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Section editor
	Seema Nagpal, MD Stanford University Palo Alto, CA, USA LinkedIn

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

27 regimens on this page 41 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 PubMed

EANO

ESMO

2014: Stupp et al. High-grade glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2010: Stupp et al. High-grade malignant glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2009: Stupp & Roila. Malignant glioma: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
- 2008: Stupp & Roila. Malignant glioma: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
- 2007: Stupp. Malignant glioma: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
- 2005: Stupp et al. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of malignant glioma PubMed

NCCN

NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - Central Nervous System Cancers.

Adjuvant 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

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 contains dosing details in manuscript 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
Eyre et al. 1986 (SWOG S7703)	1977-1981	Phase 3 (E-switch-ic)	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

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 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 PubMed
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
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
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
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
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
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
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 contains dosing details in manuscript PubMed 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 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

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 59 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 contains dosing details in manuscript 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

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

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 contains dosing details in manuscript 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

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 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
Walker et al. 1980 (BTSG 72-01)	1972-1975	Phase 3 (C)	3. Semustine	Seems to have superior OS
Urtasun et al. 1976	1974-NR	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

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 PubMed
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
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
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 contains dosing details in manuscript 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
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 contains dosing details in manuscript PubMed

Temozolomide & RT

Temozolomide & RT: Temozolomide & Radiation Therapy

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Stupp et al. 2002	NR	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
Stupp et al. 2014 (CENTRIC)	2008-2011	Phase 3 (C)	Cilengitide, Temozolomide, RT	Did not meet primary endpoint of OS
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
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 endpoints of PFS/OS

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

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 PubMed
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 contains dosing details in manuscript 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
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 contains dosing details in manuscript PubMed 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 PubMed NCT00884741
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 contains dosing details in abstract PubMed 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 PubMed 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 PubMed 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 PubMed 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 contains dosing details in manuscript PubMed 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 contains dosing details in manuscript link to PMC article PubMed 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 PubMed 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 PubMed NCT02573324
EORTC 1709/CCTG CE.8: NCT03345095

Adjuvant 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 3.4000 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	Inferior OS

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	Superior 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	Inferior 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 contains dosing details in abstract PubMed
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 contains dosing details in abstract PubMed 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 contains dosing details in abstract PubMed 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 PubMed 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	Superior 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 contains dosing details in manuscript 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

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 contains dosing details in manuscript 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

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 contains dosing details in manuscript 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

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

Regimen variant #2, 12 cycles

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Gilbert et al. 2013 (RTOG 0525)	2006-2008	Phase 3 (C)	Dose-dense Temozolomide	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
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

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 contains dosing details in manuscript 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
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 contains dosing details in manuscript PubMed 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 PubMed NCT00884741
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 contains dosing details in abstract PubMed 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 dosing details in abstract 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
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
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 contains dosing details in manuscript PubMed 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 contains dosing details in manuscript PubMed 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 contains dosing details in abstract PubMed 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 PubMed 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 contains dosing details in manuscript PubMed NCT01765088
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

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 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 contains dosing details in abstract 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

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 OS
Cloughesy et al. 2020 (GLOBE)	2015-2017	Phase 3 (C)	Ofranergene obadenovec & Bevacizumab	Did not meet primary endpoint of OS

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 contains dosing details in manuscript link to PMC article PubMed
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 contains dosing details in manuscript PubMed 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 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
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 contains dosing details in manuscript PubMed 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 contains dosing details in manuscript 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

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 PubMed
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 contains dosing details in manuscript 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

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 PubMed
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
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

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 contains dosing details in manuscript PubMed NCT00154375

Hydroxyurea & Imatinib

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Dresemann 2005	NR	Non-randomized
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 III trial.

Chemotherapy

Hydroxyurea (Hydrea) 500 mg PO twice per day

Targeted therapy

Imatinib (Gleevec) 400 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 contains dosing details in manuscript PubMed
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	Did not meet primary endpoint of PFS

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. Cediranib 2. 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 cycles

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	Did not meet primary endpoint of PFS

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 6 cycles or 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 PubMed
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 contains dosing details in manuscript link to PMC article PubMed 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 contains dosing details in manuscript link to PMC article PubMed 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 contains dosing details in manuscript 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
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 contains dosing details in manuscript PubMed NCT01290939

Lomustine & Bevacizumab

Regimen

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
Wick et al. 2017 (EORTC 26101)	2011-2014	Phase 3 (E-RT-esc)	Lomustine	Did not meet primary endpoint of OS

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

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 contains dosing details in abstract 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
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 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

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 PubMed 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. contains dosing details in abstract PubMed
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 contains dosing details in manuscript PubMed NCT00052455

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

Carboplatin & Bevacizumab

Regimen variant #1, q2wk bevacizumab

Study	Evidence
Norden et al. 2008	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 PubMed
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 contains dosing details in manuscript PubMed

CART-EGFRvIII monotherapy

Regimen

Study	Dates of enrollment	Evidence
O'Rourke et al. 2017 (UPCC 35313)	NR	Phase 1

Immunotherapy

Autologous CART-EGFRvIII cells, 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 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

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 contains dosing details in manuscript PubMed

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 contains dosing details in manuscript 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	NR	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 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	NR	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 contains dosing details in manuscript PubMed
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 contains dosing details in manuscript 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 contains dosing details in manuscript PubMed
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 contains dosing details in manuscript PubMed
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 contains dosing details in abstract PubMed
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 contains dosing details in manuscript 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

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 contains dosing details in manuscript link to PMC article PubMed

Temozolomide monotherapy

Regimen variant #1, continuous ramped dose

Study	Dates of enrollment	Evidence
Bower et al. 1997	NR	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	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 PubMed
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 contains dosing details in manuscript link to PMC article PubMed
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 contains dosing details in manuscript 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 contains dosing details in manuscript PubMed

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 PubMed

@@ Line 1: / Line 1: @@
-'''Use of this site is subject to you reading and agreeing with the terms set forth in the [[HemOnc.org_-_A_Hematology_Oncology_Wiki:General_disclaimer|disclaimer]].'''
+<span id="BackToTop"></span>
+<div class="noprint" style="background-color:LightGray; position:fixed; bottom:2%; right:0.25%; padding-left:5px; padding-right:5px; margin: 15px; opacity:0.8; border-style: solid; border-color:DarkGray; border-width: 1px">
-Is there a regimen missing from this list? Would you like to share a different dosage/schedule or an additional reference for a regimen? Have you noticed an error? Do you have an idea that will help the site grow to better meet your needs and the needs of many others? You are [[How_to_contribute|invited to contribute to the site]].
+[[#top|Back to Top]]
+</div>
+{{#lst:Editorial board transclusions|neuro}}
+''For placebo or observational studies in this condition, please visit [[Glioblastoma - null regimens|this page]].''<br>
+<big>'''Note: pediatric regimens have been moved to a dedicated page:
+*'''[[High-grade glioma, pediatric|Pediatric high-grade glioma]]
+</big>
 {| class="wikitable" style="float:right; margin-right: 5px;"
 |-
-|<div style="background-color: #66FF66; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} regimens on this page</b></font></div>
+|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div>
-<div style="background-color: #66CCFF; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} variants on this page</b></font></div>
+<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div>
 |}
 {{TOC limit|limit=3}}
 =Guidelines=
-==ASCO==
+'''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.'''
-*[http://ascopubs.org/doi/abs/10.1200/JCO.2016.70.7562 Radiation Therapy for Glioblastoma: American Society of Clinical Oncology Clinical Practice Guideline Endorsement of the American Society for Radiation Oncology Guideline (2016)] [https://www.ncbi.nlm.nih.gov/pubmed/27893327 PubMed]
+==[https://www.asco.org/ ASCO]==
+*'''2016:''' [https://doi.org/10.1200/JCO.2016.70.7562 Radiation therapy for glioblastoma: American Society of Clinical Oncology Clinical Practice Guideline endorsement of the American Society for Radiation Oncology Guideline] [https://pubmed.ncbi.nlm.nih.gov/27893327/ PubMed]
 ==EANO==
-*[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30345-5/fulltext European Association for Neuro-Oncology (EANO) guidelines for palliative care in adults with glioma (2017)] [https://www.ncbi.nlm.nih.gov/pubmed/28593859 PubMed]
+*'''2017:''' [https://doi.org/10.1016/S1470-2045(17)30345-5 European Association for Neuro-Oncology (EANO) guidelines for palliative care in adults with glioma] [https://pubmed.ncbi.nlm.nih.gov/28593859/ PubMed]
-*[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70011-7/fulltext EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma (2014)] [https://www.ncbi.nlm.nih.gov/pubmed/25079102 PubMed]
+*'''2014:''' [https://doi.org/10.1016/S1470-2045(14)70011-7 EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma] [https://pubmed.ncbi.nlm.nih.gov/25079102/ PubMed]
+==[https://www.esmo.org/ ESMO]==
-==ESMO==
+*'''2014:''' Stupp et al. [https://doi.org/10.1093/annonc/mdu050 High-grade glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/24782454/ PubMed]
-*[http://annonc.oxfordjournals.org/content/25/suppl_3/iii93.full.pdf+html High-grade glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up (2014)] [https://www.ncbi.nlm.nih.gov/pubmed/24782454 PubMed]
+**'''2010:''' Stupp et al. [https://doi.org/10.1093/annonc/mdq187 High-grade malignant glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/20555079/ PubMed]
+**'''2009:''' Stupp & Roila. [https://doi.org/10.1093/annonc/mdp151 Malignant glioma: ESMO clinical recommendations for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/19454432/ PubMed]
+**'''2008:''' Stupp & Roila. [https://doi.org/10.1093/annonc/mdn099 Malignant glioma: ESMO clinical recommendations for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/18456781/ PubMed]
+**'''2007:''' Stupp. [https://doi.org/10.1093/annonc/mdm044 Malignant glioma: ESMO clinical recommendations for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/17491055/ PubMed]
+**'''2005:''' Stupp et al. [https://doi.org/10.1093/annonc/mdi834 ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of malignant glioma] [https://pubmed.ncbi.nlm.nih.gov/15888760/ PubMed]
 ==NCCN==
-*[https://www.nccn.org/professionals/physician_gls/pdf/cns.pdf NCCN Guidelines - Central Nervous System Cancers]
+*''NCCN does not currently have guidelines at this granular level; please see [https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1425 NCCN Guidelines - Central Nervous System Cancers].''
-=Adjuvant therapy=
+=Adjuvant therapy, standard patients=
+==Bevacizumab & RT {{#subobject:ee9fbd|Regimen=1}}==
+Bevacizumab & RT: Bevacizumab & '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:31c648|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1200/JCO.2015.63.4691 Herrlinger et al. 2016 (GLARIUS)]
+|2010-2012
+| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ooc)
+|[[#Temozolomide_.26_RT|Temozolomide & RT]], then [[#Temozolomide_monotherapy_2|Temozolomide]]
+| style="background-color:#1a9850" |Superior PFS6 (primary endpoint)
+|-
+|}
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[Surgery#CNS_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====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'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*[[#Irinotecan_.26_Bevacizumab|Irinotecan & bevacizumab]] maintenance
+</div></div>
+===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. [https://doi.org/10.1200/JCO.2015.63.4691 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26976423/ PubMed] [https://clinicaltrials.gov/study/NCT00967330 NCT00967330]
 ==Carmustine & RT {{#subobject:ee9fbd|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+BCNU & RT: '''<u>BCNU</u>''' (Carmustine) & '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:cc1540|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[[#top|back to top]]
+| rowspan="2" |[https://pubmed.ncbi.nlm.nih.gov/3017551 Eyre et al. 1986 (SWOG S7703)]
-|}
+|rowspan=2|1977-1981
-RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-switch-ic)
-===Regimen {{#subobject:31c648|Variant=1}}===
+|1. [[#Dacarbazine_.26_RT_999|DTIC & RT]]
-{| border="1" style="text-align:center;" !align="left"
+| style="background-color:#d3d3d3" |Not reported
-|'''Study'''
+|-
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+|2. [[#Procarbazine_.26_RT_888|Procarbazine & RT]]
-|'''Comparator'''
+| style="background-color:#1a9850" |Superior ORR
-|[[Levels_of_Evidence#Efficacy|'''Efficacy''']]
+|-
+|[https://doi.org/10.1200/JCO.1993.11.7.1316 Dinapoli et al. 1993]
+|1985-1989
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#PCNU_.26_RT_999|PCNU & RT]]
+| style="background-color:#ffffbf" |Did not meet co-primary endpoints of TTP50%/OS50%
+|-
+|[https://doi.org/10.1002/1097-0142%2820010715%2992%3A2%3C420%3A%3AAID-CNCR1338%3E3.0.CO%3B2-3 Buckner et al. 2001]
+|1990-1994
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#BCNU.2C_Interferon_alfa.2C_RT_999|BCNU, IFN alfa, RT]]
+| style="background-color:#ffffbf" |Did not meet endpoint of OS50%
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6020014/ Ali et al. 2018 (RTOG 9006)]
+|1990-1994
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Carmustine_.26_RT|BCNU & RT]]; hyperfractionated
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+|-
+|[https://doi.org/10.1200/JCO.2005.04.6979 Buckner et al. 2006 (NCCTG 93-72-52/SWOG S9503)]
+|1994-1999
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Carmustine.2C_Cisplatin.2C_RT_999|BCNU, Cisplatin, RT]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS50%
 |-
-|rowspan=2|[http://thejns.org/doi/abs/10.3171/jns.1989.71.1.0001 Shapiro et al. 1989 (BTCG 8001)]
+|[https://doi.org/10.1200/JCO.2003.10.035 Grossman et al. 2003 (ECOG E2394)]
-|rowspan=2 style="background-color:#00CD00"|Phase III
+|1996-1999
-|Carmustine/Procarbazine & RT
+| style="background-color:#1a9851" |Phase 3 (C)
-|style="background-color:#eeee00"|Seems not superior
+|[[#Carmustine_.26_Cisplatin_999|BCNU & Cisplatin]], then [[#Radiation_therapy|RT]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|Carmustine & Hydrea/Procarbazine & VM-26 & RT
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4465052/ Blumenthal et al. 2014 (SWOG S0001)]
-|style="background-color:#eeee00"|Seems not superior
+|2001-2005
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Carmustine.2C_O6-benzylguanine.2C_RT_999|BCNU, O⁶-benzylguanine, RT]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |}
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[Surgery#CNS_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Carmustine (BCNU)]] 200 mg/m<sup>2</sup> IV over 60 minutes once on day 1
+'''42-day cycle for up to 7 cycles'''
 ====Radiotherapy====
-*Radiation therapy starting within 3 weeks after surgical resection, with ONE of the following:
+*[[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)
-**Whole brain: 172 cGy (rads) fractions x 35 fractions, given over 7 weeks for a total dose of 6020 cGy (6020 rads/~1700 rets)
+</div></div>
-**Whole brain & cone down: 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)
+===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. [https://doi.org/10.3171/jns.1978.49.3.0333 link to original article] [https://pubmed.ncbi.nlm.nih.gov/355604/ PubMed]
+#'''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. [https://doi.org/10.1056/NEJM198012043032303 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7001230/ PubMed]
+#'''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. [https://pubmed.ncbi.nlm.nih.gov/3017551/ PubMed]
+#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. [https://doi.org/10.1200/JCO.1993.11.7.1316 link to original article] [https://pubmed.ncbi.nlm.nih.gov/8315428/ PubMed]
+#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. [https://doi.org/10.1002/1097-0142%2820010715%2992%3A2%3C420%3A%3AAID-CNCR1338%3E3.0.CO%3B2-3 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11466698/ PubMed]
+#'''ECOG E2394:''' Grossman SA, O'Neill A, Grunnet M, Mehta M, Pearlman JL, Wagner H, Gilbert M, Newton HB, Hellman R; [[Study_Groups#ECOG|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. [https://doi.org/10.1200/JCO.2003.10.035 link to original article] [https://pubmed.ncbi.nlm.nih.gov/12697871/ PubMed]
+#'''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; [[Study_Groups#SWOG|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. [https://doi.org/10.1200/JCO.2005.04.6979 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16921039/ PubMed]
+#'''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. [https://doi.org/10.1007/s10147-014-0769-0 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4465052/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25407559/ PubMed] [https://clinicaltrials.gov/study/NCT00017147 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. [https://doi.org/10.1007/s11060-017-2558-x link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6020014/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29404979/ PubMed]
-''One course, followed by:''
+==Lomustine, Temozolomide, RT {{#subobject:9gg33f|Regimen=1}}==
+Lomustine, Temozolomide, RT: Lomustine, Temozolomide, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:94ta38|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1016/S0140-6736(18)31791-4 Herrlinger et al. 2019 (CeTeG/NOA-09)]
+|2011-2014
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[#Temozolomide_.26_RT|Temozolomide & RT]]
+| style="background-color:#d9ef8b" |Might have superior OS (primary endpoint)<br>Median OS: 48.1 vs 31.4 mo<br>(HR 0.60, 95% CI 0.35-1.03)
+|-
+|}
+''Note: see paper for dose adjustments to temozolomide after cycle 1.''
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[Surgery#CNS_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Lomustine (CCNU)]] 100 mg/m<sup>2</sup> PO once on day 1
+*[[Temozolomide (Temodar)]] 100 mg/m<sup>2</sup> PO once per day on days 2 to 6
+'''42-day cycle for up to 6 cycles'''
+====Radiotherapy====
+*[[External beam radiotherapy]] 59 to 6000 cGy in 30 to 33 fractions
+'''6- to 7-week course'''
+</div></div>
+===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. [https://doi.org/10.1016/S0140-6736(18)31791-4 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/30782343/ PubMed] [https://clinicaltrials.gov/study/NCT01149109 NCT01149109]
+==Nimustine & RT {{#subobject:9ff22f|Regimen=1}}==
+Nimustine & RT: Nimustine & '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#ee6b6e">
+===Regimen {{#subobject:92d838|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1007/s00280-012-2041-5 Shibui et al. 2012 (JCOG 0305)]
+|2004-2006
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Nimustine.2C_Procarbazine.2C_RT_999|Nimustine, Procarbazine, RT]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+|-
+|}
+''Note: this is of historic interest; ACNU is not generally available outside of Japan.''
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[Surgery#CNS_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Carmustine (BiCNU)]] 80 mg/m<sup>2</sup> IV over 30 to 60 minutes once per day on days 1 to 3
+*[[Nimustine (ACNU)]] 80 mg/m<sup>2</sup> IV once per day on days 1 & 36
+====Radiotherapy====
+*[[External beam radiotherapy]] 6000 cGy
-====Supportive care====
+</div></div>
-*Pulmonary function tests (PFTs) checked before start of therapy, and then when cumulative dose of [[Carmustine (BiCNU)]] reaches 800 mg/m<sup>2</sup> and 1200 mg/m<sup>2</sup>
+===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. [https://doi.org/10.1007/s00280-012-2041-5 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23228988/ PubMed] UMIN C000000108
-'''8-week cycles, with no more than a maximum cumulative dose of 1500 mg/m<sup>2</sup> [[Carmustine (BiCNU)]] given'''
+==PCV {{#subobject:7dgh28|Regimen=1}}==
+PCV: '''<u>P</u>'''rocarbazine, '''<u>C</u>'''CNU (Lomustine), '''<u>V</u>'''incristine
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:41hg22|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://clincancerres.aacrjournals.org/content/6/10/3878.long Levin et al. 2000]
+|1992-1998
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#DFMO-PCV_999|DFMO-PCV]]
+| style="background-color:#ffffbf" |Did not meet co-primary endpoints of TTP/OS
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Procarbazine (Matulane)]] 60 mg/m<sup>2</sup> PO once per day on days 8 to 21
+*[[Lomustine (CCNU)]] 100 mg/m<sup>2</sup> PO once on day 1
+*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 8 & 29
+'''42-day cycle for 7 cycles'''
+</div></div>
 ===References===
-# Shapiro WR, Green SB, Burger PC, Mahaley MS Jr, Selker RG, VanGilder JC, Robertson JT, Ransohoff J, Mealey J Jr, Strike TA et al. 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. [http://thejns.org/doi/abs/10.3171/jns.1989.71.1.0001 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/2661738 PubMed]
+#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. [https://clincancerres.aacrjournals.org/content/6/10/3878.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/11051233/ PubMed]
 ==Radiation therapy {{#subobject:7dbd68|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:b645f1|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+| rowspan="3" |[https://doi.org/10.3171/jns.1978.49.3.0333 Walker et al. 1978 (BTSG 69-01)]
+|rowspan=3|1969-1972
+| rowspan="3" style="background-color:#1a9851" |Phase 3 (E-esc)
+|1. [[Glioblastoma_-_null_regimens#Best_supportive_care|Best supportive care]]
+| style="background-color:#91cf60" |Seems to have superior OS
+|-
+|2. [[#Carmustine_monotherapy_888|Carmustine]]
+| style="background-color:#d9ef8b" |Might have superior OS
+|-
+|3. [[#Carmustine_.26_RT|Carmustine & RT]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS50%
+|-
+| rowspan="2" |[https://doi.org/10.1056/NEJM198012043032303 Walker et al. 1980 (BTSG 72-01)]
+|rowspan=2|1972-1975
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
+|1. [[#Carmustine_.26_RT|Carmustine & RT]]<br>2. [[#Semustine_.26_RT_999|Semustine & RT]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+|-
+|3. [[#Semustine_monotherapy_999|Semustine]]
+| style="background-color:#91cf60" |Seems to have superior OS
+|-
+|[https://doi.org/10.1056/NEJM197606172942503 Urtasun et al. 1976]
+|1974-NR
+| style="background-color:#1a9851" |Randomized (C)
+|[[#Metronidazole_.26_RT_888|Metronidazole & RT]]
+| style="background-color:#fc8d59" |Seems to have inferior OS
+|-
+|[https://doi.org/10.1056/NEJMoa043330 Stupp et al. 2005 (EORTC 22981/26981; NCIC-CTG CE.3)]
+|2000-2002
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Temozolomide_.26_RT|Temozolomide & RT]], then [[#Temozolomide_monotherapy_2|Temozolomide]]
+| style="background-color:#d73027" |Inferior OS (primary endpoint)
 |-
-|[[#top|back to top]]
 |}
+''Adjuvant radiotherapy alone.''
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[Surgery#CNS_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Radiotherapy====
+*[[External beam radiotherapy]]
+</div></div>
-===Regimen #1, standard radiotherapy {{#subobject:b645f1|Variant=1}}===
+===References===
-{| border="1" style="text-align:center;" !align="left"
+#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. [https://doi.org/10.1056/NEJM197606172942503 link to original article] [https://pubmed.ncbi.nlm.nih.gov/177873/ PubMed]
-|'''Study'''
+#'''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. [https://doi.org/10.3171/jns.1978.49.3.0333 link to original article] [https://pubmed.ncbi.nlm.nih.gov/355604/ PubMed]
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+#'''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. [https://doi.org/10.1056/NEJM198012043032303 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7001230/ PubMed]
-|'''Comparator'''
+#'''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; [[Study_Groups#EORTC|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. [https://doi.org/10.1056/NEJMoa043330 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15758009/ PubMed] [https://clinicaltrials.gov/study/NCT00006353 NCT00006353]
-|[[Levels_of_Evidence#Efficacy|'''Efficacy''']]
+##'''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. [https://doi.org/10.1056/NEJMoa043331 link to original article] [https://pubmed.ncbi.nlm.nih.gov/15758010/ PubMed]
+##'''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; [[Study_Groups#EORTC|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. [https://doi.org/10.1016/S1470-2045(09)70025-7 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19269895/ PubMed]
+==RT, then Carmustine {{#subobject:507405|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, WBRT {{#subobject:31c739|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[http://www.nejm.org/doi/full/10.1056/NEJMoa043330 Stupp et al. 2005]
+| rowspan="2" |[https://doi.org/10.3171/jns.1989.71.1.0001 Shapiro et al. 1989 (BTCG 8001)]
-|style="background-color:#00CD00"|Phase III
+|rowspan=2|1980-1983
-|[[#Temozolomide_.26_RT_-.3E_Temozolomide|Temozolomide & RT -> Temozolomide]]
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
-|style="background-color:#de2d26"|Inferior OS
+|1. [[#Carmustine.2FProcarbazine_.26_RT_999|Carmustine/Procarbazine & RT]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|rowspan=2|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70265-6/abstract Malmström et al. 2012 (NCBTSG)]
+|2. [[#Carmustine_.26_Hydrea.2FProcarbazine.2C_VM-26.2C_RT_999|Carmustine & Hydrea/Procarbazine, VM-26, RT]]
-|rowspan=2 style="background-color:#00CD00"|Phase III
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|[[#Radiation_therapy|Hypofractionated radiotherapy]]
-|style="background-color:#d3d3d3"|Not reported
 |-
-|[[#Temozolomide_monotherapy|Temozolomide]]
+|}
-|style="background-color:#de2d26"|Inferior OS
+''Note: Pulmonary function tests (PFTs) were checked before start of therapy, and then when cumulative dose of [[Carmustine (BCNU)]] reaches 800 mg/m<sup>2</sup> and 1200 mg/m<sup>2</sup>.''
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[Surgery#CNS_cancer_surgery|Surgery]], within 3 weeks
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====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/m<sup>2</sup> 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/m<sup>2</sup>)'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, WBRT with cone-down {{#subobject:31c739|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+| rowspan="2" |[https://doi.org/10.3171/jns.1989.71.1.0001 Shapiro et al. 1989 (BTCG 8001)]
+|rowspan=2|1980-1983
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
+|1. [[#Carmustine.2FProcarbazine_.26_RT_999|Carmustine/Procarbazine & RT]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+|-
+|2. [[#Carmustine_.26_Hydrea.2FProcarbazine.2C_VM-26.2C_RT_999|Carmustine & Hydrea/Procarbazine, VM-26, RT]]
+| style="background-color:#ffffbf" |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/m<sup>2</sup> and 1200 mg/m<sup>2</sup>.''
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[Surgery#CNS_cancer_surgery|Surgery]], within 3 weeks
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====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/m<sup>2</sup> 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/m<sup>2</sup>)'''
+</div></div>
+===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. [https://doi.org/10.3171/jns.1989.71.1.0001 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/2661738/ PubMed]
-''Adjuvant radiotherapy alone; used as a comparator arm in the referenced trials.''
+==Temozolomide & RT {{#subobject:5fe805|Regimen=1}}==
+Temozolomide & RT: Temozolomide & '''<u>R</u>'''adiation '''<u>T</u>'''herapy
-===Regimen #2, hypofractionated radiotherapy {{#subobject:c245f1|Variant=1}}===
+<div class="toccolours" style="background-color:#eeeeee">
-{| border="1" style="text-align:center;" !align="left"
+===Regimen {{#subobject:2a87ef|Variant=1}}===
-|'''Study'''
+{| class="wikitable" style="color:white; background-color:#404040"
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+|<small>'''FDA-recommended dose'''</small>
-|'''Comparator'''
+|-
-|[[Levels_of_Evidence#Efficacy|'''Efficacy''']]
+|}
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1200/jco.2002.20.5.1375 Stupp et al. 2002]
+|NR
+| style="background-color:#91cf61" |Phase 2
+| style="background-color:#d3d3d3" |
+| style="background-color:#d3d3d3" |
+|-
+|[https://doi.org/10.1056/NEJMoa043330 Stupp et al. 2005 (EORTC 22981/26981; NCIC-CTG CE.3)]
+|2000-2002
+| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
+|[[Complex_multipart_regimens#EORTC_22981.2F26981.3B_NCIC_CTG_CE.3|See link]]
+| style="background-color:#1a9850" |[[Complex_multipart_regimens#EORTC_22981.2F26981.3B_NCIC_CTG_CE.3|See link]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3816958/ Gilbert et al. 2013 (RTOG 0525)]
+|2006-2008
+| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
+| style="background-color:#d3d3d3" |
+| style="background-color:#d3d3d3" |
+|-
+|[https://doi.org/10.1016/j.ejca.2014.12.019 Westphal et al. 2015 (OSAG 101-BSA-05)]
+|2007-2010
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Temozolomide.2C_Nimotuzumab.2C_RT_999|Temozolomide, Nimotuzumab, RT]]
+| style="background-color:#ffffbf" |Did not meet co-primary endpoints of PFS12/PFS
+|-
+|[https://doi.org/10.1016/S1470-2045(14)70379-1 Stupp et al. 2014 (CENTRIC)]
+|2008-2011
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Cilengitide.2C_Temozolomide.2C_RT_999|Cilengitide, Temozolomide, RT]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351686/ Kong et al. 2016 (IcmLCBT 301)]
+|2008-2012
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Temozolomide.2C_CIK_cells.2C_RT_777|Temozolomide & RT with CIK cells]]
+| style="background-color:#fc8d59" |Seems to have inferior PFS
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201043/ Gilbert et al. 2014 (RTOG 0825)]
+|2009-2011
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[Complex_multipart_regimens#RTOG_0825|See link]]
+| style="background-color:#d73027" |[[Complex_multipart_regimens#RTOG_0825|See link]]
+|-
+|[https://doi.org/10.1056/NEJMoa1308345 Chinot et al. 2014 (AVAglio)]
+|2009-2011
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[Complex_multipart_regimens#AVAglio|See link]]
+| style="background-color:#d73027" |[[Complex_multipart_regimens#AVAglio|See link]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9925712/ Lassman et al. 2022 (INTELLANCE-1)]
+|2015-09-11 to 2018-03-31
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Depatuxizumab_mafodotin.2C_Temozolomide.2C_RT|Depatuxizumab mafodotin, Temozolomide, RT]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|rowspan=2|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70265-6/abstract Malmström et al. 2012 (NCBTSG)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9825306/ Omuro et al. 2022 (CheckMate 498)]
-|rowspan=2 style="background-color:#00CD00"|Phase III
+|2016-2018
-|[[#Radiation_therapy|Standard radiotherapy]]
+| style="background-color:#1a9851" |Phase 3 (C)
-|style="background-color:#d3d3d3"|Not reported
+|[[#Nivolumab_.26_RT_999|Nivolumab & RT]]
+| style="background-color:#1a9850" |Superior OS<br>Median OS: 14.9 vs 13.4 mo<br>(HR 0.76, 95% CI 0.63-0.92)
 |-
-|[[#Temozolomide_monotherapy|Temozolomide]]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9629431/ Lim et al. 2022 (CheckMate 548)]
-|style="background-color:#eeee00"|Seems not superior
+|2016-2019
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Temozolomide.2C_Nivolumab.2C_RT_999|Temozolomide, Nivolumab, RT]]
+| style="background-color:#ffffbf" |Did not meet co-primary endpoints of PFS/OS
 |-
 |}
+<div class="toccolours" style="background-color:#fdcdac">
-''Adjuvant radiotherapy alone; used as a comparator arm in the referenced trials.''
+====Biomarker eligibility criteria====
+*CENTRIC & CheckMate 548:[[Biomarkers#Methylated|methylated]] [[Biomarkers#MGMT]] promoter.
+*INTELLANCE-1: EGFR amplification
+</div>
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[Surgery#CNS_cancer_surgery|Surgical biopsy, partial resection, or total resection]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Temozolomide (Temodar)]] 75 mg/m<sup>2</sup> 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 DS)|Trimethoprim/Sulfamethoxazole (Bactrim)]]
+**[[Pentamidine (Nebupent)]] 300 mg nebulized inhaled
+*[[Metoclopramide (Reglan)]] or [[:Category:Serotonin 5-HT3 antagonists|5-HT3 antagonist]] recommended before the initial doses of radiation therapy & temozolomide
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|radiation therapy]], 200 cGy fractions x 30 fractions, for a total dose of 6000 cGy
+'''6-week course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*Stupp et al. 2002: [[#Temozolomide_monotherapy_2|Temozolomide]] maintenance, 4 weeks after completion of radiation therapy
+*RTOG 0525: [[#Temozolomide_monotherapy_2|Temozolomide]] versus [[#Temozolomide_monotherapy_2|temozolomide]]; dose-dense maintenance
+</div></div>
 ===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. [http://ascopubs.org/doi/full/10.1200/JCO.2004.06.082 link to original article][https://www.ncbi.nlm.nih.gov/pubmed/15051755 PubMed]
+#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. [https://doi.org/10.1200/jco.2002.20.5.1375 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11870182/ PubMed]
-# 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; European Organisation for Research and Treatment of Cancer 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. [http://www.nejm.org/doi/full/10.1056/NEJMoa043330 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15758009 PubMed]
+#'''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; [[Study_Groups#EORTC|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. [https://doi.org/10.1056/NEJMoa043330 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15758009/ PubMed] [https://clinicaltrials.gov/study/NCT00006353 NCT00006353]
-# 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. [http://www.nejm.org/doi/full/10.1056/NEJMoa065901 link to original article]  [https://www.ncbi.nlm.nih.gov/pubmed/17429084 PubMed]
+##'''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. [https://doi.org/10.1056/NEJMoa043331 link to original article] [https://pubmed.ncbi.nlm.nih.gov/15758010/ PubMed]
-# 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 (NCBTSG). 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. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70265-6/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22877848 PubMed]
+##'''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; [[Study_Groups#EORTC|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. [https://doi.org/10.1016/S1470-2045(09)70025-7 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19269895/ PubMed]
-# 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. [http://www.nejm.org/doi/full/10.1056/NEJMoa1611977 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28296618 PubMed]
+#'''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. [https://doi.org/10.1200/JCO.2013.49.6968 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3816958/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/24101040/ PubMed] [https://clinicaltrials.gov/study/NCT00304031 NCT00304031]
-# Guedes de Castro D, Matiello J, Roa W, Ghosh S, Kepka L, Kumar N, Sinaika V, Lomidze D, Hentati D, Rosenblatt E, Fidarova E. Survival outcomes with short-course radiation therapy in elderly patients with glioblastoma: data from a randomized phase 3 trial. Int J Radiat Oncol Biol Phys. 2017 Jul 15;98(4):931-938. Epub 2017 Mar 30. [https://www.ncbi.nlm.nih.gov/pubmed/28602417 PubMed]
+#'''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. [https://doi.org/10.1056/NEJMoa1308573 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201043/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24552317/ PubMed] [https://clinicaltrials.gov/study/NCT00884741 NCT00884741]
+#'''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. [https://doi.org/10.1056/NEJMoa1308345 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/24552318/ PubMed] [https://clinicaltrials.gov/study/NCT00943826 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; [[Study_Groups#EORTC|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. [https://doi.org/10.1016/S1470-2045(14)70379-1 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25163906/ PubMed] [https://clinicaltrials.gov/study/NCT00689221 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. [https://doi.org/10.1016/j.ejca.2014.12.019 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25616647/ PubMed] [https://clinicaltrials.gov/study/NCT00753246 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. [https://doi.org/10.1200/JCO.2015.63.4691 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26976423/ PubMed] [https://clinicaltrials.gov/study/NCT00967330 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. [https://doi.org/10.18632/oncotarget.12273 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351686/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/27690294/ PubMed] [https://clinicaltrials.gov/study/NCT00807027 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. [https://doi.org/10.1093/neuonc/noac116 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9629431/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35511454/ PubMed] [https://clinicaltrials.gov/study/NCT02667587 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. [https://doi.org/10.1093/neuonc/noac099 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9825306/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35419607/ PubMed] [https://clinicaltrials.gov/study/NCT02617589 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. [https://doi.org/10.1093/neuonc/noac173 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9925712/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35849035/ PubMed] [https://clinicaltrials.gov/study/NCT02573324 NCT02573324]
+#'''EORTC 1709/CCTG CE.8:''' [https://clinicaltrials.gov/study/NCT03345095 NCT03345095]
-==Temozolomide monotherapy {{#subobject:ca0ba8|Regimen=1}}==
+=Adjuvant therapy, elderly or poor performance status patients=
-{| class="wikitable" style="float:right; margin-left: 5px;"
+==Radiation therapy {{#subobject:7dbd68|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, hypofractionated (3400 cGy) {{#subobject:c245f1|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+| rowspan="2" |[https://doi.org/10.1016/S1470-2045(12)70265-6 Malmström et al. 2012]
+|rowspan=2|2000-2009
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+|1. [[#Radiation_therapy_2|RT]]; standard
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+|-
+|2. [[#Temozolomide_monotherapy_2|Temozolomide]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+|-
+|}
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[Surgery#CNS_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Radiotherapy====
+*[[External beam radiotherapy]] 10 x 3.4000 cGy fractions, five days per week, for a total dose of 3400 cGy
+'''2-week course'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, abbreviated course (4000 cGy) {{#subobject:73c680|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1200/JCO.2004.06.082 Roa et al. 2004]
+|1996-2001
+| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-de-esc)
+|[[#Radiation_therapy_2|RT]]; standard (6000 cGy)
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+|-
+|[https://doi.org/10.1056/NEJMoa1611977 Perry et al. 2017 (NCIC-CTG CE.6)]
+|2007-2013
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Temozolomide_.26_low-dose_RT|Temozolomide & LDRT]]
+| style="background-color:#d73027" |Inferior OS
 |-
-|[[#top|back to top]]
 |}
+''Note: Roa et al. 2004 was closed early due to poor accrual.''
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[Surgery#CNS_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Radiotherapy====
+*[[External beam radiotherapy]] 15 x 267 cGy fractions, five days per week, for a total dose of 4005 cGy
+'''3-week course'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #3, standard course (5040 cGy) {{#subobject:b6921d|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1056/NEJMoa065901 Keime-Guibert et al. 2007]
+|2001-2005
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[Glioblastoma_-_null_regimens#Best_supportive_care|Best supportive care]]
+| style="background-color:#1a9850" |Superior OS (primary endpoint)<br>Median OS: 29.1 vs 16.9 wk<br>(HR 0.47, 95% CI 0.29-0.76)
+|-
+|}
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[Surgery#CNS_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Radiotherapy====
+*[[External beam radiotherapy]] 28 x 180 cGy fractions, five days per week, for a total dose of 5040 cGy
+'''5.5-week course'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #4, standard course (6000 cGy) {{#subobject:b645f1|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1200/JCO.2004.06.082 Roa et al. 2004]
+|1996-2001
+| style="background-color:#1a9851" |Randomized Phase 2 (C)
+|[[#Radiation_therapy_2|RT]]; abbreviated (4000 cGy)
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+|-
+| rowspan="2" |[https://doi.org/10.1016/S1470-2045(12)70265-6 Malmström et al. 2012]
+|rowspan=2|2000-2009
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
+|1. [[#Radiation_therapy_2|RT]]; hypofractionated
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+|-
+|2. [[#Temozolomide_monotherapy_2|Temozolomide]]
+| style="background-color:#d73027" |Inferior OS
+|-
+|}
+''Note: Roa et al. 2004 was closed early due to poor accrual.''
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[Surgery#CNS_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Radiotherapy====
+*[[External beam radiotherapy]] 30 x 200 cGy fractions, five days per week, for a total dose of 6000 cGy
+'''6-week course'''
+</div></div>
+===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. [https://doi.org/10.1200/JCO.2004.06.082 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/15051755/ PubMed]
+#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. [https://doi.org/10.1056/NEJMoa065901 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/17429084/ PubMed] [https://clinicaltrials.gov/study/NCT00430911 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. [https://doi.org/10.1016/S1470-2045(12)70265-6 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/22877848/ PubMed] 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. [https://doi.org/10.1056/NEJMoa1611977 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28296618/ PubMed] [https://clinicaltrials.gov/study/NCT00482677 NCT00482677]
+#'''JCOG1910:''' jRCTs031200099
-===Regimen {{#subobject:f32f31|Variant=1}}===
+==Temozolomide monotherapy {{#subobject:eaba28|Regimen=1}}==
-{| border="1" style="text-align:center;" !align="left"
+<div class="toccolours" style="background-color:#eeeeee">
-|'''Study'''
+===Regimen {{#subobject:f90037|Variant=1}}===
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-|'''Comparator'''
+!style="width: 20%"|Study
-|[[Levels_of_Evidence#Efficacy|'''Efficacy''']]
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|rowspan=2|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70265-6/abstract Malmström et al. 2012 (NCBTSG)]
+| rowspan="2" |[https://doi.org/10.1016/S1470-2045(12)70265-6 Malmström et al. 2012]
-|rowspan=2 style="background-color:#00CD00"|Phase III
+|rowspan=2|2000-2009
-|[[#Radiation_therapy|Hypofractionated radiotherapy]]
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-switch-ooc)
-|style="background-color:#eeee00"|Seems not superior
+|1. [[#Radiation_therapy_2|Hypofractionated RT]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|[[#Radiation_therapy|Standard radiotherapy]]
+|2. [[#Radiation_therapy_2|Standard RT]]
-|style="background-color:#00CD00"|Superior OS
+| style="background-color:#1a9850" |Superior OS (primary endpoint)
 |-
 |}
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[Surgery#CNS_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Temozolomide (Temodar)]] 200 mg/m<sup>2</sup> PO once per day on days 1 to 5
 '''28-day cycle for up to 6 cycles'''
+</div></div>
+===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. [https://doi.org/10.1016/S1470-2045(12)70265-6 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22877848/ PubMed] ISRCTN81470623
+==Temozolomide & low-dose RT {{#subobject:5fe805|Regimen=1}}==
+Temozolomide & LDRT: Temozolomide & '''<u>L</u>'''ow-'''<u>D</u>'''ose '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:e80f73|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1056/NEJMoa1611977 Perry et al. 2017 (NCIC-CTG CE.6)]
+|2007-2013
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[#Radiation_therapy|Radiotherapy]]
+| style="background-color:#1a9850" |Superior OS (primary endpoint)<br>Median OS: 9.3 vs 7.6 mo<br>(HR 0.67, 95% CI 0.56-0.80)
+|-
+|}
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[Surgery#CNS_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Temozolomide (Temodar)]] 75 mg/m<sup>2</sup> 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 [[External_beam_radiotherapy|radiation therapy]], 267 cGy fractions x 15 fractions, for a total dose of 4005 cGy
+'''3-week course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*[[#Temozolomide_monotherapy_2|Temozolomide]] maintenance
+</div></div>
 ===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 (NCBTSG).. 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. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70265-6/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22877848 PubMed]
+#'''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. [https://doi.org/10.1056/NEJMoa1611977 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28296618/ PubMed] [https://clinicaltrials.gov/study/NCT00482677 NCT00482677]
-==Temozolomide & RT -> Temozolomide {{#subobject:5fe805|Regimen=1}}==
+=Maintenance after first-line therapy=
-{| class="wikitable" style="float:right; margin-left: 5px;"
+==Irinotecan & Bevacizumab {{#subobject:a72321|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:88cfaa|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://doi.org/10.1200/JCO.2015.63.4691 Herrlinger et al. 2016 (GLARIUS)]
+|2010-2012
+| style="background-color:#91cf61" |Non-randomized part of phase 2 RCT
 |-
-|[[#top|back to top]]
 |}
-RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#cbd5e8">
-===Regimen #1, low-dose RT {{#subobject:e80f73|Variant=1}}===
+====Preceding treatment====
-{| border="1" style="text-align:center;" !align="left"
+*First-line [[#Bevacizumab_.26_RT|Bevacizumab & RT]]
-|'''Study'''
+</div>
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+<div class="toccolours" style="background-color:#b3e2cd">
-|'''Comparator'''
+====Chemotherapy====
-|[[Levels_of_Evidence#Efficacy|'''Efficacy''']]
+*[[Irinotecan (Camptosar)]] by the following exposure-based criteria:
+**No concomitant EIAED: 125 mg/m<sup>2</sup> IV once on day 1
+**Concomitant EIAED: 340 mg/m<sup>2</sup> IV once on day 1
+====Targeted therapy====
+*[[Bevacizumab (Avastin)]] 10 mg/kg IV once on day 1
+'''14-day cycles'''
+</div></div>
+===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. [https://doi.org/10.1200/JCO.2015.63.4691 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26976423/ PubMed] [https://clinicaltrials.gov/study/NCT00967330 NCT00967330]
+==Temozolomide monotherapy {{#subobject:a5295c|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, 6 cycles {{#subobject:93c350|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[http://www.nejm.org/doi/full/10.1056/NEJMoa1611977 Perry et al. 2017]
+|[https://doi.org/10.1056/NEJMoa043330 Stupp et al. 2005 (EORTC 22981/26981; NCIC-CTG CE.3)]
-|style="background-color:#00CD00"|Phase III
+|2000-2002
-|[[#Radiation_therapy|Radiotherapy]]
+| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
-|style="background-color:#00CD00"|Superior OS
+|[[Complex_multipart_regimens#EORTC_22981.2F26981.3B_NCIC_CTG_CE.3|See link]]
+| style="background-color:#1a9850" |[[Complex_multipart_regimens#EORTC_22981.2F26981.3B_NCIC_CTG_CE.3|See link]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5975654/ Liau et al. 2018]
+|2007-2015
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Temozolomide_.26_DCVax-L_777|Temozolomide & DCVax-L]]
+| style="background-color:#d3d3d3" |Not reported<sup>1</sup>
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351686/ Kong et al. 2016 (IcmLCBT 301)]
+|2008-2012
+| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
+| style="background-color:#d3d3d3" |
+| style="background-color:#d3d3d3" |
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201043/ Gilbert et al. 2014 (RTOG 0825)]
+|2009-2011
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[Complex_multipart_regimens#RTOG_0825|See link]]
+| style="background-color:#d73027" |[[Complex_multipart_regimens#RTOG_0825|See link]]
+|-
+|[https://doi.org/10.1056/NEJMoa1308345 Chinot et al. 2014 (AVAglio)]
+|2009-2011
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[Complex_multipart_regimens#AVAglio|See link]]
+| style="background-color:#d73027" |[[Complex_multipart_regimens#AVAglio|See link]]
+|-
+|[https://doi.org/10.1001/jama.2015.16669 Stupp et al. 2015 (EF-14)]
+|2009-2014
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Temozolomide_.26_NovoTTF-100A|Temozolomide & NovoTTF-100A]]
+| style="background-color:#d73027" |Inferior OS
 |-
 |}
-====Chemoradiotherapy====
+''<sup>1</sup>The only publication thus far reports OS, which was not the primary endpoint of this study.''<br>
-*[[Temozolomide (Temodar)]] 75 mg/m<sup>2</sup> PO once per day, starting the first day of radiation therapy until the last day of radiation therapy, and no longer than 21 days
+''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.''
-*Concurrent radiation therapy, 2.67 Gy fractions x 15 fractions given 5 days per week, for a total dose of 40.05 Gy
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
-'''One course, followed by:'''
+*First-line [[#Temozolomide_.26_RT|Temozolomide & RT]]
+*IcmLCBT 301: First-line [[#Temozolomide_.26_RT|Temozolomide & RT]] versus [[#CIK_cells.2C_Temozolomide.2C_RT_888|CIK cells, Temozolomide, RT]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Temozolomide (Temodar)]] 150 to 200 mg/m<sup>2</sup> PO once per day on days 1 to 5
+*[[Temozolomide (Temodar)]] as follows:
+**Cycle 1: 150 mg/m<sup>2</sup> PO once per day on days 1 to 5
-'''28-day cycle for up to 12 cycles or until disease progression'''
+**Cycles 2 to 6: 200 mg/m<sup>2</sup> PO once per day on days 1 to 5
+====Supportive therapy====
-===Regimen #2, high-dose RT {{#subobject:2a87ef|Variant=1}}===
+*[[Metoclopramide (Reglan)]] or [[:Category:Serotonin 5-HT3 antagonists|5-HT3 antagonist]] required
-{| border="1" style="text-align:center;" !align="left"
+'''28-day cycle for 6 cycles'''
-|'''Study'''
+</div></div><br>
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+<div class="toccolours" style="background-color:#eeeeee">
-|'''Comparator'''
+===Regimen variant #2, 12 cycles {{#subobject:da0fc9|Variant=1}}===
-|[[Levels_of_Evidence#Efficacy|'''Efficacy''']]
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3816958/ Gilbert et al. 2013 (RTOG 0525)]
+|2006-2008
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Dose-dense_Temozolomide_monotherapy_999|Dose-dense Temozolomide]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|[http://www.nejm.org/doi/full/10.1056/NEJMoa043330 Stupp et al. 2005]
+|[https://doi.org/10.1056/NEJMoa1611977 Perry et al. 2017 (NCIC-CTG CE.6)]
-|style="background-color:#00CD00"|Phase III
+|2007-2013
-|[[#Radiation_therapy|Radiotherapy]]
+| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
-|style="background-color:#00CD00"|Superior OS
+| style="background-color:#d3d3d3" |
+| style="background-color:#d3d3d3" |
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201043/ Gilbert et al. 2014]
+|[https://doi.org/10.1016/S1470-2045(17)30517-X Weller et al. 2017 (ACT IV)]
-|style="background-color:#00CD00"|Phase III
+|2012-2014
-|Bevacizumab, Temozolomide, RT
+| style="background-color:#1a9851" |Phase 3 (C)
-|style="background-color:#de2d26"|Inferior PFS
+|[[#Rindopepimut_.26_Temozolomide_999|Rindopepimut & Temozolomide]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|[http://www.nejm.org/doi/full/10.1056/NEJMoa1308345 Chinot et al. 2014]
+|[https://doi.org/10.1001/jamanetworkopen.2022.53285 Guo et al. 2023 (CSNO2012001)]
-|style="background-color:#00CD00"|Phase III
+|2012-05-01 to 2016-03-30
-|Bevacizumab, Temozolomide, RT
+| style="background-color:#1a9851" |Phase 3 (C)
-|style="background-color:#de2d26"|Inferior PFS
+|[[#Temozolomide_.26_Interferon_alfa_888|Temozolomide & Interferon alfa]]
+| style="background-color:#d73027" |Inferior OS
 |-
 |}
-''Note: although this regimen had inferior PFS in Gilbert et al. 2014, the effect size did not reach the prespecified improvement target.''
+''Note: treatment in ACT IV was given for a minimum of 6 cycles.''
-====Chemoradiotherapy====
+<div class="toccolours" style="background-color:#cbd5e8">
-*[[Temozolomide (Temodar)]] 75 mg/m<sup>2</sup> PO once per day, used starting the first day of radiation therapy until the last day of radiation therapy, and no longer than 49 days
+====Preceding treatment====
-*Concurrent radiation therapy, 2 Gy fractions x 30 fractions given 5 days per week, for a total dose of 60 Gy
+*RTOG 0525 & CSNO2012001: [[Surgery#CNS_cancer_surgery|Surgery]], then adjuvant [[#Temozolomide_.26_RT|temozolomide & RT]]
+*NCIC-CTG CE.6: [[Surgery#CNS_cancer_surgery|Surgery]], then adjuvant [[#Temozolomide_.26_low-dose_RT|temozolomide & low-dose RT]] versus [[#Radiation_therapy_2|RT]]
+*ACT IV: [[Surgery#CNS_cancer_surgery|Resection]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Temozolomide (Temodar)]] 150 to 200 mg/m<sup>2</sup> PO once per day on days 1 to 5
+'''28-day cycle for up to 12 cycles'''
+</div></div>
-====Supportive medications====
+===References===
-*PCP prophylaxis with ONE of the following:
+#'''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; [[Study_Groups#EORTC|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. [https://doi.org/10.1056/NEJMoa043330 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15758009/ PubMed] [https://clinicaltrials.gov/study/NCT00006353 NCT00006353]
-**[[Trimethoprim/Sulfamethoxazole (Bactrim DS)|Trimethoprim/Sulfamethoxazole (Bactrim)]]
+##'''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. [https://doi.org/10.1056/NEJMoa043331 link to original article] [https://pubmed.ncbi.nlm.nih.gov/15758010/ PubMed]
-**[[Pentamidine (Nebupent)]] 300 mg nebulized inhaled
+##'''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; [[Study_Groups#EORTC|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. [https://doi.org/10.1016/S1470-2045(09)70025-7 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19269895/ PubMed]
-*[[Metoclopramide (Reglan)]] or [[Antiemesis|5-HT3 antagonist]] recommended before the initial doses of radiation therapy & temozolomide
+#'''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. [https://doi.org/10.1200/JCO.2013.49.6968 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3816958/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/24101040/ PubMed] [https://clinicaltrials.gov/study/NCT00304031 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. [https://doi.org/10.1056/NEJMoa1308573 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201043/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24552317/ PubMed] [https://clinicaltrials.gov/study/NCT00884741 NCT00884741]
-'''One course'''
+#'''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. [https://doi.org/10.1056/NEJMoa1308345 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/24552318/ PubMed] [https://clinicaltrials.gov/study/NCT00943826 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. [https://doi.org/10.1001/jama.2015.16669 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/26670971/ PubMed] [https://clinicaltrials.gov/study/NCT00916409 NCT00916409]
-''4 weeks after completion of radiation therapy, patients received additional therapy:''
+##'''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. [https://doi.org/10.1001/jama.2017.18718 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5820703/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29260225/ PubMed]
+#'''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. [https://doi.org/10.1200/JCO.2015.63.4691 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26976423/ PubMed] [https://clinicaltrials.gov/study/NCT00967330 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. [https://doi.org/10.18632/oncotarget.12273 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351686/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/27690294/ PubMed] [https://clinicaltrials.gov/study/NCT00807027 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. [https://doi.org/10.1056/NEJMoa1611977 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28296618/ PubMed] [https://clinicaltrials.gov/study/NCT00482677 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. [https://doi.org/10.1016/S1470-2045(17)30517-X link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/28844499/ PubMed] [https://clinicaltrials.gov/study/NCT01480479 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. [https://doi.org/10.1186/s12967-018-1507-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5975654/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29843811/ PubMed] [https://clinicaltrials.gov/study/NCT00045968 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. [https://doi.org/10.1001/jamanetworkopen.2022.53285 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/36705923/ PubMed] [https://clinicaltrials.gov/study/NCT01765088 NCT01765088]
+#'''CALGB A071102:''' [https://clinicaltrials.gov/study/NCT02152982 NCT02152982]
+==Temozolomide & NovoTTF-100A {{#subobject:4bee42|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:d00b22|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1001/jama.2015.16669 Stupp et al. 2015 (EF-14)]
+|2009-2014
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[#Temozolomide_monotherapy_2|Temozolomide]]
+| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 7.1 vs 4 mo<br>(HR 0.62, 98.7% CI 0.43-0.89)<br><br>Superior OS<sup>1</sup> (secondary endpoint)<br>Median OS: 20.9 vs 16 mo<br>(HR 0.63, 95% CI 0.53-0.76)
+|-
+|}
+''<sup>1</sup>Reported efficacy is based on the 2017 update.''<br>
+''Note: Temozolomide dose is increased only if prior dose was tolerated.''
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*Adjuvant [[#Temozolomide_.26_RT|Temozolomide & RT]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Temozolomide (Temodar)]] as follows:
 **Cycle 1: 150 mg/m<sup>2</sup> PO once per day on days 1 to 5
-**If tolerated, in cycles 2 to 6: 200 mg/m<sup>2</sup> PO once per day on days 1 to 5
+**Cycles 2 to 6: 200 mg/m<sup>2</sup> PO once per day on days 1 to 5
-====Supportive medications====
-*[[Metoclopramide (Reglan)]] or [[Antiemesis|5-HT3 antagonist]] required
 '''28-day cycle for 6 cycles'''
+====Tumor treating fields, CNS====
+*[[NovoTTF-100A system (Optune)]] for at least 18 hours per day
+'''Up to to 24-month course'''
+</div></div>
 ===References===
-# 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; European Organisation for Research and Treatment of Cancer 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. [http://www.nejm.org/doi/full/10.1056/NEJMoa043330 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15758009 PubMed]
+#'''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. [https://doi.org/10.1001/jama.2015.16669 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/26670971/ PubMed] [https://clinicaltrials.gov/study/NCT00916409 NCT00916409]
-## '''Subgroup 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. [http://www.nejm.org/doi/full/10.1056/NEJMoa043331 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15758010 PubMed]
+##'''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. [https://doi.org/10.1001/jama.2017.18718 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5820703/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29260225/ PubMed]
-# 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. [http://www.nejm.org/doi/full/10.1056/NEJMoa1308573 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201043/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24552317 PubMed]
-# 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. [http://www.nejm.org/doi/full/10.1056/NEJMoa1308345 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24552318 PubMed]
-# 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. [http://www.nejm.org/doi/full/10.1056/NEJMoa1611977 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28296618 PubMed]
-=Recurrent disease, salvage therapy=
+=Recurrent disease, non-curative therapy, randomized data=
 ==Bevacizumab monotherapy {{#subobject:fc9abc|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, limited duration {{#subobject:c6f29b|Variant=1}}===
+{| class="wikitable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://doi.org/10.1200/jco.2008.19.8721 Friedman et al. 2009 (AVF3708g)]
+|2006-2007
+| style="background-color:#91cf61" |Phase 2 (RT)
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Targeted therapy====
+*[[Bevacizumab (Avastin)]] 10 mg/kg IV once on day 1
+'''14-day cycle for up to 52 cycles (2 years)'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, indefinite {{#subobject:35ed36|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2645088/ Kreisl et al. 2008 (NCI 06-C-0064E)]
+|2006-2007
+| style="background-color:#91cf61" |Phase 2 (RT)
+| style="background-color:#d3d3d3" |
+| style="background-color:#d3d3d3" |
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7243167/ Reardon et al. 2020 (CheckMate 143)]
+|2014-09 to 2015-05
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Nivolumab_monotherapy_999|Nivolumab]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7229248/ Cloughesy et al. 2020 (GLOBE)]
+|2015-2017
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Ofranergene_obadenovec_.26_Bevacizumab_999|Ofranergene obadenovec & Bevacizumab]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|[[#top|back to top]]
 |}
-===Regimen #1 {{#subobject:c6f29b|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
-{| border="1" style="text-align:center;" !align="left"
+====Targeted therapy====
-|'''Study'''
+*[[Bevacizumab (Avastin)]] 10 mg/kg IV once on day 1
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+'''14-day cycles'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*NCI 06-C-0064E, upon progression: [[#Irinotecan_.26_Bevacizumab_2|Irinotecan & Bevacizumab]]
+</div></div>
+===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. [https://doi.org/10.1200/jco.2008.16.3055 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2645088/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19114704/ PubMed]
+<!-- Presented in part at the 12th Annual Meeting of the Society for Neuro-Oncology, November 15-18, 2007, Dallas, TX, and at the 44th Annual Meeting of the American Society of Clinical Oncology, May 30-June 3, 2008, Chicago, IL. -->
+#'''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. [https://doi.org/10.1200/jco.2008.19.8721 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19720927/ PubMed] [https://clinicaltrials.gov/study/NCT00345163 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. [https://doi.org/10.1016/S1470-2045(14)70314-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25035291/ PubMed] 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. [https://doi.org/10.1016/j.ejca.2015.03.025 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25899986/ PubMed]
+#'''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. [https://doi.org/10.1093/neuonc/noz232 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7229248/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31844890/ PubMed] [https://clinicaltrials.gov/study/NCT02511405 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. [https://doi.org/10.1001/jamaoncol.2020.1024 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7243167/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/32437507/ PubMed] [https://clinicaltrials.gov/study/NCT02017717 NCT02017717]
+==Carmustine monotherapy {{#subobject:5ead84|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:fc297c|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://doi.org/10.1001/jama.1972.03210050021004 Fewer et al. 1972]
+|1968-12 to 1970-08-01
+| style="background-color:#ffffbe" |Retrospective
 |-
-|[http://jco.ascopubs.org/content/27/28/4733.long Friedman et al. 2009]
+|[https://doi.org/10.1212/01.wnl.0000140495.33615.ca Brandes et al. 2004a]
-|style="background-color:#eeee00"|Phase II
+|2002-06 to 2003-10
+| style="background-color:#91cf61" |Phase 2
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Bevacizumab (Avastin)]] 10 mg/kg IV once per day on days 1, 15, 29
+*[[Carmustine (BCNU)]] 80 mg/m<sup>2</sup> IV once per day on days 1 to 3
+====Supportive therapy====
-'''6-week cycle for up to 104 weeks, until progression of disease, or unacceptable toxicity'''
+*Antiemesis prophylaxis with [[Ondansetron (Zofran)]]
+*[[:Category:Steroids|Steroids]] at lowest dose necessary
-===Regimen #2 {{#subobject:35ed36|Variant=1}}===
+'''8-week cycle for up to 6 cycles'''
-{| border="1" style="text-align:center;" !align="left"
+</div></div>
-|'''Study'''
+===References===
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+#'''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. [https://doi.org/10.1001/jama.1972.03210050021004 link to original article] [https://pubmed.ncbi.nlm.nih.gov/4343318/ PubMed]
+#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. [https://doi.org/10.1212/01.wnl.0000140495.33615.ca link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15477552/ PubMed]
+==Gliadel wafer monotherapy {{#subobject:3fdb9e|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:caa94a|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1016/s0140-6736(95)90755-6 Brem et al. 1995]
+|1989-1992
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[Glioblastoma_-_null_regimens#Placebo|Placebo wafer]]
+| style="background-color:#1a9850" |Superior OS
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1920672/ Westphal et al. 2003]
+|1997-1999
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[Glioblastoma_-_null_regimens#Placebo|Placebo wafer]]
+| style="background-color:#91cf60" |Seems to have superior OS
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2645088/ Kreisl et al. 2008]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2940677/ Kunwar et al. 2010 (PRECISE)]
-|style="background-color:#EEEE00"|Phase II
+|2004-03 to 2005-12
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Cintredekin_besudotox_monotherapy_999|Cintredekin besudotox]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |}
-====Chemotherapy====
+<div class="toccolours" style="background-color:#b3e2cd">
-*[[Bevacizumab (Avastin)]] 10 mg/kg IV once per day on days 1 & 15
+====Local therapy====
+*[[Carmustine wafer, polifeprosan 20 (Gliadel wafer)]]
-'''4-week cycles, given until progression of disease, or unacceptable toxicity'''; upon progression, patients received [[#Irinotecan_monotherapy_.26_Bevacizumab_.28Avastin.29_2|Irinotecan (Camptosar) & Bevacizumab (Avastin)]]
+</div></div>
 ===References===
-# 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. [http://jco.ascopubs.org/content/27/5/740.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2645088/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19114704 PubMed]
+#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. [https://doi.org/10.1016/s0140-6736(95)90755-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7723496/ PubMed]
-<!-- Presented in part at the 12th Annual Meeting of the Society for Neuro-Oncology, November 15-18, 2007, Dallas, TX, and at the 44th Annual Meeting of the American Society of Clinical Oncology, May 30-June 3, 2008, Chicago, IL. -->
+#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. [https://doi.org/10.1093/neuonc/5.2.79 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1920672/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/12672279/ PubMed]
-# 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. [http://jco.ascopubs.org/content/27/28/4733.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19720927 PubMed]
+#'''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. [https://doi.org/10.1093/neuonc/nop054 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2940677/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20511192/ PubMed] [https://clinicaltrials.gov/study/NCT00076986 NCT00076986]
-==Bevacizumab & Carboplatin {{#subobject:f5673c|Regimen=1}}==
+==Hydroxyurea monotherapy {{#subobject:227c90|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:6ea460|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[[#top|back to top]]
+|[https://doi.org/10.1007/s11060-009-9976-3 Dresemann et al. 2009 (CSTI571BDE40)]
-|}
+|2004-2006
-===Regimen #1 {{#subobject:401e2e|Variant=1}}===
+| style="background-color:#1a9851" |Phase 3 (C)
-{| border="1" style="text-align:center;" !align="left"
+|[[#Hydroxyurea_.26_Imatinib|Hydroxyurea & Imatinib]]
-|'''Study'''
+| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
-|-
-|[http://journals.lww.com/neurosurgery/pages/articleviewer.aspx?year=2010&issue=07000&article=00013&type=abstract Thompson et al. 2010]
-|style="background-color:#ff0000"|Retrospective
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Bevacizumab (Avastin)]] 10 mg/kg IV once on day 1
+*[[Hydroxyurea (Hydrea)]] 500 mg PO three times per day on days 1 to 42
-*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1
+'''42-day cycles'''
+</div></div>
-'''28-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. [https://doi.org/10.1007/s11060-009-9976-3 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19688297/ PubMed] [https://clinicaltrials.gov/study/NCT00154375 NCT00154375]
-===Regimen #2 {{#subobject:ffa90b|Variant=1}}===
+==Hydroxyurea & Imatinib {{#subobject:1b771d|Regimen=1}}==
-{| border="1" style="text-align:center;" !align="left"
+<div class="toccolours" style="background-color:#eeeeee">
-|'''Study'''
+===Regimen {{#subobject:1c1791|Variant=1}}===
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1093/annonc/mdi317 Dresemann 2005]
+|NR
+| style="background-color:#91cf61" |Non-randomized
+| style="background-color:#d3d3d3" |
+| style="background-color:#d3d3d3" |
 |-
-|[http://www.neurology.org/content/70/10/779.long Norden et al. 2008]
+|[https://doi.org/10.1007/s11060-009-9976-3 Dresemann et al. 2009 (CSTI571BDE40)]
-|style="background-color:#ff0000"|Retrospective
+|2004-2006
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[#Hydroxyurea_monotherapy|Hydroxyurea]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 |-
 |}
+''Note: this combination did not succeed in the randomized phase III trial.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Bevacizumab (Avastin)]] 10 mg/kg IV once every 2 weeks
+*[[Hydroxyurea (Hydrea)]] 500 mg PO twice per day
-*[[Carboplatin (Paraplatin)]] AUC 5 to 6 IV (reference does not list schedule of carboplatin)
+====Targeted therapy====
+*[[Imatinib (Gleevec)]] 400 mg PO once per day
+'''Continued indefinitely'''
+</div></div>
 ===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. [http://www.neurology.org/content/70/10/779.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18316689 PubMed]
+#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. [https://doi.org/10.1093/annonc/mdi317 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16033874/ PubMed]
-# '''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. [http://journals.lww.com/neurosurgery/pages/articleviewer.aspx?year=2010&issue=07000&article=00013&type=abstract link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4905718/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20559095 PubMed]
+#'''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. [https://doi.org/10.1007/s11060-009-9976-3 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19688297/ PubMed] [https://clinicaltrials.gov/study/NCT00154375 NCT00154375]
+==Lomustine monotherapy {{#subobject:dc7f4|Regimen=1}}==
-==Bevacizumab & Irinotecan {{#subobject:a9cf4a|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable" style="float:right; margin-left: 5px;"
+===Regimen variant #1, 100 mg/m<sup>2</sup> {{#subobject:701e36|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834468/ Wick et al. 2010 (JCBF)]
+|2006-03 to 2007-08
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Enzastaurin_monotherapy_999|Enzastaurin]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 |-
-|[[#top|back to top]]
 |}
-===Regimen #1, every 2 week schedule {{#subobject:a156f1|Variant=1}}===
+''Note: this was the lower bound of the range specified in the trial.''
-{| border="1" style="text-align:center;" !align="left"
+<div class="toccolours" style="background-color:#b3e2cd">
-|'''Study'''
+====Chemotherapy====
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+*[[Lomustine (CCNU)]] 100 mg/m<sup>2</sup> 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'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, 110 mg/m<sup>2</sup>, uncapped {{#subobject:193934|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[http://jco.ascopubs.org/content/25/30/4714.long Chen et al. 2007]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4021043/ Batchelor et al. 2013 (REGAL)]
-|style="background-color:#eeee00"|Pilot, >20 pts
+|2008-10 to 2009-09
+| style="background-color:#1a9851" |Phase 3 (C)
+|1. [[#Cediranib_monotherapy_999|Cediranib]]<br>2. [[#Cediranib_.26_Lomustine_999|Cediranib & Lomustine]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 |-
-|[http://jco.ascopubs.org/content/25/30/4722.long Vredenburgh et al. 2007]
+|}
-|style="background-color:#EEEE00"|Phase II
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Lomustine (CCNU)]] 110 mg/m<sup>2</sup> PO once on day 1
+'''42-day cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #3, 110 mg/m<sup>2</sup>, capped {{#subobject:193934|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[http://www.neurology.org/content/70/10/779.long Norden et al. 2008]
+|[https://doi.org/10.1016/S1470-2045(14)70314-6 Taal et al. 2014 (BELOB)]
-|style="background-color:#EEEE00"|Phase II
+|2009-12-11 to 2011-11-10
+| style="background-color:#1a9851" |Randomized Phase 2 (C)
+|[[#Lomustine_.26_Bevacizumab|Lomustine & Bevacizumab]]
+| style="background-color:#d3d3d3" |Not reported
 |-
-|[http://jco.ascopubs.org/content/27/28/4733.long Friedman et al. 2009]
+|[https://doi.org/10.1056/NEJMoa1707358 Wick et al. 2017 (EORTC 26101)]
-|style="background-color:#eeee00"|Phase II
+|2011-2014
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Lomustine_.26_Bevacizumab|Lomustine & Bevacizumab]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
-''Note: Friedman et al. 2009 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/m<sup>2</sup> IV over 90 minutes once on day 1, '''given first'''
+*[[Lomustine (CCNU)]] 110 mg/m<sup>2</sup> (maximum dose of 200 mg) PO once on day 1
-**Patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) are treated with a higher dose: 340 mg/m<sup>2</sup> (Vredenburgh et al. 2007 & Norden et al. 2008) or 350 mg/m<sup>2</sup> (Chen et al. 2007) IV over 90 minutes once on day 1, '''given first'''
+'''42-day cycles'''
-*[[Bevacizumab (Avastin)]] 10 mg/kg IV once on day 1, '''given second, 90 minutes after the start of irinotecan'''
+</div></div><br>
-**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
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #4, 130 mg/m<sup>2</sup> {{#subobject:704e36|Variant=1}}===
-====Supportive medications====
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-*[[Steroid conversions|Steroids]] were generally maintained at the same dose
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
-'''14-day cycles, given until progression of disease or unacceptable toxicity'''
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
-===Regimen #2 {{#subobject:7da12|Variant=1}}===
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-{| border="1" style="text-align:center;" !align="left"
+|-
-|'''Study'''
+|[https://doi.org/10.1016/0360-3016(89)90920-6 Bleehen et al. 1989]
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+|1983-1986
+| style="background-color:#1a9851" |Randomized (C)
+|[[#Benznidazole_.26_Lomustine_999|Benznidazole & Lomustine]]
+| style="background-color:#ffffbf" |Did not meet endpoint
 |-
-|[http://jco.ascopubs.org/content/25/30/4722.long Vredenburgh et al. 2007]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834468/ Wick et al. 2010 (JCBF)]
-|style="background-color:#ff0000"|Phase II, <20 pts
+|2006-03 to 2007-08
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Enzastaurin_monotherapy_999|Enzastaurin]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 |-
 |}
+''Note: this was the upper bound of the range specified in JCBF.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Irinotecan (Camptosar)]] 125 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1, 8, 22, 29, '''given first'''
+*[[Lomustine (CCNU)]] 130 mg/m<sup>2</sup> PO once on day 1
-**Patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) are treated with a higher dose: 350 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1, 8, 22, 29, '''given first'''
+====Supportive therapy====
-*[[Bevacizumab (Avastin)]] 15 mg/kg IV once per day on days 1 & 22, '''given second, 90 minutes after the start of irinotecan'''
+*Enzyme-inducing antiepileptic drugs (EIAEDs) needed to be discontinued 14 days before enrolling in JCBF
-**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
+'''42-day cycle for 6 cycles or indefinitely (JCBF)'''
+</div></div>
-====Supportive medications====
-*[[Steroid conversions|Steroids]] were generally maintained at the same dose
-'''42-day (6-week) cycles, given until progression of disease or unacceptable toxicity'''
 ===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. [http://jco.ascopubs.org/content/25/30/4714.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17947718 PubMed]
+#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. [https://doi.org/10.1016/0360-3016(89)90920-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/2539345/ PubMed]
-# 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. [http://jco.ascopubs.org/content/25/30/4722.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17947719 PubMed]
+#'''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. [https://doi.org/10.1200/jco.2009.23.2595 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834468/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20124186/ PubMed] [https://clinicaltrials.gov/study/NCT00295815 NCT00295815]
-# 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. [http://www.neurology.org/content/70/10/779.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18316689 PubMed]
+#'''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. [https://doi.org/10.1200/JCO.2012.47.2464 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4021043/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23940216/ PubMed] [https://clinicaltrials.gov/study/NCT00777153 NCT00777153]
-<!-- Presented in part at the 12th Annual Meeting of the Society for Neuro-Oncology, November 15-18, 2007, Dallas, TX, and at the 44th Annual Meeting of the American Society of Clinical Oncology, May 30-June 3, 2008, Chicago, IL. -->
+#'''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. [https://doi.org/10.1016/S1470-2045(14)70314-6 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25035291/ PubMed] NTR1929
-# 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. [http://jco.ascopubs.org/content/27/28/4733.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19720927 PubMed]
+##'''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. [https://doi.org/10.1016/j.ejca.2015.03.025 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25899986/ PubMed]
+#'''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. [https://doi.org/10.1056/NEJMoa1707358 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/29141164/ PubMed] [https://clinicaltrials.gov/study/NCT01290939 NCT01290939]
-==Carmustine monotherapy {{#subobject:5ead84|Regimen=1}}==
+==Lomustine & Bevacizumab {{#subobject:dc7f64|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:1a7gh4|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1016/S1470-2045(14)70314-6 Taal et al. 2014 (BELOB)]
+|2009-12-11 to 2011-11-10
+| style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
+|[[#Lomustine_monotherapy|Lomustine]]
+| style="background-color:#d3d3d3" |Not reported
+|-
+|[https://doi.org/10.1056/NEJMoa1707358 Wick et al. 2017 (EORTC 26101)]
+|2011-2014
+| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
+|[[#Lomustine_monotherapy|Lomustine]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|[[#top|back to top]]
 |}
-===Regimen {{#subobject:fc297c|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
-{| border="1" style="text-align:center;" !align="left"
+====Chemotherapy====
-|'''Study'''
+*[[Lomustine (CCNU)]] 110 mg/m<sup>2</sup> IV once on day 1
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+====Targeted therapy====
+*[[Bevacizumab (Avastin)]] 10 mg/kg IV once per day on days 1, 15, 29
+'''42-day cycles'''
+</div></div>
+===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. [https://doi.org/10.1016/S1470-2045(14)70314-6 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/25035291/ PubMed] 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. [https://doi.org/10.1016/j.ejca.2015.03.025 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25899986/ PubMed]
+#'''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. [https://doi.org/10.1056/NEJMoa1707358 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29141164/ PubMed] [https://clinicaltrials.gov/study/NCT01290939 NCT01290939]
+==NovoTTF-100A monotherapy {{#subobject:1674af|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:4a488e|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[http://www.neurology.org/content/63/7/1281.long Brandes et al. 2004]
+|[https://doi.org/10.1016/j.ejca.2012.04.011 Stupp et al. 2012 (EF-11)]
-|style="background-color:#EEEE00"|Phase II
+|2006-2009
+| style="background-color:#1a9851" |Phase 3 (E-switch-ooc)
+|Investigator's choice of chemotherapy
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |}
-====Chemotherapy====
+<div class="toccolours" style="background-color:#b3e2cd">
-*[[Carmustine (BiCNU)]] 80 mg/m<sup>2</sup> IV once per day on days 1 to 3
+====Tumor treating fields, CNS====
+*[[NovoTTF-100A system (Optune)]]
-====Supportive medications====
+</div></div>
-*[[Antiemesis]] prophylaxis with [[Ondansetron (Zofran)]]
-*[[Steroid conversions|Steroids]] at lowest dose necessary
-'''8-week cycle for up to 6 cycles'''
 ===References===
-# 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. [http://www.neurology.org/content/63/7/1281.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15477552 PubMed]
+#'''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. [https://doi.org/10.1016/j.ejca.2012.04.011 link to original article] [https://pubmed.ncbi.nlm.nih.gov/22608262/ PubMed] [https://clinicaltrials.gov/study/NCT00379470 NCT00379470]
-==CART-EGFRvIII cells {{#subobject:ed311c|Regimen=1}}==
+==PCV {{#subobject:7dh158|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+PCV: '''<u>P</u>'''rocarbazine, '''<u>C</u>'''CNU (Lomustine), '''<u>V</u>'''incristine
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, 60/110/1.4 {{#subobject:c3f4c2|Variant=1}}===
+{| class="wikitable" style="width: 40%; text-align:center;"
+! style="width: 25%" |Study
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://pubmed.ncbi.nlm.nih.gov/7407756 Levin et al. 1980]
+| style="background-color:#91cf61" |Non-randomized
 |-
-|[[#top|back to top]]
 |}
-===Regimen {{#subobject:26961a|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
-{| border="1" style="text-align:center;" !align="left"
+====Chemotherapy====
-|'''Study'''
+*[[Procarbazine (Matulane)]] 60 mg/m<sup>2</sup> PO once per day on days 8 to 21
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+*[[Lomustine (CCNU)]] 110 mg/m<sup>2</sup> PO once on day 1
+*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 8 & 29
+'''42-day cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, 100/100/1.5 {{#subobject:41002c|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[http://stm.sciencemag.org/content/9/399/eaaa0984.full O'Rourke et al. 2017]
+|[https://doi.org/10.1200/JCO.2009.27.1932 Brada et al. 2010 (MRC BR12)]
-|style="background-color:#ff0000"|Phase I
+|2003-2008
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Temozolomide_monotherapy_3|Temozolomide]]
+| style="background-color:#ffffbf" |Did not meet co-primary endpoints of PFS3/OS
 |-
 |}
-====Immunotherapy====
+<div class="toccolours" style="background-color:#b3e2cd">
-*Autologous CART-EGFRvIII cells, see paper for details
+====Chemotherapy====
+*[[Procarbazine (Matulane)]] 100 mg/m<sup>2</sup> PO once per day on days 1 to 10
-'''One treatment'''
+*[[Lomustine (CCNU)]] 100 mg/m<sup>2</sup> PO once on day 1
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1
+'''42-day cycle for up to 6 cycles'''
+</div></div>
 ===References===
-# '''Phase I:''' 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). [https://www.ncbi.nlm.nih.gov/pubmed/28724573 PubMed] [http://stm.sciencemag.org/content/9/399/eaaa0984.full link to original article]
+#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. '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/7407756/ PubMed]
+#'''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. [https://doi.org/10.1200/JCO.2009.27.1932 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20855843/ PubMed] [https://clinicaltrials.gov/study/NCT00052455 NCT00052455]
-==Cyclophosphamide monotherapy {{#subobject:1724a|Regimen=1}}==
+=Recurrent disease, non-curative therapy, non-randomized or retrospective data=
-{| class="wikitable" style="float:right; margin-left: 5px;"
+==Carboplatin & Bevacizumab {{#subobject:f5673c|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, q2wk bevacizumab {{#subobject:ffa90b|Variant=1}}===
+{| class="wikitable" style="width: 40%; text-align:center;"
+! style="width: 25%" |Study
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://doi.org/10.1212/01.wnl.0000304121.57857.38 Norden et al. 2008]
+| style="background-color:#ffffbe" |Retrospective
 |-
-|[[#top|back to top]]
 |}
-===Regimen {{#subobject:d0ffd5|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
-{| border="1" style="text-align:center;" !align="left"
+====Chemotherapy====
-|'''Study'''
+*[[Carboplatin (Paraplatin)]] AUC 5 to 6 IV (reference does not list schedule of carboplatin)
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+====Targeted therapy====
+*[[Bevacizumab (Avastin)]] 10 mg/kg IV once on day 1
+'''14-day cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, q4wk bevacizumab {{#subobject:401e2e|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[http://onlinelibrary.wiley.com/doi/10.1002/cncr.20072/full Chamberlain & Tsao-Wei, 2004]
+|[https://doi.org/10.1227/01.neu.0000370918.51053.bc Thompson et al. 2010]
-|style="background-color:#EEEE00"|Phase II
+|2006-2008
+| style="background-color:#ffffbe" |Retrospective
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Cyclophosphamide (Cytoxan)]] 750 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 2
+*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1
+====Targeted therapy====
-====Supportive medications====
+*[[Bevacizumab (Avastin)]] 10 mg/kg IV once on day 1
-*[[Dexamethasone (Decadron)]] allowed for control of neurologic symptoms
-*[[Ondansetron (Zofran)]] 0.15 mg/kg IV once prior to cyclophosphamide
-*[[Dexamethasone (Decadron)]] 4 mg IV once prior to cyclophosphamide
-*1 liter normal saline IV over 2 hours prior to cyclophosphamide
-*[[Prochlorperazine (Compazine)]] (dose/schedule not specified) prn nausea/vomiting
 '''28-day cycles'''
+</div></div>
 ===References===
-# Chamberlain MC, Tsao-Wei DD. Salvage chemotherapy with cyclophosphamide for recurrent, temozolomide-refractory glioblastoma multiforme. Cancer. 2004 Mar 15;100(6):1213-20. [http://onlinelibrary.wiley.com/doi/10.1002/cncr.20072/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15022289 PubMed]
+#'''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. [https://doi.org/10.1212/01.wnl.0000304121.57857.38 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18316689/ PubMed]
+#'''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. [https://doi.org/10.1227/01.neu.0000370918.51053.bc link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4905718/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20559095/ PubMed]
-==Hydroxyurea & Imatinib {{#subobject:1b771d|Regimen=1}}==
+==CART-EGFRvIII monotherapy {{#subobject:ed311c|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:26961a|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5762203/ O'Rourke et al. 2017 (UPCC 35313)]
+|NR
+| style="background-color:#ffffbe" |Phase 1
 |-
-|[[#top|back to top]]
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
+*Autologous [[CART-EGFRvIII]] cells, see paper for details
+'''One treatment'''
+</div></div>
+===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). [https://doi.org/10.1126/scitranslmed.aaa0984 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5762203/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28724573/ PubMed] [https://clinicaltrials.gov/study/NCT02209376 NCT02209376]
-===Regimen {{#subobject:1c1791|Variant=1}}===
+==Cyclophosphamide monotherapy {{#subobject:1724fa|Regimen=1}}==
-{| border="1" style="text-align:center;" !align="left"
+<div class="toccolours" style="background-color:#eeeeee">
-|'''Study'''
+===Regimen {{#subobject:d0ffd5|Variant=1}}===
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[http://annonc.oxfordjournals.org/content/16/10/1702.long Dresemann et al. 2005]
+|[https://doi.org/10.1002/cncr.20072 Chamberlain & Tsao-Wei 2004]
-|style="background-color:#EEEE00"|Non-randomized
+|1999-11 to 2003-01
+| style="background-color:#91cf61" |Phase 2
 |-
 |}
+<div class="toccolours" style="background-color:#fdcdac">
+====Prior treatment criteria====
+*Temozolomide exposure, with refractory disease
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Imatinib (Gleevec)]] 400 mg PO once per day
+*[[Cyclophosphamide (Cytoxan)]] 750 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 2
-*[[Hydroxyurea (Hydrea)]] 500 mg PO BID
+====Supportive therapy====
+*[[Dexamethasone (Decadron)]] allowed for control of neurologic symptoms
-'''Given until progression of disease'''
+*[[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'''
+</div></div>
 ===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. [http://annonc.oxfordjournals.org/content/16/10/1702.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16033874 PubMed]
+#Chamberlain MC, Tsao-Wei DD. Salvage chemotherapy with cyclophosphamide for recurrent, temozolomide-refractory glioblastoma multiforme. Cancer. 2004 Mar 15;100(6):1213-20. [https://doi.org/10.1002/cncr.20072 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15022289/ PubMed]
 ==Irinotecan monotherapy {{#subobject:14c7e6|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen {{#subobject:24c9e2|Variant=1}}===
-{| border="1" style="text-align:center;" !align="left"
+{| class="wikitable" style="width: 40%; text-align:center;"
-|'''Study'''
+! style="width: 25%" |Study
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[http://jco.ascopubs.org/content/17/5/1516.long Friedman et al. 1999]
+|[https://doi.org/10.1200/jco.1999.17.5.1516 Friedman et al. 1999]
-|style="background-color:#EEEE00"|Phase II
+| style="background-color:#91cf61" |Phase 2
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Irinotecan (Camptosar)]] 125 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
-**If tolerated, dose could be increased to 150 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
+====Supportive therapy====
+*[[:Category:Steroids|Steroids]] at lowest dose necessary
-====Supportive medications====
-*[[Steroid conversions|Steroids]] at lowest dose necessary
 *Avoid laxatives and magnesium-containing antacids due to potential for diarrhea
+'''42-day cycles'''
-'''42-day (6-week) cycles, given until progression of disease or unacceptable toxicity'''
+</div>
+<div class="toccolours" style="background-color:#fff2ae">
+====Dose and schedule modifications====
+*If tolerated, irinotecan dose could be increased to 150 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
+</div></div>
 ===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. [http://jco.ascopubs.org/content/17/5/1516.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10334539 PubMed]
+#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. [https://doi.org/10.1200/jco.1999.17.5.1516 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10334539/ PubMed]
+==Irinotecan & Bevacizumab {{#subobject:a9cf4a|Regimen=1}}==
-==Lomustine monotherapy {{#subobject:dc7f4|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable" style="float:right; margin-left: 5px;"
+===Regimen variant #1, q2wk bev {{#subobject:a156f1|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[[#top|back to top]]
+|[https://doi.org/10.1200/jco.2006.10.5825 Chen et al. 2007]
-|}
+|2005-06 to 2006-02
-===Regimen {{#subobject:704e36|Variant=1}}===
+| style="background-color:#91cf61" |Pilot, >20 pts
-{| border="1" style="text-align:center;" !align="left"
-|'''Study'''
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
-|'''Comparator'''
-|[[Levels_of_Evidence#Efficacy|'''Efficacy''']]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834468/ Wick et al. 2010]
+|[https://doi.org/10.1158/1078-0432.CCR-06-2309 Vredenburgh et al. 2007]
-|style="background-color:#00CD00"|Phase III
+|NR
-|Enzastaurin
+| style="background-color:#91cf61" |Phase 2
-|style="background-color:#eeee00"|Seems not superior
 |-
-|}
+|[https://doi.org/10.1212/01.wnl.0000304121.57857.38 Norden et al. 2008]
-====Chemotherapy====
+|2005-06 to 2007-03
-*[[Lomustine (Ceenu)]] 100 to 130 mg/m<sup>2</sup> PO once on day 1
+| style="background-color:#ffffbe" |Retrospective
-====Supportive medications====
-*Enzyme-inducing antiepileptic drugs (EIAEDs) needed to be discontinued 14 days before enrolling in the trial
-'''6-week cycles, given until progression of disease or unacceptable toxicity'''
-===References===
-# 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. [http://jco.ascopubs.org/content/28/7/1168.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834468/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20124186 PubMed]
-==PCV==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#top|back to top]]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2645088/ Kreisl et al. 2008 (NCI 06-C-0064E)]
-|}
+|2006-2007
-PCV: '''<u>P</u>'''rocarbazine, '''<u>C</u>'''CNU (Lomustine), '''<u>V</u>'''incristine
+| style="background-color:#91cf61" |Phase 2
-===Regimen #1 {{#subobject:c3f4c2|Variant=1}}===
-{| border="1" style="text-align:center;" !align="left"
-|'''Study'''
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
 |-
-|[https://www.ncbi.nlm.nih.gov/pubmed/7407756 Levin et al. 1980]
+|[https://doi.org/10.1200/jco.2008.19.8721 Friedman et al. 2009 (AVF3708g)]
-|style="background-color:#EEEE00"|Non-randomized
+|2006-2007
+| style="background-color:#91cf61" |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.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Procarbazine (Matulane)]] 60 mg/m<sup>2</sup> PO once per day on days 8 to 21
+*[[Irinotecan (Camptosar)]] 125 mg/m<sup>2</sup> IV over 90 minutes once on day 1, '''given first'''
-*[[Lomustine (Ceenu)]] 110 mg/m<sup>2</sup> PO once on day 1
+**Patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) are treated with a higher dose: 340 mg/m<sup>2</sup> or 350 mg/m<sup>2</sup> (Chen et al. 2007) IV over 90 minutes once on day 1, '''given first'''
-*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 8 & 29
+====Targeted therapy====
+*[[Bevacizumab (Avastin)]] 10 mg/kg IV once on day 1, '''given second, 90 minutes after the start of irinotecan'''
-'''6-week cycles, given until progression of disease or unacceptable toxicity'''
+**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====
-===Regimen #2, higher doses {{#subobject:aba32b|Variant=1}}===
+*[[:Category:Steroids|Steroids]] were generally maintained at the same dose
-{| border="1" style="text-align:center;" !align="left"
+'''14-day cycles'''
-|'''Study'''
+</div></div><br>
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, q3wk bev {{#subobject:7da12|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[http://jco.ascopubs.org/content/12/10/2013.long Cairncross et al. 1994]
+|[https://doi.org/10.1158/1078-0432.CCR-06-2309 Vredenburgh et al. 2007]
-|style="background-color:#EEEE00"|Phase II
+|NR
+| style="background-color:#ffffbe" |Phase 2, fewer than 20 pts
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Procarbazine (Matulane)]] 75 mg/m<sup>2</sup> PO once per day on days 8 to 21
+*[[Irinotecan (Camptosar)]] 125 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1, 8, 22, 29, '''given first'''
-*[[Lomustine (Ceenu)]] 130 mg/m<sup>2</sup> PO once on day 1
+**Patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) are treated with a higher dose: 350 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1, 8, 22, 29, '''given first'''
-*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> (dose not capped) IV once per day on days 8 & 29
+====Targeted therapy====
+*[[Bevacizumab (Avastin)]] 15 mg/kg IV once per day on days 1 & 22, '''given second, 90 minutes after the start of irinotecan'''
-'''6-week cycles, given until progression of disease or unacceptable toxicity'''
+**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====
+*[[:Category:Steroids|Steroids]] were generally maintained at the same dose
+'''42-day cycles'''
+</div></div>
 ===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. '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/7407756 PubMed]
+#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. [https://doi.org/10.1200/jco.2006.10.5825 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17947718/ PubMed]
+#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. [https://doi.org/10.1158/1078-0432.CCR-06-2309 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17317837/ PubMed]
+##'''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. [https://doi.org/10.1200/jco.2007.12.2440 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17947719/ PubMed]
+#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. [https://doi.org/10.1212/01.wnl.0000304121.57857.38 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18316689/ PubMed]
+#'''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. [https://doi.org/10.1200/jco.2008.16.3055 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2645088/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/19114704/ PubMed]
+<!-- Presented in part at the 12th Annual Meeting of the Society for Neuro-Oncology, November 15-18, 2007, Dallas, TX, and at the 44th Annual Meeting of the American Society of Clinical Oncology, May 30-June 3, 2008, Chicago, IL. -->
+#'''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. [https://doi.org/10.1200/jco.2008.19.8721 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19720927/ PubMed] [https://clinicaltrials.gov/study/NCT00345163 NCT00345163]
 ==Procarbazine monotherapy {{#subobject:69a372|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen {{#subobject:d1a052|Variant=1}}===
-{| border="1" style="text-align:center;" !align="left"
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-|'''Study'''
+!style="width: 33%"|Study
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2363506/ Yung et al. 2000]
-|style="background-color:#EEEE00"|Phase II
+|1995-01-05 to 1997-10-28
+| style="background-color:#91cf61" |Phase 2
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Procarbazine (Matulane)]] as follows:
+*[[Procarbazine (Matulane)]] by the following exposure-based criteria:
-**Patients who had never previously received chemotherapy: 150 mg/m<sup>2</sup> PO once per day on days 1 to 28
+**No prior exposure to chemotherapy: 150 mg/m<sup>2</sup> PO once per day on days 1 to 28
-**Patients who previously received chemotherapy started with 125 mg/m<sup>2</sup> PO once per day on days 1 to 28
+**Patients who previously received chemotherapy: 125 mg/m<sup>2</sup> PO once per day on days 1 to 28
+====Supportive therapy====
-====Supportive medications====
+*[[:Category:Steroids|Steroids]] at lowest dose necessary
-*[[Steroid conversions|Steroids]] at lowest dose necessary
+'''8-week cycle for up to 13 cycles (2 years)'''
+</div></div>
-'''8-week cycle for up to 2 years, progression of disease, or unacceptable toxicity'''
 ===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. [http://www.nature.com/bjc/journal/v83/n5/full/6691316a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2363506/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/10944597 PubMed]
+#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. [https://doi.org/10.1054/bjoc.2000.1316 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2363506/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/10944597/ PubMed]
 ==Temozolomide monotherapy {{#subobject:e73a18|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, continuous ramped dose {{#subobject:f8gu19|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[[#top|back to top]]
+|[https://doi.org/10.1007/s002800050691 Bower et al. 1997]
-|}
+|NR
-===Regimen #1, continuous therapy {{#subobject:f18af9|Variant=1}}===
+| style="background-color:#91cf61" |Phase 2
-{| border="1" style="text-align:center;" !align="left"
-|'''Study'''
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
-|-
-|[http://onlinelibrary.wiley.com/doi/10.1002/cncr.23813/full Perry et al. 2008 (RESCUE)]
-|style="background-color:#EEEE00"|Phase II
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-Patients who have first recurrence after surgery and conventional external beam radiation:
+*[[Temozolomide (Temodar)]] as follows:
-*[[Temozolomide (Temodar)]] 150 to 200 mg/m<sup>2</sup> PO once per day on days 1 to 5
+**Cycle 1: 150 mg/m<sup>2</sup> PO once per day on days 1 to 5
+**Cycle 2 onwards: 200 mg/m<sup>2</sup> PO once per day on days 1 to 5
 '''28-day cycles'''
+</div></div><br>
-Patients with progressive disease are changed to:
+<div class="toccolours" style="background-color:#eeeeee">
-*[[Temozolomide (Temodar)]] 50 mg/m<sup>2</sup> PO once per day, taken continuously without treatment break
+===Regimen variant #2, continuous low-dose {{#subobject:f18af9|Variant=1}}===
+{| class="wikitable" style="width: 40%; text-align:center;"
-'''Given until progression of disease or unacceptable toxicity'''
+! style="width: 25%" |Study
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-Patients who had recurrent/progressive disease after surgery and concurrent radiation and temozolomide are treated with:
-*[[Temozolomide (Temodar)]] 50 mg/m<sup>2</sup> PO once per day, taken continuously without treatment break
-'''Given until progression of disease or unacceptable toxicity'''
-===Regimen #2, traditional dosing {{#subobject:f06af9|Variant=1}}===
-{| border="1" style="text-align:center;" !align="left"
-|'''Study'''
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
 |-
-|[http://onlinelibrary.wiley.com/doi/10.1002/cncr.22961/full Nicholson et al. 2007]
+|[https://doi.org/10.1002/cncr.23813 Perry et al. 2008 (RESCUE)]
-|style="background-color:#EEEE00"|Non-randomized
+|2001-01 to 2005-07
+| style="background-color:#ffffbe" |Retrospective
 |-
 |}
+''Note: See paper for details of when this regimen is used.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Temozolomide (Temodar)]] 200 mg/m<sup>2</sup> PO once per day on days 1 to 5
+*[[Temozolomide (Temodar)]] 50 mg/m<sup>2</sup> PO once per day
-**Patients who previously received craniospinal irradiation (CSI) instead received 180 mg/m<sup>2</sup> PO once per day on days 1 to 5
+'''Continued indefinitely'''
+</div></div><br>
-'''28-day cycle for up to 11 cycles'''
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #3, 2 years {{#subobject:4cde86|Variant=1}}===
-===Regimen #3 {{#subobject:4cde86|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-{| border="1" style="text-align:center;" !align="left"
+!style="width: 33%"|Study
-|'''Study'''
+!style="width: 33%"|Dates of enrollment
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2363506/ Yung et al. 2000]
-|style="background-color:#EEEE00"|Phase II
+|1995-01-05 to 1997-10-28
+| style="background-color:#91cf61" |Phase 2
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Temozolomide (Temodar)]] as follows:
+*[[Temozolomide (Temodar)]] by the following exposure-based criteria:
 **Patients who had never previously received chemotherapy: 200 mg/m<sup>2</sup> PO once per day on days 1 to 5
-**Patients who previously received chemotherapy started with 150 mg/m<sup>2</sup> PO once per day on days 1 to 5
+**Patients who previously received chemotherapy: 150 mg/m<sup>2</sup> PO once per day on days 1 to 5
+'''28-day cycle for up to 26 cycles (2 years)'''
-'''28-day cycle for up to 2 years, until progression of disease, or unacceptable toxicity'''
+</div></div>
 ===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. [http://www.nature.com/bjc/journal/v83/n5/full/6691316a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2363506/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/10944597 PubMed]
+#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. [https://doi.org/10.1007/s002800050691 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9332462/ PubMed]
-# Nicholson HS, Kretschmar CS, Krailo M, Bernstein M, Kadota R, Fort D, Friedman H, Harris MB, Tedeschi-Blok N, Mazewski C, Sato J, Reaman GH. Phase 2 study of temozolomide in children and adolescents with recurrent central nervous system tumors: a report from the Children's Oncology Group. Cancer. 2007 Oct 1;110(7):1542-50. [http://onlinelibrary.wiley.com/doi/10.1002/cncr.22961/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17705175 PubMed]
+#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. [https://doi.org/10.1054/bjoc.2000.1316 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2363506/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/10944597/ PubMed]
-# 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. [http://onlinelibrary.wiley.com/doi/10.1002/cncr.23813/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18756530 PubMed]
+#'''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. [https://doi.org/10.1002/cncr.23813 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18756530/ PubMed] [https://clinicaltrials.gov/study/NCT00392171 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. [http://jco.ascopubs.org/content/28/12/2051.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20308655 PubMed]
+##'''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. [https://doi.org/10.1200/jco.2009.26.5520 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20308655/ PubMed]
+=Response criteria=
+==Response Assessment in Neuro-Oncology Working Group==
+*'''2010:''' [https://doi.org/10.1200/JCO.2009.26.3541 Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group] [https://pubmed.ncbi.nlm.nih.gov/20231676/ PubMed]
 [[Category:Glioblastoma regimens]]
 [[Category:Disease-specific pages]]
-[[Category:Disease index]]
+[[Category:High-grade gliomas]]

Difference between revisions of "Glioblastoma"

Latest revision as of 20:42, 29 June 2024

Guidelines

ASCO

EANO

ESMO

NCCN

Adjuvant therapy, standard patients

Bevacizumab & RT

Regimen

Preceding treatment

Targeted therapy

Radiotherapy

Subsequent treatment

References

Carmustine & RT

Regimen

Preceding treatment

Chemotherapy

Radiotherapy

References

Lomustine, Temozolomide, RT

Regimen

Preceding treatment

Chemotherapy

Radiotherapy

References

Nimustine & RT

Regimen

Preceding treatment

Chemotherapy

Radiotherapy

References

PCV

Regimen

Chemotherapy

References

Radiation therapy

Regimen

Preceding treatment

Radiotherapy

References

RT, then Carmustine

Regimen variant #1, WBRT

Preceding treatment

Radiotherapy

Chemotherapy

Regimen variant #2, WBRT with cone-down

Preceding treatment

Radiotherapy

Chemotherapy

References

Temozolomide & RT

Regimen

Biomarker eligibility criteria

Preceding treatment

Chemotherapy

Supportive therapy

Radiotherapy

Subsequent treatment

References

Adjuvant therapy, elderly or poor performance status patients

Radiation therapy

Regimen variant #1, hypofractionated (3400 cGy)

Preceding treatment

Radiotherapy

Regimen variant #2, abbreviated course (4000 cGy)

Preceding treatment

Radiotherapy

Regimen variant #3, standard course (5040 cGy)

Preceding treatment

Radiotherapy

Regimen variant #4, standard course (6000 cGy)

Preceding treatment

Radiotherapy

References

Temozolomide monotherapy

Regimen

Preceding treatment

Chemotherapy

Regimen variant #1, 100 mg/m²

Regimen variant #2, 110 mg/m², uncapped

Regimen variant #3, 110 mg/m², capped

Regimen variant #4, 130 mg/m²