB, Dirven L, Kanner AA, Lavy-Shahaf G, Weinberg U, Taillibert S, Toms SA, Honnorat J, Chen TC, Sroubek J, David C, Idbaih A, Easaw JC, Kim CY, Bruna J, Hottinger AF, Kew Y, Roth P, Desai R, Villano JL, Kirson ED, Ram Z, Stupp R. Influence of Treatment With Tumor-Treating Fields on Health-Related Quality of Life of Patients With Newly Diagnosed Glioblastoma: A Secondary Analysis of a Randomized Clinical Trial. JAMA Oncol. 2018 Apr 1;4(4):495-504. Epub 2018 Feb 1. link to original article link to PMC article EuroPMC
=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====
*Bevacizumab (Avastin) 10 mg/kg IV once on day 1
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 OSMedian 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 OSMedian OS: 7.9 vs 6.8 mo(HR 0.83, 95% CI 0.63-1.10)
====Targeted therapy====
*Bevacizumab (Avastin) 10 mg/kg IV once on day 1
14-day cycles
====Subsequent treatment====
*NCI 06-C-0064E, upon progression: Irinotecan & Bevacizumab
===References===
#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 EuroPMC
#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 EuroPMC NCT00345163
#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 EuroPMC NTR1929
##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 EuroPMC
#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 EuroPMC NCT02511405
#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 EuroPMC 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====
*Carmustine (BCNU) 80 mg/m2 IV once per day on days 1 to 3
====Supportive therapy====
*Antiemesis prophylaxis with Ondansetron (Zofran)
*Steroids at lowest dose necessary
8-week cycle for up to 6 cycles
===References===
#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 EuroPMC
#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 EuroPMC
==Gliadel wafer monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Brem et al. 1995 	1989-1992 	Phase 3 (E-esc)	Placebo wafer 	Longer OS
Westphal et al. 2003 	1997-1999 	Phase 3 (E-esc)	Placebo wafer 	Seems to have longer OS
Kunwar et al. 2010 (PRECISE)	2004-03 to 2005-12 	Phase 3 (C) 	Cintredekin besudotox	Did not meet primary endpoint of OSMedian OS: 8.8 vs 9.1 mo
====Local therapy====
*Carmustine wafer, polifeprosan 20 (Gliadel wafer)
===References===
#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 EuroPMC
#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 EuroPMC
#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 EuroPMC 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 PFSMedian PFS: 6 vs 6 wk(HR 0.93, 95% CI 0.71-1.20)
====Chemotherapy====
*Hydroxyurea (Hydrea) 500 mg PO three times per day on days 1 to 42
42-day cycles
===References===
#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 EuroPMC 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====
*Hydroxyurea (Hydrea) 500 mg PO twice per day
====Targeted therapy====
*Imatinib (Gleevec) 400 mg PO once per day
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 PFSMedian PFS: 6 vs 6 wk(HR 1.08, 95% CI 0.83-1.41)
Note: this combination did not succeed in the randomized phase 3 trial.
====Chemotherapy====
*Hydroxyurea (Hydrea) 500 mg PO twice per day
====Targeted therapy====
*Imatinib (Gleevec) 600 mg PO once per day
Continued indefinitely
===References===
#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 EuroPMC
#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 EuroPMC 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 longer PFSMedian 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====
*Lomustine (CCNU) 100 mg/m2 PO once on day 1
====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. Cediranib2. Cediranib & Lomustine	Did not meet primary endpoint of PFS
====Chemotherapy====
*Lomustine (CCNU) 110 mg/m2 PO once on day 1
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====
*Lomustine (CCNU) 110 mg/m2 (maximum dose of 200 mg) PO once on day 1
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 longer PFSMedian 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====
*Lomustine (CCNU) 130 mg/m2 PO once on day 1
====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===
#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 EuroPMC
#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 EuroPMC NCT00295815
#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 EuroPMC NCT00777153
#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 EuroPMC NTR1929
##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 EuroPMC
#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 EuroPMC 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====
*Lomustine (CCNU) 110 mg/m2 IV once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1, 15, 29
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====
*Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1, 15, 29
42-day cycles
===References===
#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 EuroPMC NTR1929
##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 EuroPMC
#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 EuroPMC 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====
*NovoTTF-100A system (Optune)
===References===
#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 EuroPMC NCT00379470
==PCV==
PCV: Procarbazine, CCNU (Lomustine), Vincristine
===Regimen variant #1, 60/110/1.4===
Study 	Evidence
Levin et al. 1980	Non-randomized
====Chemotherapy====
*Procarbazine (Matulane) 60 mg/m2 PO once per day on days 8 to 21
*Lomustine (CCNU) 110 mg/m2 PO once on day 1
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once per day on days 8 & 29
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====
*Procarbazine (Matulane) 100 mg/m2 PO once per day on days 1 to 10
*Lomustine (CCNU) 100 mg/m2 PO once on day 1
*Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once on day 1
42-day cycle for up to 6 cycles
===References===
#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 EuroPMC
#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 EuroPMC 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====
*Carboplatin (Paraplatin) AUC 5 to 6 IV (reference does not list schedule of carboplatin)
====Targeted therapy====
*Bevacizumab (Avastin) 10 mg/kg IV once on day 1
14-day cycles
===Regimen variant #2, q4wk bevacizumab===
Study 	Dates of enrollment	Evidence
Thompson et al. 2010	2006-2008 	Retrospective
====Chemotherapy====
*Carboplatin (Paraplatin) AUC 5 IV once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 10 mg/kg IV once on day 1
28-day cycles
 
===References===
#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 EuroPMC
#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 EuroPMC
==CART-EGFRvIII monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
O'Rourke et al. 2017 (UPCC 35313)	Not reported 	Phase 1
====Immunotherapy====
*Autologous CART-EGFRvIII cells IV, see paper for details
One treatment
===References===
#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 EuroPMC 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====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV over 30 minutes once per day on days 1 & 2
====Supportive therapy====
*Dexamethasone (Decadron) allowed for control of neurologic symptoms
*Ondansetron (Zofran) 0.15 mg/kg IV once per day on days 1 & 2, prior to cyclophosphamide
*Dexamethasone (Decadron) 4 mg IV once per day on days 1 & 2, prior to cyclophosphamide
*1 liter normal saline IV over 2 hours once per day on days 1 & 2, prior to cyclophosphamide
*Prochlorperazine (Compazine) (dose/schedule not specified) prn nausea/vomiting
28-day cycles
===References===
#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 EuroPMC
==Irinotecan monotherapy==
===Regimen===
Study 	Evidence
Friedman et al. 1999	Phase 2
====Chemotherapy====
*Irinotecan (Camptosar) 125 mg/m2 IV once per day on days 1, 8, 15, 22
====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===
#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 EuroPMC
==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===
#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 EuroPMC
#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 EuroPMC
##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 EuroPMC
#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 EuroPMC
#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 EuroPMC
#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 EuroPMC 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====
*Steroids at lowest dose necessary
8-week cycle for up to 13 cycles (2 years)
===References===
#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 EuroPMC
==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====
*Temozolomide (Temodar) 50 mg/m2 PO once per day
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===
#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 EuroPMC
#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 EuroPMC
#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 EuroPMC NCT00392171
##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 EuroPMC
=Response criteria=
==Response Assessment in Neuro-Oncology Working Group==
*2010: Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group EuroPMC
Category:Glioblastoma regimens
Category:Disease-specific pages
Category:High-grade gliomas