Revision as of 23:07, 8 January 2020

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

27 regimens on this page 41 variants on this page

Guidelines

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

2017: European Association for Neuro-Oncology (EANO) guidelines for palliative care in adults with glioma PubMed
2014: EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma PubMed

ESMO

2014: Stupp et al. High-grade glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

NCCN

NCCN Guidelines - Central Nervous System Cancers

Adjuvant therapy, standard patients

Bevacizumab & RT

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Bevacizumab & RT: Bevacizumab & Radiation Therapy

Regimen

Study	Evidence	Comparator	Comparative Efficacy
Herrlinger et al. 2016 (GLARIUS)	Randomized Phase II (E-switch-ooc)	Temozolomide & RT, then Temozolomide	Superior PFS-6

To be completed

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 PubMed

Carmustine & RT

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BCNU & RT: BCNU (Carmustine) & Radiation Therapy

Variant #1, concurrent

Study	Evidence	Comparator	Comparative Efficacy
Eyre et al. 1986 (SWOG S7703)	Phase III (E-switch-ic)	1. DTIC & RT	Not reported
Eyre et al. 1986 (SWOG S7703)	Phase III (E-switch-ic)	2. Procarbazine & RT	Superior ORR
Dinapoli et al. 1993	Phase III (C)	PCNU & RT	Did not meet primary endpoints of TTP50%/OS50%
Buckner et al. 2001	Phase III (C)	BCNU, IFN alfa, RT	Did not meet endpoint of OS50%
Grossman et al. 2003 (ECOG E2394)	Phase III (C)	BCNU & Cisplatin, then RT	Did not meet primary endpoint of OS
Buckner et al. 2006 (NCCTG 93-72-52/SWOG S9503)	Phase III (C)	BCNU, Cisplatin, RT	Did not meet primary endpoint of OS50%
Blumenthal et al. 2014 (SWOG S0001)	Phase III (C)	BCNU, O⁶-benzylguanine, RT	Did not meet primary endpoint of OS
Ali et al. 2018 (RTOG 9006)	Phase III (C)	BCNU & RT; hyperfractionated	Did not meet primary endpoint of OS

Preceding treatment

Surgery

Chemotherapy

Carmustine (BCNU)

Radiotherapy

External beam radiotherapy

Variant #2, sequential

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

Preceding treatment

Surgery

Radiotherapy

External beam radiotherapy starting within 3 weeks after surgical resection, with ONE of the following:
- Whole brain: 172 cGy (rads) fractions x 35 fractions, given over 7 weeks for a total dose of 6020 cGy (6020 rads/~1700 rets)
- 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)

2- to 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

Supportive care

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

8-week cycles, with no more than a maximum cumulative dose of 1500 mg/m² Carmustine (BCNU) given

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
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 verified protocol 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; Eastern Cooperative Oncology Group. 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 93-72-52; Southwest Oncology Group 9503 Trials. 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 PubMed
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 PubMed

Lomustine, Temozolomide, RT

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

Regimen

Study	Evidence	Comparator	Comparative Efficacy
Herrlinger et al. 2019 (CeTeG/NOA-09)	Phase III (E-esc)	Temozolomide & RT	Seems to have superior OS

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 60 Gy 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 verified protocol PubMed

Nimustine & RT

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Nimustine & RT: Nimustine & Radiation Therapy

Regimen

Study	Evidence	Comparator	Comparative Efficacy
Shibui et al. 2012 (JCOG 0305)	Phase III (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)

Radiotherapy

External beam radiotherapy

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 PubMed

Radiation therapy

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Urtasun et al. 1976	Randomized (C)	Metronidazole & RT	Seems to have inferior OS
Walker et al. 1978 (BTSG 69-01)	Phase III (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)	Phase III (C)	1. Carmustine & RT 2. Semustine & RT	Did not meet primary endpoint of OS
Walker et al. 1980 (BTSG 72-01)	Phase III (C)	3. Semustine	Seems to have superior OS
Stupp et al. 2005 (EORTC 22981/26981; NCIC CTG CE.3)	Phase III (C)	Temozolomide & RT, then Temozolomide	Inferior OS

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; 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. link to original article contains verified protocol PubMed
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; European Organisation for Research and Treatment of Cancer 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

Temozolomide & RT

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Temozolomide & RT: Temozolomide & Radiation Therapy

Regimen

Study	Evidence	Comparator	Comparative Efficacy
Stupp et al. 2005 (EORTC 22981/26981; NCIC CTG CE.3)	Phase III (E-RT-esc)	See link	See link
Gilbert et al. 2013 (RTOG 0525)	Non-randomized portion of RCT
Gilbert et al. 2014 (RTOG 0825)	Phase III (C)	See link	See link
Chinot et al. 2014 (AVAglio)	Phase III (C)	See link	See link
Stupp et al. 2014 (CENTRIC)	Phase III (C)	Cilengitide, Temozolomide, RT	Did not meet primary endpoint of OS
Westphal et al. 2015 (OSAG 101-BSA-05)	Phase III (C)	Temozolomide, Nimotuzumab, RT	Did not meet primary endpoints of PFS12/PFS50%
Kong et al. 2017	Phase III (C)	Temozolomide & RT with CIK cells	Seems to have inferior PFS

Note: patients in CENTRIC were required to have methylated MGMT promoter.

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 medications

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, 2 Gy fractions x 30 fractions, for a total dose of 60 Gy

6-week course

Subsequent treatment

Most protocols: Temozolomide maintenance, 4 weeks after completion of radiation therapy
RTOG 0525: Temozolomide versus dose-dense temozolomide maintenance

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; 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. link to original article contains verified protocol PubMed
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; European Organisation for Research and Treatment of Cancer 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 verified protocol 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. link to original article link to PMC article PubMed
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 protocol PubMed
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; European Organisation for Research and Treatment of Cancer (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
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
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
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. link to original article link to PMC article contains verified protocol PubMed
HERBY: Grill J, Massimino M, Bouffet E, Azizi AA, McCowage G, Cañete A, Saran F, Le Deley MC, Varlet P, Morgan PS, Jaspan T, Jones C, Giangaspero F, Smith H, Garcia J, Elze MC, Rousseau RF, Abrey L, Hargrave D, Vassal G. Phase II, Open-label, randomized, multicenter trial (HERBY) of bevacizumab in pediatric patients with newly diagnosed high-grade glioma. J Clin Oncol. 2018 Apr 1;36(10):951-958. Epub 2018 Feb 7. link to original article PubMed

Adjuvant therapy, elderly or poor performance status patients

Best supportive care

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Keime-Guibert et al. 2007	Phase III (C)	RT x 50 Gy	Inferior OS

No antineoplastic therapy after primary surgery.

Preceding treatment

Surgery

References

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 protocol PubMed

Radiation therapy

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Variant #1, hypofractionated (34 Gy)

Study	Evidence	Comparator	Comparative Efficacy
Malmström et al. 2012	Phase III (E-switch-ic)	1. Standard RT	Did not meet primary endpoint of OS
Malmström et al. 2012	Phase III (E-switch-ic)	2. Temozolomide	Did not meet primary endpoint of OS

Preceding treatment

Surgery

Radiotherapy

External beam radiotherapy 10 x 3.40 Gy fractions, five days per week, for a total dose of 34 Gy

2-week course

Variant #2, abbreviated course (40 Gy)

Study	Evidence	Comparator	Comparative Efficacy
Roa et al. 2004	Randomized Phase II (E-switch-de-esc)	Standard RT (60 Gy)	Did not meet primary endpoint of OS
Perry et al. 2017 (NCIC CTG CE.6)	Phase III (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 2.67 Gy fractions, five days per week, for a total dose of 40.05 Gy

3-week course

Variant #3, standard course (50.4 Gy)

Study	Evidence	Comparator	Comparative Efficacy
Keime-Guibert et al. 2007	Phase III (E-esc)	Best supportive care	Superior OS

Preceding treatment

Surgery

Radiotherapy

External beam radiotherapy 28 x 1.80 Gy fractions, five days per week, for a total dose of 50.4 Gy

5.5-week course

Variant #4, standard course (60 Gy)

Study	Evidence	Comparator	Comparative Efficacy
Roa et al. 2004	Randomized Phase II (C)	Abbreviated RT (40 Gy)	Did not meet primary endpoint of OS
Malmström et al. 2012	Phase III (C)	1. Hypofractionated RT	Did not meet primary endpoint of OS
Malmström et al. 2012	Phase III (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 2.00 Gy fractions, five days per week, for a total dose of 60 Gy

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 protocol 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 protocol 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. link to original article contains protocol 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. link to original article PubMed

Temozolomide monotherapy

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Regimen

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

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 (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. link to original article contains verified protocol PubMed

Temozolomide & low-dose RT

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Temozolomide & LDRT: Temozolomide & Low-Dose Radiation Therapy

Regimen

Study	Evidence	Comparator	Comparative Efficacy
Perry et al. 2017 (NCIC CTG CE.6)	Phase III (E-switch-esc)	Radiotherapy	Superior OS

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, 2.67 Gy fractions x 15 fractions, for a total dose of 40.05 Gy

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 verified protocol PubMed

Maintenance after first-line therapy

Irinotecan & Bevacizumab

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Regimen

Study	Evidence
Herrlinger et al. 2016 (GLARIUS)	Non-randomized portion of RCT

To be completed

Preceding treatment

Bevacizumab & RT

Chemotherapy

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 PubMed

Temozolomide monotherapy

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Variant #1, 6 cycles

Study	Evidence	Comparator	Comparative Efficacy
Stupp et al. 2005 (EORTC 22981/26981; NCIC CTG CE.3)	Phase III (E-RT-esc)	See link	See link
Gilbert et al. 2014 (RTOG 0825)	Phase III (C)	See link	See link
Chinot et al. 2014 (AVAglio)	Phase III (C)	See link	See link
Stupp et al. 2015 (EF-14)	Phase III (C)	Temozolomide & NovoTTF-100A	Inferior OS
Kong et al. 2017	Non-randomized portion of RCT

Note: patients in RTOG 0825 could extend maintenance to 12 cycles if no major adverse events and evidence of ongoing benefit.

Preceding treatment

Temozolomide & RT

Chemotherapy

Temozolomide (Temodar) as follows:
- Cycle 1: 150 mg/m² PO once per day on days 1 to 5
- If tolerated, in cycles 2 to 6: 200 mg/m² PO once per day on days 1 to 5

Supportive medications

Metoclopramide (Reglan) or 5-HT3 antagonist required

28-day cycle for 6 cycles

Variant #2, 12 cycles

Study	Evidence	Comparator	Comparative Efficacy
Gilbert et al. 2013 (RTOG 0525)	Phase III (C)	Dose-dense Temozolomide	Did not meet primary endpoint of OS
Perry et al. 2017 (NCIC CTG CE.6)	Non-randomized portion of RCT
Weller et al. 2017 (ACT IV)	Phase III (C)	Rindopepimut & Temozolomide	Did not meet primary endpoint of OS
Grill et al. 2018 (HERBY)	Randomized Phase II (C)	See link	See link

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

Preceding treatment

RTOG 0525: Surgery, then adjuvant temozolomide & RT
NCIC CTG CE.6: Surgery, then adjuvant temozolomide & low-dose RT
ACT IV: Resection
HERBY: Surgery, then adjuvant temozolomide & RT

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; 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. link to original article contains verified protocol PubMed
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; European Organisation for Research and Treatment of Cancer 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 verified protocol 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. link to original article link to PMC article PubMed
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 protocol 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. link to original article contains protocol PubMed
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 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
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. link to original article link to PMC article contains verified protocol 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. link to original article contains verified protocol PubMed
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 protocol PubMed
HERBY: Grill J, Massimino M, Bouffet E, Azizi AA, McCowage G, Cañete A, Saran F, Le Deley MC, Varlet P, Morgan PS, Jaspan T, Jones C, Giangaspero F, Smith H, Garcia J, Elze MC, Rousseau RF, Abrey L, Hargrave D, Vassal G. Phase II, open-label, randomized, multicenter trial (HERBY) of bevacizumab in pediatric patients with newly diagnosed high-grade glioma. J Clin Oncol. 2018 Apr 1;36(10):951-958. Epub 2018 Feb 7. link to original article contains protocol PubMed

Temozolomide & NovoTTF-100A

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Stupp et al. 2015 (EF-14)	Phase III (E-esc)	Temozolomide	Superior OS

Preceding treatment

Temozolomide & RT

Chemotherapy

Temozolomide (Temodar) as follows:
- Cycle 1: 150 mg/m² PO once per day on days 1 to 5
- If tolerated, in 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 protocol PubMed
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 PubMed

Recurrent disease, non-curative therapy, randomized data

Carmustine monotherapy

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Regimen

Study	Evidence
Fewer et al. 1972	Retrospective
Brandes et al. 2004a	Phase II

Chemotherapy

Carmustine (BCNU) 80 mg/m² IV once per day on days 1 to 3

Supportive medications

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 verified protocol PubMed

Gliadel wafer monotherapy

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Brem et al. 1995	Phase III (E-esc)	Placebo wafer	Superior OS
Westphal et al. 2003	Phase III (E-esc)	Placebo wafer	Seems to have superior OS
Kunwar et al. 2010 (PRECISE)	Phase III (C)	Cintredekin besudotox	Did not meet primary endpoint of OS

Chemotherapy, CNS

Carmustine wafer, polifeprosan 20 (Gliadel)

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; The 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

Hydroxyurea monotherapy

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Dresemann et al. 2009	Phase III (C)	Hydroxyurea & Imatinib	Did not meet primary endpoint of PFS

Chemotherapy

Hydroxyurea (Hydrea)

References

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

Hydroxyurea & Imatinib

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Dresemann et al. 2005	Non-randomized
Dresemann et al. 2009	Phase III (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
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 verified protocol PubMed
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

Lomustine monotherapy

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Variant #1, 100 mg/m²

Study	Evidence	Comparator	Comparative Efficacy
Wick et al. 2010 (JCBF)	Phase III (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 medications

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

42-day cycles

Variant #2, 110 mg/m², uncapped

Study	Evidence	Comparator	Comparative Efficacy
Batchelor et al. 2013 (REGAL)	Phase III (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

Variant #3, 110 mg/m², capped

Study	Evidence	Comparator	Comparative Efficacy
Taal et al. 2014 (BELOB)	Randomized Phase II (C)	Lomustine & Bevacizumab	Not reported
Wick et al. 2017 (EORTC 26101)	Phase III (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

Variant #4, 130 mg/m²

Study	Evidence	Comparator	Comparative Efficacy
Bleehen et al. 1989	Phase III (C)	Benznidazole & Lomustine	Did not meet endpoint
Wick et al. 2010 (JCBF)	Phase III (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 medications

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 SD 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 verified protocol link to PMC article PubMed
REGAL: Batchelor TT, Mulholland P, Neyns B, Nabors LB, Campone M, Wick A, Mason W, Mikkelsen T, Phuphanich S, Ashby LS, Degroot 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 verified protocol link to PMC article PubMed
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 verified protocol PubMed
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 (LWNO). 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. 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 verified protocol PubMed

Lomustine & Bevacizumab

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Taal et al. 2014 (BELOB)	Randomized Phase II (E-esc)	Lomustine	Not reported
Wick et al. 2017 (EORTC 26101)	Phase III (E-RT-esc)	Lomustine	Did not meet primary endpoint of OS

Chemotherapy

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 verified protocol PubMed
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 (LWNO). 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. 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 verified protocol PubMed

NovoTTF-100A monotherapy

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Stupp et al. 2012 (EF-11)	Phase III (E-switch-ooc)	Investigator's choice	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

PCV

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PCV: Procarbazine, CCNU (Lomustine), Vincristine

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

Variant #2, 100/100/1.5

Study	Evidence	Comparator	Comparative Efficacy
Brada et al. 2010	Phase III (C)	Temozolomide	Did not meet 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 protocol PubMed
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 verified protocol PubMed

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

Bevacizumab monotherapy

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Variant #1

Study	Evidence
Friedman et al. 2009 (AVF3708g)	Phase II (RT)

Chemotherapy

Bevacizumab (Avastin) 10 mg/kg IV once on day 1

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

Variant #2

Study	Evidence
Kreisl et al. 2008 (NCI 06-C-0064E)	Phase II (RT)

Chemotherapy

Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1 & 15

28-day cycles

Subsequent treatment

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 verified protocol 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 verified protocol PubMed
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
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 (LWNO). 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. PubMed

Carboplatin & Bevacizumab

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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)
Bevacizumab (Avastin) 10 mg/kg IV once on day 1

14-day cycles

Variant #2, q4wk bevacizumab

Study	Evidence
Thompson et al. 2010	Retrospective

Chemotherapy

Carboplatin (Paraplatin) AUC 5 IV once on day 1
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 PubMed

CART-EGFRvIII cells

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Regimen

Study	Evidence
O'Rourke et al. 2017	Phase I

Immunotherapy

Autologous CART-EGFRvIII cells, see paper for details

One treatment

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). PubMed link to original article

Cyclophosphamide monotherapy

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Regimen

Study	Evidence
Chamberlain & Tsao-Wei 2004	Phase II

Chemotherapy

Cyclophosphamide (Cytoxan) 750 mg/m² IV over 30 minutes once per day on days 1 & 2

Supportive medications

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 (Cytoxan)
Dexamethasone (Decadron) 4 mg IV once per day on days 1 & 2, prior to Cyclophosphamide (Cytoxan)
1 liter normal saline IV over 2 hours once per day on days 1 & 2, prior to Cyclophosphamide (Cytoxan)
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 verified protocol PubMed

Irinotecan monotherapy

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Regimen

Study	Evidence
Friedman et al. 1999	Phase II

Chemotherapy

Irinotecan (Camptosar) 125 mg/m² IV once per day on days 1, 8, 15, 22
- If tolerated, dose could be increased to 150 mg/m² IV once per day on days 1, 8, 15, 22

Supportive medications

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

42-day cycles

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 verified protocol PubMed

Irinotecan & Bevacizumab

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Variant #1, q2wk bev

Study	Evidence
Chen et al. 2007	Pilot, >20 pts
Vredenburgh et al. 2007	Phase II
Norden et al. 2008	Phase II
Kreisl et al. 2008 (NCI 06-C-0064E)	Phase II
Friedman et al. 2009 (AVF3708g)	Phase II

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
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 medications

Steroids were generally maintained at the same dose

14-day cycles

Variant #2, q3wk bev

Study	Evidence
Vredenburgh et al. 2007	Phase II, <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
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 medications

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 verified protocol 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 verified protocol 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 verified protocol 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 verified protocol 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 protocol 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 verified protocol PubMed

Procarbazine monotherapy

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Variant #1, 125 mg/m²

Study	Evidence
Yung et al. 2000	Phase II

Note: this is the starting dose for patients who previously received chemotherapy; no instructions for dose escalation are given.

Chemotherapy

Procarbazine (Matulane) 125 mg/m² PO once per day on days 1 to 28

Supportive medications

Steroids at lowest dose necessary

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

Variant #2, 150 mg/m²

Study	Evidence
Yung et al. 2000	Phase II

Note: this dosing is intended for patients who have never previously received chemotherapy.

Chemotherapy

Procarbazine (Matulane) 150 mg/m² PO once per day on days 1 to 28
- Patients who previously received chemotherapy started with 125 mg/m² PO once per day on days 1 to 28

Supportive medications

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 verified protocol link to PMC article PubMed

Temozolomide monotherapy

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Variant #1, continuous

Study	Evidence
Perry et al. 2008 (RESCUE)	Phase II

See paper for details of when this regimen is used.

Chemotherapy

Temozolomide (Temodar) 50 mg/m² PO once per day

Continued indefinitely

Variant #2, 11 cycles

Study	Evidence
Nicholson et al. 2007	Non-randomized

Chemotherapy

Temozolomide (Temodar) 150 to 200 mg/m² PO once per day on days 1 to 5
- Patients who previously received craniospinal irradiation (CSI) instead received 180 mg/m² PO once per day on days 1 to 5

28-day cycle for up to 11 cycles

Variant #3, 2 years

Study	Evidence
Yung et al. 2000	Phase II

Chemotherapy

Temozolomide (Temodar) as follows:
- Patients who had never previously received chemotherapy: 200 mg/m² PO once per day on days 1 to 5
- Patients who previously received chemotherapy started with 150 mg/m² PO once per day on days 1 to 5

28-day cycle for up to 26 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 verified protocol link to PMC article 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. link to original article contains verified protocol 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 verified protocol PubMed
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 verified protocol 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: @@
 {| class="wikitable" style="text-align:center; width:50%;"
-!colspan="2" align="center" style="color:white; font-size:125%; background-color:#08519c"|'''Section editor'''
+! colspan="2" align="center" style="color:white; font-size:125%; background-color:#08519c" |'''Section editor'''
 |-
-|style="background-color:#F0F0F0"|[[File:SeemaNagpal.jpg|frameless|upright=0.3|center]]
+| style="background-color:#F0F0F0" |[[File:SeemaNagpal.jpg|frameless|upright=0.3|center]]
 |<big>[[User:Seemanagpal|Seema Nagpal, MD]]<br>Stanford University<br>Palo Alto, CA</big>
 |-
@@ Line 15: / Line 15: @@
 =Guidelines=
 ==[https://www.asco.org/ ASCO]==
 *'''2016:''' [https://ascopubs.org/doi/full/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://www.ncbi.nlm.nih.gov/pubmed/27893327 PubMed]
 ==EANO==
 *'''2017:''' [https://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] [https://www.ncbi.nlm.nih.gov/pubmed/28593859 PubMed]
 *'''2014:''' [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70011-7/fulltext EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma] [https://www.ncbi.nlm.nih.gov/pubmed/25079102 PubMed]
 ==[http://www.esmo.org/ ESMO]==
 *'''2014:''' Stupp et al. [https://www.esmo.org/Guidelines/Neuro-Oncology/High-Grade-Malignant-Glioma High-grade glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]
 ==[https://www.nccn.org/ NCCN]==
 *[https://www.nccn.org/professionals/physician_gls/pdf/cns.pdf NCCN Guidelines - Central Nervous System Cancers]
@@ Line 35: / Line 40: @@
 ===Regimen {{#subobject:31c648|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
 |[https://ascopubs.org/doi/full/10.1200/JCO.2015.63.4691 Herrlinger et al. 2016 (GLARIUS)]
-|style="background-color:#1a9851"|Randomized Phase II (E-switch-ooc)
+| style="background-color:#1a9851" |Randomized Phase II (E-switch-ooc)
 |[[#Temozolomide_.26_RT|Temozolomide & RT]], then [[#Temozolomide_monotherapy_2|Temozolomide]]
-|style="background-color:#1a9850"|Superior PFS-6
+| style="background-color:#1a9850" |Superior PFS-6
 |-
 |}
 To be completed
 ====Preceding treatment====
 *[[Surgery#CNS_cancer_surgery|Surgery]]
 ====Chemotherapy====
 *[[Bevacizumab (Avastin)]]
 ====Radiotherapy====
 *[[External beam radiotherapy]]
 ====Subsequent treatment====
 *[[#Irinotecan_.26_Bevacizumab|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. [https://ascopubs.org/doi/full/10.1200/JCO.2015.63.4691 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26976423 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://ascopubs.org/doi/full/10.1200/JCO.2015.63.4691 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26976423 PubMed]
 ==Carmustine & RT {{#subobject:ee9fbd|Regimen=1}}==
@@ Line 67: / Line 80: @@
 ===Variant #1, concurrent {{#subobject:cc1540|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|rowspan=2|[https://www.ncbi.nlm.nih.gov/pubmed/3017551 Eyre et al. 1986 (SWOG S7703)]
+| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pubmed/3017551 Eyre et al. 1986 (SWOG S7703)]
-|rowspan=2 style="background-color:#1a9851"|Phase III (E-switch-ic)
+| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)
 |1. DTIC & RT
-|style="background-color:#d3d3d3"|Not reported
+| style="background-color:#d3d3d3" |Not reported
 |-
 |2. Procarbazine & RT
@@ Line 81: / Line 94: @@
 |-
 |[https://ascopubs.org/doi/abs/10.1200/JCO.1993.11.7.1316 Dinapoli et al. 1993]
-|style="background-color:#1a9851"|Phase III (C)
+| style="background-color:#1a9851" |Phase III (C)
 |PCNU & RT
-|style="background-color:#ffffbf"|Did not meet primary endpoints of TTP50%/OS50%
+| style="background-color:#ffffbf" |Did not meet primary endpoints of TTP50%/OS50%
 |-
 |[https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0142%2820010715%2992%3A2%3C420%3A%3AAID-CNCR1338%3E3.0.CO%3B2-3 Buckner et al. 2001]
-|style="background-color:#1a9851"|Phase III (C)
+| style="background-color:#1a9851" |Phase III (C)
 |BCNU, IFN alfa, RT
-|style="background-color:#ffffbf"|Did not meet endpoint of OS50%
+| style="background-color:#ffffbf" |Did not meet endpoint of OS50%
 |-
 |[https://ascopubs.org/doi/full/10.1200/JCO.2003.10.035 Grossman et al. 2003 (ECOG E2394)]
-|style="background-color:#1a9851"|Phase III (C)
+| style="background-color:#1a9851" |Phase III (C)
 |BCNU & Cisplatin, then RT
-|style="background-color:#ffffbf"|Did not meet primary endpoint of OS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |[https://ascopubs.org/doi/full/10.1200/JCO.2005.04.6979 Buckner et al. 2006 (NCCTG 93-72-52/SWOG S9503)]
-|style="background-color:#1a9851"|Phase III (C)
+| style="background-color:#1a9851" |Phase III (C)
 |BCNU, Cisplatin, RT
-|style="background-color:#ffffbf"|Did not meet primary endpoint of OS50%
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS50%
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4465052/ Blumenthal et al. 2014 (SWOG S0001)]
-|style="background-color:#1a9851"|Phase III (C)
+| style="background-color:#1a9851" |Phase III (C)
 |BCNU, O⁶-benzylguanine, RT
-|style="background-color:#ffffbf"|Did not meet primary endpoint of OS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |[https://link.springer.com/article/10.1007%2Fs11060-017-2558-x Ali et al. 2018 (RTOG 9006)]
-|style="background-color:#1a9851"|Phase III (C)
+| style="background-color:#1a9851" |Phase III (C)
 |[[#Carmustine_.26_RT|BCNU & RT]]; hyperfractionated
-|style="background-color:#ffffbf"|Did not meet primary endpoint of OS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |}
 ====Preceding treatment====
 *[[Surgery#CNS_cancer_surgery|Surgery]]
 ====Chemotherapy====
 *[[Carmustine (BCNU)]]
 ====Radiotherapy====
 *[[External beam radiotherapy]]
 ===Variant #2, sequential {{#subobject:31c648|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|rowspan=2|[http://thejns.org/doi/full/10.3171/jns.1989.71.1.0001 Shapiro et al. 1989 (BTCG 8001)]
+| rowspan="2" |[http://thejns.org/doi/full/10.3171/jns.1989.71.1.0001 Shapiro et al. 1989 (BTCG 8001)]
-|rowspan=2 style="background-color:#1a9851"|Phase III (C)
+| rowspan="2" style="background-color:#1a9851" |Phase III (C)
 |1. Carmustine, Procarbazine, RT
-|style="background-color:#ffffbf"|Did not meet primary endpoint of OS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |2. Carmustine & Hydrea/Procarbazine & VM-26 & RT
-|style="background-color:#ffffbf"|Did not meet primary endpoint of OS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |}
 ====Preceding treatment====
 *[[Surgery#CNS_cancer_surgery|Surgery]]
 ====Radiotherapy====
 *[[External beam radiotherapy]] starting within 3 weeks after surgical resection, with ONE of the following:
 **Whole brain: 172 cGy (rads) fractions x 35 fractions, given over 7 weeks for a total dose of 6020 cGy (6020 rads/~1700 rets)
@@ Line 143: / Line 164: @@
 '''2- to 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
 ====Supportive care====
 *Pulmonary function tests (PFTs) 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>
@@ Line 151: / Line 174: @@
 ===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. [http://thejns.org/doi/abs/10.3171/jns.1978.49.3.0333 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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://www.nejm.org/doi/full/10.1056/NEJM198012043032303 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7001230 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. [http://thejns.org/doi/abs/10.3171/jns.1978.49.3.0333 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/355604 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://www.ncbi.nlm.nih.gov/pubmed/3017551 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://www.nejm.org/doi/full/10.1056/NEJM198012043032303 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7001230 PubMed]
-# '''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. [http://thejns.org/doi/full/10.3171/jns.1989.71.1.0001 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/2661738 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://www.ncbi.nlm.nih.gov/pubmed/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://ascopubs.org/doi/abs/10.1200/JCO.1993.11.7.1316 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8315428 PubMed]
+#'''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. [http://thejns.org/doi/full/10.3171/jns.1989.71.1.0001 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/2661738 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://onlinelibrary.wiley.com/doi/full/10.1002/1097-0142%2820010715%2992%3A2%3C420%3A%3AAID-CNCR1338%3E3.0.CO%3B2-3 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11466698 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://ascopubs.org/doi/abs/10.1200/JCO.1993.11.7.1316 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8315428 PubMed]
-# '''ECOG E2394:''' Grossman SA, O'Neill A, Grunnet M, Mehta M, Pearlman JL, Wagner H, Gilbert M, Newton HB, Hellman R; Eastern Cooperative Oncology Group. 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://ascopubs.org/doi/full/10.1200/JCO.2003.10.035 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12697871 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://onlinelibrary.wiley.com/doi/full/10.1002/1097-0142%2820010715%2992%3A2%3C420%3A%3AAID-CNCR1338%3E3.0.CO%3B2-3 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11466698 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 93-72-52; Southwest Oncology Group 9503 Trials. 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://ascopubs.org/doi/full/10.1200/JCO.2005.04.6979 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16921039 PubMed]
+#'''ECOG E2394:''' Grossman SA, O'Neill A, Grunnet M, Mehta M, Pearlman JL, Wagner H, Gilbert M, Newton HB, Hellman R; Eastern Cooperative Oncology Group. 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://ascopubs.org/doi/full/10.1200/JCO.2003.10.035 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12697871 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://link.springer.com/article/10.1007%2Fs10147-014-0769-0 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4465052/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25407559 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 93-72-52; Southwest Oncology Group 9503 Trials. 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://ascopubs.org/doi/full/10.1200/JCO.2005.04.6979 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16921039 PubMed]
-# '''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://link.springer.com/article/10.1007%2Fs11060-017-2558-x link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29404979 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://link.springer.com/article/10.1007%2Fs10147-014-0769-0 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4465052/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25407559 PubMed]
+#'''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://link.springer.com/article/10.1007%2Fs11060-017-2558-x link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29404979 PubMed]
 ==Lomustine, Temozolomide, RT {{#subobject:9gg33f|Regimen=1}}==
@@ Line 170: / Line 194: @@
 ===Regimen {{#subobject:94ta38|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
 |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)31791-4/fulltext Herrlinger et al. 2019 (CeTeG/NOA-09)]
-|style="background-color:#1a9851"|Phase III (E-esc)
+| style="background-color:#1a9851" |Phase III (E-esc)
 |[[#Temozolomide_.26_RT|Temozolomide & RT]]
 | style="background-color:#91cf60" |Seems to have superior OS
@@ Line 183: / Line 207: @@
 ''Note: see paper for dose adjustments to temozolomide after cycle 1.''
 ====Preceding treatment====
 *[[Surgery#CNS_cancer_surgery|Surgery]]
 ====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
@@ Line 190: / Line 217: @@
 '''42-day cycle for up to 6 cycles'''
 ====Radiotherapy====
 *[[External beam radiotherapy]] 59 to 60 Gy 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. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)31791-4/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30782343 PubMed]
+#'''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://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)31791-4/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30782343 PubMed]
 ==Nimustine & RT {{#subobject:9ff22f|Regimen=1}}==
@@ Line 203: / Line 233: @@
 ===Regimen {{#subobject:92d838|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
 |[https://link.springer.com/article/10.1007%2Fs00280-012-2041-5 Shibui et al. 2012 (JCOG 0305)]
-|style="background-color:#1a9851"|Phase III (C)
+| style="background-color:#1a9851" |Phase III (C)
 |Nimustine, Procarbazine, RT
-|style="background-color:#ffffbf"|Did not meet primary endpoint of OS
+| 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.''
 ====Preceding treatment====
 *[[Surgery#CNS_cancer_surgery|Surgery]]
 ====Chemotherapy====
 *[[Nimustine (ACNU)]]
 ====Radiotherapy====
 *[[External beam radiotherapy]]
 ===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://link.springer.com/article/10.1007%2Fs00280-012-2041-5 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23228988 PubMed]
+#'''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://link.springer.com/article/10.1007%2Fs00280-012-2041-5 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23228988 PubMed]
 ==Radiation therapy {{#subobject:7dbd68|Regimen=1}}==
@@ Line 231: / Line 268: @@
 ===Regimen {{#subobject:b645f1|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
 |[https://www.nejm.org/doi/full/10.1056/NEJM197606172942503 Urtasun et al. 1976]
-|style="background-color:#1a9851"|Randomized (C)
+| style="background-color:#1a9851" |Randomized (C)
 |Metronidazole & RT
 | style="background-color:#fc8d59" |Seems to have inferior OS
 |-
-|rowspan=3|[http://thejns.org/doi/abs/10.3171/jns.1978.49.3.0333 Walker et al. 1978 (BTSG 69-01)]
+| rowspan="3" |[http://thejns.org/doi/abs/10.3171/jns.1978.49.3.0333 Walker et al. 1978 (BTSG 69-01)]
-|rowspan=3 style="background-color:#1a9851"|Phase III (E-esc)
+| rowspan="3" style="background-color:#1a9851" |Phase III (E-esc)
 |1. Best supportive care
 | style="background-color:#91cf60" |Seems to have superior OS
@@ Line 252: / Line 289: @@
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS50%
 |-
-|rowspan=2|[https://www.nejm.org/doi/full/10.1056/NEJM198012043032303 Walker et al. 1980 (BTSG 72-01)]
+| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM198012043032303 Walker et al. 1980 (BTSG 72-01)]
-|rowspan=2 style="background-color:#1a9851"|Phase III (C)
+| rowspan="2" style="background-color:#1a9851" |Phase III (C)
 |1. [[#Carmustine_.26_RT|Carmustine & RT]]<br> 2. Semustine & RT
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
@@ Line 261: / Line 298: @@
 |-
 |[https://www.nejm.org/doi/full/10.1056/NEJMoa043330 Stupp et al. 2005 (EORTC 22981/26981; NCIC CTG CE.3)]
-|style="background-color:#1a9851"|Phase III (C)
+| style="background-color:#1a9851" |Phase III (C)
 |[[#Temozolomide_.26_RT|Temozolomide & RT]], then [[#Temozolomide_monotherapy_2|Temozolomide]]
-|style="background-color:#d73027"|Inferior OS
+| style="background-color:#d73027" |Inferior OS
 |-
 |}
 ''Adjuvant radiotherapy alone.''
 ====Preceding treatment====
 *[[Surgery#CNS_cancer_surgery|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. [https://www.nejm.org/doi/full/10.1056/NEJM197606172942503 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/177873 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. [http://thejns.org/doi/abs/10.3171/jns.1978.49.3.0333 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/355604 PubMed]
+#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://www.nejm.org/doi/full/10.1056/NEJM197606172942503 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/177873 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://www.nejm.org/doi/full/10.1056/NEJM198012043032303 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7001230 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. [http://thejns.org/doi/abs/10.3171/jns.1978.49.3.0333 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/355604 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; 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. [https://www.nejm.org/doi/full/10.1056/NEJMoa043330 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15758009 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://www.nejm.org/doi/full/10.1056/NEJM198012043032303 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7001230 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://www.nejm.org/doi/full/10.1056/NEJMoa043331 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15758010 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; 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. [https://www.nejm.org/doi/full/10.1056/NEJMoa043330 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15758009 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; European Organisation for Research and Treatment of Cancer 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://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(09)70025-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19269895 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://www.nejm.org/doi/full/10.1056/NEJMoa043331 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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; European Organisation for Research and Treatment of Cancer 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://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(09)70025-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19269895 PubMed]
 ==Temozolomide & RT {{#subobject:5fe805|Regimen=1}}==
@@ Line 287: / Line 329: @@
 ===Regimen {{#subobject:2a87ef|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
 |[https://www.nejm.org/doi/full/10.1056/NEJMoa043330 Stupp et al. 2005 (EORTC 22981/26981; NCIC CTG CE.3)]
-|style="background-color:#1a9851"|Phase III (E-RT-esc)
+| style="background-color:#1a9851" |Phase III (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]]
+| 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)]
@@ Line 303: / Line 345: @@
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201043/ Gilbert et al. 2014 (RTOG 0825)]
-|style="background-color:#1a9851"|Phase III (C)
+| style="background-color:#1a9851" |Phase III (C)
 |[[Complex_multipart_regimens#RTOG_0825|See link]]
 | style="background-color:#d73027" |[[Complex_multipart_regimens#RTOG_0825|See link]]
 |-
 |[https://www.nejm.org/doi/full/10.1056/NEJMoa1308345 Chinot et al. 2014 (AVAglio)]
-|style="background-color:#1a9851"|Phase III (C)
+| style="background-color:#1a9851" |Phase III (C)
 |[[Complex_multipart_regimens#AVAglio|See link]]
 | style="background-color:#d73027" |[[Complex_multipart_regimens#AVAglio|See link]]
 |-
 |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70379-1/fulltext Stupp et al. 2014 (CENTRIC)]
-|style="background-color:#1a9851"|Phase III (C)
+| style="background-color:#1a9851" |Phase III (C)
 |Cilengitide, Temozolomide, RT
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |[https://www.ejcancer.com/article/S0959-8049(15)00008-8/fulltext Westphal et al. 2015 (OSAG 101-BSA-05)]
-|style="background-color:#1a9851"|Phase III (C)
+| style="background-color:#1a9851" |Phase III (C)
 |Temozolomide, Nimotuzumab, RT
 | style="background-color:#ffffbf" |Did not meet primary endpoints of PFS12/PFS50%
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351686/ Kong et al. 2017]
-|style="background-color:#1a9851"|Phase III (C)
+| style="background-color:#1a9851" |Phase III (C)
 |Temozolomide & RT with CIK cells
-|style="background-color:#fc8d59"|Seems to have inferior PFS
+| style="background-color:#fc8d59" |Seems to have inferior PFS
 |-
 |}
-''Note: patients in CENTRIC were required to have methylated MGMT promoter.''
+''Note: patients in CENTRIC were required to have [[Biomarkers#Methylated|methylated]] MGMT promoter.''
 ====Preceding treatment====
 *[[Surgery#CNS_cancer_surgery|Surgical biopsy, partial resection, or total resection]]
 ====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 medications====
 *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]], 2 Gy fractions x 30 fractions, for a total dose of 60 Gy
 '''6-week course'''
 ====Subsequent treatment====
 *Most protocols: [[#Temozolomide_monotherapy_2|Temozolomide maintenance]], 4 weeks after completion of radiation therapy
 *RTOG 0525: [[#Temozolomide_monotherapy_2|Temozolomide]] versus dose-dense temozolomide maintenance
 ===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; 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. [https://www.nejm.org/doi/full/10.1056/NEJMoa043330 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15758009 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://www.nejm.org/doi/full/10.1056/NEJMoa043331 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15758010 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; 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. [https://www.nejm.org/doi/full/10.1056/NEJMoa043330 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15758009 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; European Organisation for Research and Treatment of Cancer 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://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(09)70025-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19269895 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://www.nejm.org/doi/full/10.1056/NEJMoa043331 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15758010 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://ascopubs.org/doi/full/10.1200/JCO.2013.49.6968 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3816958/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24101040 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; European Organisation for Research and Treatment of Cancer 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://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(09)70025-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19269895 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://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]
+#'''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://ascopubs.org/doi/full/10.1200/JCO.2013.49.6968 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3816958/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24101040 PubMed]
-# '''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://www.nejm.org/doi/full/10.1056/NEJMoa1308345 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24552318 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://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]
-# '''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; European Organisation for Research and Treatment of Cancer (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://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70379-1/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25163906 PubMed]
+#'''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://www.nejm.org/doi/full/10.1056/NEJMoa1308345 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24552318 PubMed]
-# '''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://www.ejcancer.com/article/S0959-8049(15)00008-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25616647 PubMed]
+#'''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; European Organisation for Research and Treatment of Cancer (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://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70379-1/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25163906 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://ascopubs.org/doi/full/10.1200/JCO.2015.63.4691 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26976423 PubMed]
+#'''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://www.ejcancer.com/article/S0959-8049(15)00008-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25616647 PubMed]
-# 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. [http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=12273&path%5B%5D=38864 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351686/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27690294 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://ascopubs.org/doi/full/10.1200/JCO.2015.63.4691 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26976423 PubMed]
-# '''HERBY:''' Grill J, Massimino M, Bouffet E, Azizi AA, McCowage G, Cañete A, Saran F, Le Deley MC, Varlet P, Morgan PS, Jaspan T, Jones C, Giangaspero F, Smith H, Garcia J, Elze MC, Rousseau RF, Abrey L, Hargrave D, Vassal G. Phase II, Open-label, randomized, multicenter trial (HERBY) of bevacizumab in pediatric patients with newly diagnosed high-grade glioma. J Clin Oncol. 2018 Apr 1;36(10):951-958. Epub 2018 Feb 7. [https://ascopubs.org/doi/full/10.1200/JCO.2017.76.0611 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29412784 PubMed]
+#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. [http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=12273&path%5B%5D=38864 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351686/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27690294 PubMed]
+#'''HERBY:''' Grill J, Massimino M, Bouffet E, Azizi AA, McCowage G, Cañete A, Saran F, Le Deley MC, Varlet P, Morgan PS, Jaspan T, Jones C, Giangaspero F, Smith H, Garcia J, Elze MC, Rousseau RF, Abrey L, Hargrave D, Vassal G. Phase II, Open-label, randomized, multicenter trial (HERBY) of bevacizumab in pediatric patients with newly diagnosed high-grade glioma. J Clin Oncol. 2018 Apr 1;36(10):951-958. Epub 2018 Feb 7. [https://ascopubs.org/doi/full/10.1200/JCO.2017.76.0611 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29412784 PubMed]
 =Adjuvant therapy, elderly or poor performance status patients=
@@ Line 367: / Line 418: @@
 ===Regimen===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
 |[https://www.nejm.org/doi/full/10.1056/NEJMoa065901 Keime-Guibert et al. 2007]
-|style="background-color:#1a9851"|Phase III (C)
+| style="background-color:#1a9851" |Phase III (C)
 |[[#Radiation_therapy_2|RT x 50 Gy]]
 | style="background-color:#d73027" |Inferior OS
@@ Line 380: / Line 431: @@
 ''No antineoplastic therapy after primary surgery.''
 ====Preceding treatment====
 *[[Surgery#CNS_cancer_surgery|Surgery]]
 ===References===
-# 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://www.nejm.org/doi/full/10.1056/NEJMoa065901 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17429084 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://www.nejm.org/doi/full/10.1056/NEJMoa065901 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17429084 PubMed]
 ==Radiation therapy {{#subobject:7dbd68|Regimen=1}}==
@@ Line 392: / Line 445: @@
 ===Variant #1, hypofractionated (34 Gy) {{#subobject:c245f1|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|rowspan=2|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70265-6/abstract Malmström et al. 2012]
+| rowspan="2" |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70265-6/abstract Malmström et al. 2012]
-|rowspan=2 style="background-color:#1a9851"|Phase III (E-switch-ic)
+| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)
 |1. Standard RT
-|style="background-color:#ffffbf"|Did not meet primary endpoint of OS
+| 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
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |}
 ====Preceding treatment====
 *[[Surgery#CNS_cancer_surgery|Surgery]]
 ====Radiotherapy====
 *[[External beam radiotherapy]] 10 x 3.40 Gy fractions, five days per week, for a total dose of 34 Gy
@@ Line 415: / Line 471: @@
 ===Variant #2, abbreviated course (40 Gy) {{#subobject:73c680|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
 |[https://ascopubs.org/doi/full/10.1200/JCO.2004.06.082 Roa et al. 2004]
-|style="background-color:#1a9851"|Randomized Phase II (E-switch-de-esc)
+| style="background-color:#1a9851" |Randomized Phase II (E-switch-de-esc)
 |Standard RT (60 Gy)
-|style="background-color:#ffffbf"|Did not meet primary endpoint of OS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |[https://www.nejm.org/doi/full/10.1056/NEJMoa1611977 Perry et al. 2017 (NCIC CTG CE.6)]
-|style="background-color:#1a9851"|Phase III (C)
+| style="background-color:#1a9851" |Phase III (C)
 |[[#Temozolomide_.26_low-dose_RT|Temozolomide & LDRT]]
-|style="background-color:#d73027"|Inferior OS
+| style="background-color:#d73027" |Inferior OS
 |-
 |}
 ''Note: Roa et al. 2004 was closed early due to poor accrual.''
 ====Preceding treatment====
 *[[Surgery#CNS_cancer_surgery|Surgery]]
 ====Radiotherapy====
 *[[External beam radiotherapy]] 15 x 2.67 Gy fractions, five days per week, for a total dose of 40.05 Gy
@@ Line 441: / Line 500: @@
 ===Variant #3, standard course (50.4 Gy) {{#subobject:b6921d|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
 |[https://www.nejm.org/doi/full/10.1056/NEJMoa065901 Keime-Guibert et al. 2007]
-|style="background-color:#1a9851"|Phase III (E-esc)
+| style="background-color:#1a9851" |Phase III (E-esc)
 |[[#Best_supportive_care|Best supportive care]]
 | style="background-color:#1a9850" |Superior OS
@@ Line 453: / Line 512: @@
 |}
 ====Preceding treatment====
 *[[Surgery#CNS_cancer_surgery|Surgery]]
 ====Radiotherapy====
 *[[External beam radiotherapy]] 28 x 1.80 Gy fractions, five days per week, for a total dose of 50.4 Gy
@@ Line 461: / Line 523: @@
 ===Variant #4, standard course (60 Gy) {{#subobject:b645f1|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
 |[https://ascopubs.org/doi/full/10.1200/JCO.2004.06.082 Roa et al. 2004]
-|style="background-color:#1a9851"|Randomized Phase II (C)
+| style="background-color:#1a9851" |Randomized Phase II (C)
 |Abbreviated RT (40 Gy)
-|style="background-color:#ffffbf"|Did not meet primary endpoint of OS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|rowspan=2|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70265-6/abstract Malmström et al. 2012]
+| rowspan="2" |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70265-6/abstract Malmström et al. 2012]
-|rowspan=2 style="background-color:#1a9851"|Phase III (C)
+| rowspan="2" style="background-color:#1a9851" |Phase III (C)
 |1. Hypofractionated RT
-|style="background-color:#ffffbf"|Did not meet primary endpoint of OS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |2. [[#Temozolomide_monotherapy_2|Temozolomide]]
-|style="background-color:#d73027"|Inferior OS
+| style="background-color:#d73027" |Inferior OS
 |-
 |}
 ''Note: Roa et al. 2004 was closed early due to poor accrual.''
 ====Preceding treatment====
 *[[Surgery#CNS_cancer_surgery|Surgery]]
 ====Radiotherapy====
 *[[External beam radiotherapy]] 30 x 2.00 Gy fractions, five days per week, for a total dose of 60 Gy
@@ Line 489: / Line 554: @@
 ===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://ascopubs.org/doi/full/10.1200/JCO.2004.06.082 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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://www.nejm.org/doi/full/10.1056/NEJMoa065901 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17429084 PubMed]
+#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://ascopubs.org/doi/full/10.1200/JCO.2004.06.082 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15051755 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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70265-6/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22877848 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://www.nejm.org/doi/full/10.1056/NEJMoa065901 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17429084 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://www.nejm.org/doi/full/10.1056/NEJMoa1611977 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28296618 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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70265-6/abstract link to original article] '''contains 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://www.nejm.org/doi/full/10.1056/NEJMoa1611977 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28296618 PubMed]
 ==Temozolomide monotherapy {{#subobject:eaba28|Regimen=1}}==
@@ Line 501: / Line 567: @@
 ===Regimen {{#subobject:f90037|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|rowspan=2|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70265-6/abstract Malmström et al. 2012]
+| rowspan="2" |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70265-6/abstract Malmström et al. 2012]
-|rowspan=2 style="background-color:#1a9851"|Phase III (E-switch-ooc)
+| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ooc)
 |1. [[#Radiation_therapy_2|Hypofractionated RT]]
-|style="background-color:#ffffbf"|Did not meet primary endpoint of OS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |2. [[#Radiation_therapy_2|Standard RT]]
-|style="background-color:#1a9850"|Superior OS
+| style="background-color:#1a9850" |Superior OS
 |-
 |}
 ====Preceding treatment====
 *[[Surgery#CNS_cancer_surgery|Surgery]]
 ====Chemotherapy====
 *[[Temozolomide (Temodar)]] 200 mg/m<sup>2</sup> PO once per day on days 1 to 5
@@ Line 523: / Line 592: @@
 ===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. [https://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]
+#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. [https://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]
 ==Temozolomide & low-dose RT {{#subobject:5fe805|Regimen=1}}==
@@ Line 533: / Line 603: @@
 ===Regimen {{#subobject:e80f73|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
 |[https://www.nejm.org/doi/full/10.1056/NEJMoa1611977 Perry et al. 2017 (NCIC CTG CE.6)]
-|style="background-color:#1a9851"|Phase III (E-switch-esc)
+| style="background-color:#1a9851" |Phase III (E-switch-esc)
 |[[#Radiation_therapy|Radiotherapy]]
-|style="background-color:#1a9850"|Superior OS
+| style="background-color:#1a9850" |Superior OS
 |-
 |}
 ====Preceding treatment====
 *[[Surgery#CNS_cancer_surgery|Surgery]]
 ====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]], 2.67 Gy fractions x 15 fractions, for a total dose of 40.05 Gy
 '''3-week course'''
 ====Subsequent treatment====
 *[[#Temozolomide_monotherapy_2|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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1611977 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28296618 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://www.nejm.org/doi/full/10.1056/NEJMoa1611977 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28296618 PubMed]
 =Maintenance after first-line therapy=
@@ Line 566: / Line 643: @@
 ===Regimen {{#subobject:88cfaa|Variant=1}}===
 {| class="wikitable" style="width: 50%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
 |[https://ascopubs.org/doi/full/10.1200/JCO.2015.63.4691 Herrlinger et al. 2016 (GLARIUS)]
-|style="background-color:#91cf61"|Non-randomized portion of RCT
+| style="background-color:#91cf61" |Non-randomized portion of RCT
 |-
 |}
 To be completed
 ====Preceding treatment====
 *[[#Bevacizumab_.26_RT|Bevacizumab & RT]]
 ====Chemotherapy====
 *[[Irinotecan (Camptosar)]]
 *[[Bevacizumab (Avastin)]]
 ===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://ascopubs.org/doi/full/10.1200/JCO.2015.63.4691 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26976423 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://ascopubs.org/doi/full/10.1200/JCO.2015.63.4691 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26976423 PubMed]
 ==Temozolomide monotherapy {{#subobject:a5295c|Regimen=1}}==
@@ Line 590: / Line 671: @@
 ===Variant #1, 6 cycles {{#subobject:93c350|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
 |[https://www.nejm.org/doi/full/10.1056/NEJMoa043330 Stupp et al. 2005 (EORTC 22981/26981; NCIC CTG CE.3)]
-|style="background-color:#1a9851"|Phase III (E-RT-esc)
+| style="background-color:#1a9851" |Phase III (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]]
+| 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/PMC4201043/ Gilbert et al. 2014 (RTOG 0825)]
-|style="background-color:#1a9851"|Phase III (C)
+| style="background-color:#1a9851" |Phase III (C)
 |[[Complex_multipart_regimens#RTOG_0825|See link]]
 | style="background-color:#d73027" |[[Complex_multipart_regimens#RTOG_0825|See link]]
 |-
 |[https://www.nejm.org/doi/full/10.1056/NEJMoa1308345 Chinot et al. 2014 (AVAglio)]
-|style="background-color:#1a9851"|Phase III (C)
+| style="background-color:#1a9851" |Phase III (C)
 |[[Complex_multipart_regimens#AVAglio|See link]]
 | style="background-color:#d73027" |[[Complex_multipart_regimens#AVAglio|See link]]
 |-
 |[https://jamanetwork.com/journals/jama/fullarticle/2475463 Stupp et al. 2015 (EF-14)]
-|style="background-color:#1a9851"|Phase III (C)
+| style="background-color:#1a9851" |Phase III (C)
 |[[#Temozolomide_.26_NovoTTF-100A|Temozolomide & NovoTTF-100A]]
-|style="background-color:#d73027"|Inferior OS
+| style="background-color:#d73027" |Inferior OS
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351686/ Kong et al. 2017]
-|style="background-color:#91cf61"|Non-randomized portion of RCT
+| style="background-color:#91cf61" |Non-randomized portion of RCT
-|style="background-color:#d3d3d3"|
+| style="background-color:#d3d3d3" |
-|style="background-color:#d3d3d3"|
+| style="background-color:#d3d3d3" |
 |-
 |}
 ''Note: patients in RTOG 0825 could extend maintenance to 12 cycles if no major adverse events and evidence of ongoing benefit.''
 ====Preceding treatment====
 *[[#Temozolomide_.26_RT|Temozolomide & RT]]
 ====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
 ====Supportive medications====
 *[[Metoclopramide (Reglan)]] or [[:Category:Serotonin 5-HT3 antagonists|5-HT3 antagonist]] required
@@ Line 636: / Line 721: @@
 ===Variant #2, 12 cycles {{#subobject:da0fc9|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3816958/ Gilbert et al. 2013 (RTOG 0525)]
@@ Line 647: / Line 732: @@
 |-
 |[https://www.nejm.org/doi/full/10.1056/NEJMoa1611977 Perry et al. 2017 (NCIC CTG CE.6)]
-|style="background-color:#91cf61"|Non-randomized portion of RCT
+| style="background-color:#91cf61" |Non-randomized portion of RCT
-|style="background-color:#d3d3d3"|
+| style="background-color:#d3d3d3" |
-|style="background-color:#d3d3d3"|
+| style="background-color:#d3d3d3" |
 |-
 |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30517-X/fulltext Weller et al. 2017 (ACT IV)]
@@ Line 657: / Line 742: @@
 |-
 |[https://ascopubs.org/doi/full/10.1200/JCO.2017.76.0611 Grill et al. 2018 (HERBY)]
-|style="background-color:#1a9851"|Randomized Phase II (C)
+| style="background-color:#1a9851" |Randomized Phase II (C)
 |[[Complex_multipart_regimens#HERBY|See link]]
-|style="background-color:#ffffbf" |[[Complex_multipart_regimens#HERBY|See link]]
+| style="background-color:#ffffbf" |[[Complex_multipart_regimens#HERBY|See link]]
 |-
 |}
 ''Note: treatment in ACT IV was given for a minimum of 6 cycles.''
 ====Preceding treatment====
 *RTOG 0525: [[Surgery#CNS_cancer_surgery|Surgery]], then [[#Temozolomide_.26_RT|adjuvant temozolomide & RT]]
 *NCIC CTG CE.6: [[Surgery#CNS_cancer_surgery|Surgery]], then [[#Temozolomide_.26_low-dose_RT|adjuvant temozolomide & low-dose RT]]
 *ACT IV: Resection
 *HERBY: [[Surgery#CNS_cancer_surgery|Surgery]], then [[#Temozolomide_.26_RT|adjuvant temozolomide & RT]]
 ====Chemotherapy====
-*[[Temozolomide (Temodar)]] 150 to 200 mg/m<sup>2</sup> PO once per day on days 1 to 5
+*[[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'''
 ===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; 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. [https://www.nejm.org/doi/full/10.1056/NEJMoa043330 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15758009 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://www.nejm.org/doi/full/10.1056/NEJMoa043331 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15758010 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; 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. [https://www.nejm.org/doi/full/10.1056/NEJMoa043330 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15758009 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; European Organisation for Research and Treatment of Cancer 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://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(09)70025-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19269895 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://www.nejm.org/doi/full/10.1056/NEJMoa043331 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15758010 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://ascopubs.org/doi/full/10.1200/JCO.2013.49.6968 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3816958/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24101040 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; European Organisation for Research and Treatment of Cancer 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://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(09)70025-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19269895 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://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]
+#'''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://ascopubs.org/doi/full/10.1200/JCO.2013.49.6968 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3816958/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24101040 PubMed]
-# '''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://www.nejm.org/doi/full/10.1056/NEJMoa1308345 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24552318 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://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]
-# '''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://jamanetwork.com/journals/jama/fullarticle/2475463 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26670971 PubMed]
+#'''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://www.nejm.org/doi/full/10.1056/NEJMoa1308345 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24552318 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://jamanetwork.com/journals/jama/fullarticle/2666504 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29260225 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://jamanetwork.com/journals/jama/fullarticle/2475463 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26670971 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://ascopubs.org/doi/full/10.1200/JCO.2015.63.4691 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26976423 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://jamanetwork.com/journals/jama/fullarticle/2666504 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29260225 PubMed]
-# 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. [http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=12273&path%5B%5D=38864 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351686/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27690294 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://ascopubs.org/doi/full/10.1200/JCO.2015.63.4691 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26976423 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://www.nejm.org/doi/full/10.1056/NEJMoa1611977 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28296618 PubMed]
+#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. [http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=12273&path%5B%5D=38864 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351686/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27690294 PubMed]
-# '''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://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30517-X/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28844499 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://www.nejm.org/doi/full/10.1056/NEJMoa1611977 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28296618 PubMed]
-# '''HERBY:''' Grill J, Massimino M, Bouffet E, Azizi AA, McCowage G, Cañete A, Saran F, Le Deley MC, Varlet P, Morgan PS, Jaspan T, Jones C, Giangaspero F, Smith H, Garcia J, Elze MC, Rousseau RF, Abrey L, Hargrave D, Vassal G. Phase II, open-label, randomized, multicenter trial (HERBY) of bevacizumab in pediatric patients with newly diagnosed high-grade glioma. J Clin Oncol. 2018 Apr 1;36(10):951-958. Epub 2018 Feb 7. [https://ascopubs.org/doi/full/10.1200/JCO.2017.76.0611 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29412784 PubMed]
+#'''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://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30517-X/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28844499 PubMed]
+#'''HERBY:''' Grill J, Massimino M, Bouffet E, Azizi AA, McCowage G, Cañete A, Saran F, Le Deley MC, Varlet P, Morgan PS, Jaspan T, Jones C, Giangaspero F, Smith H, Garcia J, Elze MC, Rousseau RF, Abrey L, Hargrave D, Vassal G. Phase II, open-label, randomized, multicenter trial (HERBY) of bevacizumab in pediatric patients with newly diagnosed high-grade glioma. J Clin Oncol. 2018 Apr 1;36(10):951-958. Epub 2018 Feb 7. [https://ascopubs.org/doi/full/10.1200/JCO.2017.76.0611 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29412784 PubMed]
 ==Temozolomide & NovoTTF-100A {{#subobject:4bee42|Regimen=1}}==
@@ Line 695: / Line 784: @@
 ===Regimen {{#subobject:d00b22|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
 |[https://jamanetwork.com/journals/jama/fullarticle/2475463 Stupp et al. 2015 (EF-14)]
-|style="background-color:#1a9851"|Phase III (E-esc)
+| style="background-color:#1a9851" |Phase III (E-esc)
 |[[#Temozolomide_monotherapy_2|Temozolomide]]
-|style="background-color:#1a9850"|Superior OS
+| style="background-color:#1a9850" |Superior OS
 |-
 |}
 ====Preceding treatment====
 *[[#Temozolomide_.26_RT|Temozolomide & RT]]
 ====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
@@ Line 716: / Line 808: @@
 ====Tumor treating fields, CNS====
 *[[NovoTTF-100A system (Optune)]] for at least 18 hours per day
@@ Line 721: / Line 814: @@
 ===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. [https://jamanetwork.com/journals/jama/fullarticle/2475463 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26670971 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://jamanetwork.com/journals/jama/fullarticle/2666504 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29260225 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://jamanetwork.com/journals/jama/fullarticle/2475463 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26670971 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://jamanetwork.com/journals/jama/fullarticle/2666504 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29260225 PubMed]
 =Recurrent disease, non-curative therapy, randomized data=
@@ Line 732: / Line 826: @@
 ===Regimen {{#subobject:fc297c|Variant=1}}===
 {| class="wikitable" style="width: 50%; text-align:center;"
-!style="width: 50%"|Study
+! style="width: 50%" |Study
-!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
 |[https://jamanetwork.com/journals/jama/article-abstract/345130 Fewer et al. 1972]
@@ Line 739: / Line 833: @@
 |-
 |[http://www.neurology.org/content/63/7/1281.long Brandes et al. 2004a]
-|style="background-color:#91cf61"|Phase II
+| style="background-color:#91cf61" |Phase II
 |-
 |}
 ====Chemotherapy====
 *[[Carmustine (BCNU)]] 80 mg/m<sup>2</sup> IV once per day on days 1 to 3
 ====Supportive medications====
-*Antiemesis prophylaxis with [[Ondansetron (Zofran)]]
+*Antiemesis prophylaxis with [[Ondansetron (Zofran)]]
 *[[:Category:Steroids|Steroids]] at lowest dose necessary
@@ Line 752: / Line 848: @@
 ===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. [https://jamanetwork.com/journals/jama/article-abstract/345130 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [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]
+#'''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://jamanetwork.com/journals/jama/article-abstract/345130 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [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]
 ==Gliadel wafer monotherapy {{#subobject:3fdb9e|Regimen=1}}==
@@ Line 762: / Line 859: @@
 ===Regimen {{#subobject:caa94a|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
 |[https://www.thelancet.com/journals/lancet/article/PIIS0140673695907556/fulltext Brem et al. 1995]
-|style="background-color:#1a9851"|Phase III (E-esc)
+| style="background-color:#1a9851" |Phase III (E-esc)
 |Placebo wafer
 | style="background-color:#1a9850" |Superior OS
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1920672/ Westphal et al. 2003]
-|style="background-color:#1a9851"|Phase III (E-esc)
+| style="background-color:#1a9851" |Phase III (E-esc)
 |Placebo wafer
 | style="background-color:#91cf60" |Seems to have superior OS
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2940677/ Kunwar et al. 2010 (PRECISE)]
-|style="background-color:#1a9851"|Phase III (C)
+| style="background-color:#1a9851" |Phase III (C)
 |Cintredekin besudotox
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
@@ Line 784: / Line 881: @@
 |}
 ====Chemotherapy, CNS====
 *[[Carmustine wafer, polifeprosan 20 (Gliadel)]]
 ===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; The 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://www.thelancet.com/journals/lancet/article/PIIS0140673695907556/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7723496 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. [https://academic.oup.com/neuro-oncology/article/5/2/79/1070081 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1920672/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/12672279 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; The 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://www.thelancet.com/journals/lancet/article/PIIS0140673695907556/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7723496 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://academic.oup.com/neuro-oncology/article/12/8/871/1073747 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2940677/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20511192 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. [https://academic.oup.com/neuro-oncology/article/5/2/79/1070081 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1920672/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/12672279 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://academic.oup.com/neuro-oncology/article/12/8/871/1073747 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2940677/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20511192 PubMed]
 ==Hydroxyurea monotherapy {{#subobject:227c90|Regimen=1}}==
@@ Line 798: / Line 897: @@
 ===Regimen {{#subobject:6ea460|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
 |[https://link.springer.com/article/10.1007%2Fs11060-009-9976-3 Dresemann et al. 2009]
-|style="background-color:#1a9851"|Phase III (C)
+| style="background-color:#1a9851" |Phase III (C)
 |[[#Hydroxyurea_.26_Imatinib|Hydroxyurea & Imatinib]]
-|style="background-color:#ffffbf"|Did not meet primary endpoint of PFS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 |-
 |}
 ====Chemotherapy====
 *[[Hydroxyurea (Hydrea)]]
 ===References===
-# 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://link.springer.com/article/10.1007%2Fs11060-009-9976-3 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19688297 PubMed]
+#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://link.springer.com/article/10.1007%2Fs11060-009-9976-3 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19688297 PubMed]
 ==Hydroxyurea & Imatinib {{#subobject:1b771d|Regimen=1}}==
@@ Line 822: / Line 923: @@
 ===Regimen {{#subobject:1c1791|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
 |[http://annonc.oxfordjournals.org/content/16/10/1702.long Dresemann et al. 2005]
-|style="background-color:#91cf61"|Non-randomized
+| style="background-color:#91cf61" |Non-randomized
 | style="background-color:#d3d3d3" |
 | style="background-color:#d3d3d3" |
 |-
 |[https://link.springer.com/article/10.1007%2Fs11060-009-9976-3 Dresemann et al. 2009]
-|style="background-color:#1a9851"|Phase III (E-esc)
+| style="background-color:#1a9851" |Phase III (E-esc)
 |[[#Hydroxyurea_monotherapy|Hydroxyurea]]
-|style="background-color:#ffffbf"|Did not meet primary endpoint of PFS
+| style="background-color:#ffffbf" |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
 *[[Imatinib (Gleevec)]] 400 mg PO once per day
@@ Line 846: / Line 948: @@
 ===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]
-# 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://link.springer.com/article/10.1007%2Fs11060-009-9976-3 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19688297 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. [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]
+#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://link.springer.com/article/10.1007%2Fs11060-009-9976-3 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19688297 PubMed]
 ==Lomustine monotherapy {{#subobject:dc7f4|Regimen=1}}==
@@ Line 856: / Line 959: @@
 ===Variant #1, 100 mg/m<sup>2</sup> {{#subobject:701e36|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834468/ Wick et al. 2010 (JCBF)]
-|style="background-color:#1a9851"|Phase III (C)
+| style="background-color:#1a9851" |Phase III (C)
 |Enzastaurin
-|style="background-color:#ffffbf"|Did not meet primary endpoint of PFS
+| style="background-color:#ffffbf" |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/m<sup>2</sup> PO once on day 1
 ====Supportive medications====
 *Enzyme-inducing antiepileptic drugs (EIAEDs) needed to be discontinued 14 days before enrolling in the trial
@@ Line 878: / Line 983: @@
 ===Variant #2, 110 mg/m<sup>2</sup>, uncapped {{#subobject:193934|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4021043/ Batchelor et al. 2013 (REGAL)]
-|style="background-color:#1a9851"|Phase III (C)
+| style="background-color:#1a9851" |Phase III (C)
 |1. Cediranib<br> 2. Cediranib & Lomustine
-|style="background-color:#ffffbf"|Did not meet primary endpoint of PFS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 |-
 |}
 ====Chemotherapy====
 *[[Lomustine (CCNU)]] 110 mg/m<sup>2</sup> PO once on day 1
@@ Line 896: / Line 1,002: @@
 ===Variant #3, 110 mg/m<sup>2</sup>, capped {{#subobject:193934|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
 |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70314-6/fulltext Taal et al. 2014 (BELOB)]
-|style="background-color:#1a9851"|Randomized Phase II (C)
+| style="background-color:#1a9851" |Randomized Phase II (C)
 |[[#Lomustine_.26_Bevacizumab|Lomustine & Bevacizumab]]
-|style="background-color:#d3d3d3"|Not reported
+| style="background-color:#d3d3d3" |Not reported
 |-
 |[https://www.nejm.org/doi/full/10.1056/NEJMoa1707358 Wick et al. 2017 (EORTC 26101)]
-|style="background-color:#1a9851"|Phase III (C)
+| style="background-color:#1a9851" |Phase III (C)
 |[[#Lomustine_.26_Bevacizumab|Lomustine & Bevacizumab]]
-|style="background-color:#ffffbf"|Did not meet primary endpoint of OS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |}
 ====Chemotherapy====
 *[[Lomustine (CCNU)]] 110 mg/m<sup>2</sup> (maximum dose of 200 mg) PO once on day 1
@@ Line 919: / Line 1,026: @@
 ===Variant #4, 130 mg/m<sup>2</sup> {{#subobject:704e36|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
 |[https://www.sciencedirect.com/science/article/pii/0360301689909206 Bleehen et al. 1989]
-|style="background-color:#1a9851"|Phase III (C)
+| style="background-color:#1a9851" |Phase III (C)
 |Benznidazole & Lomustine
-|style="background-color:#ffffbf"|Did not meet endpoint
+| style="background-color:#ffffbf" |Did not meet endpoint
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834468/ Wick et al. 2010 (JCBF)]
-|style="background-color:#1a9851"|Phase III (C)
+| style="background-color:#1a9851" |Phase III (C)
 |Enzastaurin
-|style="background-color:#ffffbf"|Did not meet primary endpoint of PFS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 |-
 |}
 ''Note: this was the upper bound of the range specified in JCBF.''
 ====Chemotherapy====
 *[[Lomustine (CCNU)]] 130 mg/m<sup>2</sup> PO once on day 1
 ====Supportive medications====
 *Enzyme-inducing antiepileptic drugs (EIAEDs) needed to be discontinued 14 days before enrolling in JCBF
@@ Line 945: / Line 1,054: @@
 ===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. [https://www.sciencedirect.com/science/article/pii/0360301689909206 link to SD article] [https://www.ncbi.nlm.nih.gov/pubmed/2539345 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. [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]
+#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://www.sciencedirect.com/science/article/pii/0360301689909206 link to SD article] [https://www.ncbi.nlm.nih.gov/pubmed/2539345 PubMed]
-# '''REGAL:''' Batchelor TT, Mulholland P, Neyns B, Nabors LB, Campone M, Wick A, Mason W, Mikkelsen T, Phuphanich S, Ashby LS, Degroot 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://ascopubs.org/doi/full/10.1200/JCO.2012.47.2464 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4021043/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23940216 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. [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]
-# '''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://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70314-6/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25035291 PubMed]
+#'''REGAL:''' Batchelor TT, Mulholland P, Neyns B, Nabors LB, Campone M, Wick A, Mason W, Mikkelsen T, Phuphanich S, Ashby LS, Degroot 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://ascopubs.org/doi/full/10.1200/JCO.2012.47.2464 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4021043/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23940216 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 (LWNO). 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://www.ncbi.nlm.nih.gov/pubmed/25899986 PubMed]
+#'''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://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70314-6/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25035291 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://www.nejm.org/doi/full/10.1056/NEJMoa1707358 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29141164 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 (LWNO). 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://www.ncbi.nlm.nih.gov/pubmed/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://www.nejm.org/doi/full/10.1056/NEJMoa1707358 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29141164 PubMed]
 ==Lomustine & Bevacizumab {{#subobject:dc7f64|Regimen=1}}==
@@ Line 959: / Line 1,069: @@
 ===Regimen {{#subobject:1a7gh4|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
 |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70314-6/fulltext Taal et al. 2014 (BELOB)]
-|style="background-color:#1a9851"|Randomized Phase II (E-esc)
+| style="background-color:#1a9851" |Randomized Phase II (E-esc)
 |[[#Lomustine_monotherapy|Lomustine]]
-|style="background-color:#d3d3d3"|Not reported
+| style="background-color:#d3d3d3" |Not reported
 |-
 |[https://www.nejm.org/doi/full/10.1056/NEJMoa1707358 Wick et al. 2017 (EORTC 26101)]
-|style="background-color:#1a9851"|Phase III (E-RT-esc)
+| style="background-color:#1a9851" |Phase III (E-RT-esc)
 |[[#Lomustine_monotherapy|Lomustine]]
-|style="background-color:#ffffbf"|Did not meet primary endpoint of OS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |}
 ====Chemotherapy====
 *[[Lomustine (CCNU)]]
 *[[Bevacizumab (Avastin)]]
@@ Line 982: / Line 1,093: @@
 ===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://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70314-6/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25035291 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 (LWNO). 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://www.ncbi.nlm.nih.gov/pubmed/25899986 PubMed]
+#'''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://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70314-6/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25035291 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://www.nejm.org/doi/full/10.1056/NEJMoa1707358 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29141164 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 (LWNO). 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://www.ncbi.nlm.nih.gov/pubmed/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://www.nejm.org/doi/full/10.1056/NEJMoa1707358 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29141164 PubMed]
 ==NovoTTF-100A monotherapy {{#subobject:1674af|Regimen=1}}==
@@ Line 993: / Line 1,105: @@
 ===Regimen {{#subobject:4a488e|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
 |[https://www.ejcancer.com/article/S0959-8049(12)00352-8/fulltext Stupp et al. 2012 (EF-11)]
-|style="background-color:#1a9851"|Phase III (E-switch-ooc)
+| style="background-color:#1a9851" |Phase III (E-switch-ooc)
 |Investigator's choice
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
@@ Line 1,005: / Line 1,117: @@
 |}
 ====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. [https://www.ejcancer.com/article/S0959-8049(12)00352-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22608262 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://www.ejcancer.com/article/S0959-8049(12)00352-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22608262 PubMed]
 ==PCV==
@@ Line 1,018: / Line 1,132: @@
 ===Variant #1, 60/110/1.4 {{#subobject:c3f4c2|Variant=1}}===
 {| class="wikitable" style="width: 50%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
 |[https://www.ncbi.nlm.nih.gov/pubmed/7407756 Levin et al. 1980]
-|style="background-color:#91cf61"|Non-randomized
+| style="background-color:#91cf61" |Non-randomized
 |-
 |}
 ====Chemotherapy====
 *[[Procarbazine (Matulane)]] 60 mg/m<sup>2</sup> PO once per day on days 8 to 21
 *[[Lomustine (CCNU)]] 110 mg/m<sup>2</sup> PO once on day 1
@@ Line 1,034: / Line 1,149: @@
 ===Variant #2, 100/100/1.5 {{#subobject:41002c|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+! style="width: 25%" |Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
 |[https://ascopubs.org/doi/full/10.1200/JCO.2009.27.1932 Brada et al. 2010]
@@ Line 1,046: / Line 1,161: @@
 |}
 ====Chemotherapy====
 *[[Procarbazine (Matulane)]] 100 mg/m<sup>2</sup> PO once per day on days 1 to 10
 *[[Lomustine (CCNU)]] 100 mg/m<sup>2</sup> PO once on day 1
@@ Line 1,052: / Line 1,168: @@
 '''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 protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/7407756 PubMed]
-# 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://ascopubs.org/doi/full/10.1200/JCO.2009.27.1932 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20855843 PubMed]
+#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]
+#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://ascopubs.org/doi/full/10.1200/JCO.2009.27.1932 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20855843 PubMed]
 =Recurrent disease, non-curative therapy, non-randomized or retrospective data=
@@ Line 1,063: / Line 1,180: @@
 ===Variant #1 {{#subobject:c6f29b|Variant=1}}===
 {| class="wikitable" style="width: 50%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
 |[http://jco.ascopubs.org/content/27/28/4733.long Friedman et al. 2009 (AVF3708g)]
-|style="background-color:#91cf61"|Phase II (RT)
+| style="background-color:#91cf61" |Phase II (RT)
 |-
 |}
 ====Chemotherapy====
 *[[Bevacizumab (Avastin)]] 10 mg/kg IV once on day 1
@@ Line 1,077: / Line 1,195: @@
 ===Variant #2 {{#subobject:35ed36|Variant=1}}===
 {| class="wikitable" style="width: 50%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2645088/ Kreisl et al. 2008 (NCI 06-C-0064E)]
-|style="background-color:#91cf61"|Phase II (RT)
+| style="background-color:#91cf61" |Phase II (RT)
 |-
 |}
 ====Chemotherapy====
 *[[Bevacizumab (Avastin)]] 10 mg/kg IV once per day on days 1 & 15
 '''28-day cycles'''
 ====Subsequent treatment====
 *Upon progression: [[#Irinotecan_.26_Bevacizumab_2|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. [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]
+#'''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. [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]
 <!-- 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. [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]
+#'''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. [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]
-# '''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://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70314-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25035291 PubMed]
+#'''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://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70314-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25035291 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 (LWNO). 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://www.ncbi.nlm.nih.gov/pubmed/25899986 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 (LWNO). 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://www.ncbi.nlm.nih.gov/pubmed/25899986 PubMed]
 ==Carboplatin & Bevacizumab {{#subobject:f5673c|Regimen=1}}==
@@ Line 1,105: / Line 1,226: @@
 ===Variant #1, q2wk bevacizumab {{#subobject:ffa90b|Variant=1}}===
 {| class="wikitable" style="width: 50%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
 |[http://www.neurology.org/content/70/10/779.long Norden et al. 2008]
-|style="background-color:#ffffbe"|Retrospective
+| style="background-color:#ffffbe" |Retrospective
 |-
 |}
 ====Chemotherapy====
 *[[Carboplatin (Paraplatin)]] AUC 5 to 6 IV (reference does not list schedule of carboplatin)
 *[[Bevacizumab (Avastin)]] 10 mg/kg IV once on day 1
@@ Line 1,120: / Line 1,242: @@
 ===Variant #2, q4wk bevacizumab {{#subobject:401e2e|Variant=1}}===
 {| class="wikitable" style="width: 50%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[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:#ffffbe"|Retrospective
+| style="background-color:#ffffbe" |Retrospective
 |-
 |}
 ====Chemotherapy====
 *[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1
 *[[Bevacizumab (Avastin)]] 10 mg/kg IV once on day 1
@@ Line 1,134: / Line 1,257: @@
 ===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]
-# '''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]
+#'''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]
+#'''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]
 ==CART-EGFRvIII cells {{#subobject:ed311c|Regimen=1}}==
@@ Line 1,144: / Line 1,268: @@
 ===Regimen {{#subobject:26961a|Variant=1}}===
 {| class="wikitable" style="width: 50%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
 |[http://stm.sciencemag.org/content/9/399/eaaa0984.full O'Rourke et al. 2017]
-|style="background-color:#ffffbe"|Phase I
+| style="background-color:#ffffbe" |Phase I
 |-
 |}
 ====Immunotherapy====
 *Autologous CART-EGFRvIII cells, see paper for details
@@ Line 1,157: / Line 1,282: @@
 ===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]
+#'''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]
 ==Cyclophosphamide monotherapy {{#subobject:1724a|Regimen=1}}==
@@ Line 1,166: / Line 1,292: @@
 ===Regimen {{#subobject:d0ffd5|Variant=1}}===
 {| class="wikitable" style="width: 50%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
 |[https://onlinelibrary.wiley.com/doi/10.1002/cncr.20072/full Chamberlain & Tsao-Wei 2004]
-|style="background-color:#91cf61"|Phase II
+| style="background-color:#91cf61" |Phase II
 |-
 |}
 ====Chemotherapy====
 *[[Cyclophosphamide (Cytoxan)]] 750 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 2
 ====Supportive medications====
 *[[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 (Cytoxan)]]
@@ Line 1,186: / Line 1,314: @@
 ===References===
-# Chamberlain MC, Tsao-Wei DD. Salvage chemotherapy with cyclophosphamide for recurrent, temozolomide-refractory glioblastoma multiforme. Cancer. 2004 Mar 15;100(6):1213-20. [https://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]
+#Chamberlain MC, Tsao-Wei DD. Salvage chemotherapy with cyclophosphamide for recurrent, temozolomide-refractory glioblastoma multiforme. Cancer. 2004 Mar 15;100(6):1213-20. [https://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]
 ==Irinotecan monotherapy {{#subobject:14c7e6|Regimen=1}}==
@@ Line 1,195: / Line 1,324: @@
 ===Regimen {{#subobject:24c9e2|Variant=1}}===
 {| class="wikitable" style="width: 50%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[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]
-|style="background-color:#91cf61"|Phase II
+| style="background-color:#91cf61" |Phase II
 |-
 |}
 ====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 medications====
 *[[:Category:Steroids|Steroids]] at lowest dose necessary
 *Avoid laxatives and magnesium-containing antacids due to potential for diarrhea
@@ Line 1,213: / Line 1,344: @@
 ===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. [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]
 ==Irinotecan & Bevacizumab {{#subobject:a9cf4a|Regimen=1}}==
@@ Line 1,222: / Line 1,354: @@
 ===Variant #1, q2wk bev {{#subobject:a156f1|Variant=1}}===
 {| class="wikitable" style="width: 50%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
 |[http://jco.ascopubs.org/content/25/30/4714.long Chen et al. 2007]
-|style="background-color:#91cf61"|Pilot, >20 pts
+| style="background-color:#91cf61" |Pilot, >20 pts
 |-
 |[http://clincancerres.aacrjournals.org/content/13/4/1253.long Vredenburgh et al. 2007]
-|style="background-color:#91cf61"|Phase II
+| style="background-color:#91cf61" |Phase II
 |-
 |[http://www.neurology.org/content/70/10/779.long Norden et al. 2008]
-|style="background-color:#91cf61"|Phase II
+| style="background-color:#91cf61" |Phase II
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2645088/ Kreisl et al. 2008 (NCI 06-C-0064E)]
-|style="background-color:#91cf61"|Phase II
+| style="background-color:#91cf61" |Phase II
 |-
 |[http://jco.ascopubs.org/content/27/28/4733.long Friedman et al. 2009 (AVF3708g)]
-|style="background-color:#91cf61"|Phase II
+| style="background-color:#91cf61" |Phase II
 |-
 |}
 ''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/m<sup>2</sup> 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/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'''
 *[[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 medications====
-*[[:Category:Steroids|Steroids]] were generally maintained at the same dose
+*[[:Category:Steroids|Steroids]] were generally maintained at the same dose
 '''14-day cycles'''
@@ Line 1,255: / Line 1,389: @@
 ===Variant #2, q3wk bev {{#subobject:7da12|Variant=1}}===
 {| class="wikitable" style="width: 50%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
 |[http://clincancerres.aacrjournals.org/content/13/4/1253.long Vredenburgh et al. 2007]
-|style="background-color:#ffffbe"|Phase II, <20 pts
+| style="background-color:#ffffbe" |Phase II, <20 pts
 |-
 |}
 ====Chemotherapy====
 *[[Irinotecan (Camptosar)]] 125 mg/m<sup>2</sup> 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/m<sup>2</sup> IV over 90 minutes once per day on days 1, 8, 22, 29, '''given first'''
 *[[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 medications====
-*[[:Category:Steroids|Steroids]] were generally maintained at the same dose
+*[[:Category:Steroids|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. [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]
-# 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. [http://clincancerres.aacrjournals.org/content/13/4/1253.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17317837 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. [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]
-## '''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. [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]
+#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. [http://clincancerres.aacrjournals.org/content/13/4/1253.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17317837 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. [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]
+##'''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. [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]
-# '''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. [http://jco.ascopubs.org/content/27/5/740.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2645088/ link to PMC article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19114704 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. [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]
+#'''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. [http://jco.ascopubs.org/content/27/5/740.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2645088/ link to PMC article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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. [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]
+#'''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. [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]
 ==Procarbazine monotherapy {{#subobject:69a372|Regimen=1}}==
@@ Line 1,289: / Line 1,426: @@
 ===Variant #1, 125 mg/m<sup>2</sup> {{#subobject:d0f821|Variant=1}}===
 {| class="wikitable" style="width: 50%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2363506/ Yung et al. 2000]
-|style="background-color:#91cf61"|Phase II
+| style="background-color:#91cf61" |Phase II
 |-
 |}
 ''Note: this is the starting dose for patients who previously received chemotherapy; no instructions for dose escalation are given.''
 ====Chemotherapy====
 *[[Procarbazine (Matulane)]] 125 mg/m<sup>2</sup> PO once per day on days 1 to 28
 ====Supportive medications====
 *[[:Category:Steroids|Steroids]] at lowest dose necessary
@@ Line 1,307: / Line 1,446: @@
 ===Variant #2, 150 mg/m<sup>2</sup> {{#subobject:d1a052|Variant=1}}===
 {| class="wikitable" style="width: 50%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2363506/ Yung et al. 2000]
-|style="background-color:#91cf61"|Phase II
+| style="background-color:#91cf61" |Phase II
 |-
 |}
 ''Note: this dosing is intended for patients who have never previously received chemotherapy.''
 ====Chemotherapy====
 *[[Procarbazine (Matulane)]] 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
 ====Supportive medications====
 *[[:Category:Steroids|Steroids]] at lowest dose necessary
@@ Line 1,325: / Line 1,466: @@
 ===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. [https://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://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]
 ==Temozolomide monotherapy {{#subobject:e73a18|Regimen=1}}==
@@ Line 1,334: / Line 1,476: @@
 ===Variant #1, continuous {{#subobject:f18af9|Variant=1}}===
 {| class="wikitable" style="width: 50%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
 |[https://onlinelibrary.wiley.com/doi/10.1002/cncr.23813/full Perry et al. 2008 (RESCUE)]
-|style="background-color:#91cf61"|Phase II
+| style="background-color:#91cf61" |Phase II
 |-
 |}
 ''See paper for details of when this regimen is used.''
 ====Chemotherapy====
 *[[Temozolomide (Temodar)]] 50 mg/m<sup>2</sup> PO once per day
@@ Line 1,349: / Line 1,492: @@
 ===Variant #2, 11 cycles {{#subobject:f06af9|Variant=1}}===
 {| class="wikitable" style="width: 50%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
 |[https://onlinelibrary.wiley.com/doi/10.1002/cncr.22961/full Nicholson et al. 2007]
-|style="background-color:#91cf61"|Non-randomized
+| style="background-color:#91cf61" |Non-randomized
 |-
 |}
 ====Chemotherapy====
 *[[Temozolomide (Temodar)]] 150 to 200 mg/m<sup>2</sup> PO once per day on days 1 to 5
 **Patients who previously received craniospinal irradiation (CSI) instead received 180 mg/m<sup>2</sup> PO once per day on days 1 to 5
@@ Line 1,364: / Line 1,508: @@
 ===Variant #3, 2 years {{#subobject:4cde86|Variant=1}}===
 {| class="wikitable" style="width: 50%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2363506/ Yung et al. 2000]
-|style="background-color:#91cf61"|Phase II
+| style="background-color:#91cf61" |Phase II
 |-
 |}
 ====Chemotherapy====
 *[[Temozolomide (Temodar)]] as follows:
 **Patients who had never previously received chemotherapy: 200 mg/m<sup>2</sup> PO once per day on days 1 to 5
@@ Line 1,379: / Line 1,524: @@
 ===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. [https://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]
-# 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. [https://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://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]
-# '''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://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]
+#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. [https://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]
-## '''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]
+#'''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://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]
+##'''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]
 =Response criteria=
 ==Response Assessment in Neuro-Oncology Working Group==
-* '''2010:''' [https://ascopubs.org/doi/full/10.1200/JCO.2009.26.3541 Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group] [https://www.ncbi.nlm.nih.gov/pubmed/20231676 PubMed]
+*'''2010:''' [https://ascopubs.org/doi/full/10.1200/JCO.2009.26.3541 Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group] [https://www.ncbi.nlm.nih.gov/pubmed/20231676 PubMed]
 [[Category:Glioblastoma regimens]]
 [[Category:Disease-specific pages]]
 [[Category:High-grade gliomas]]

Difference between revisions of "Glioblastoma"

Revision as of 23:07, 8 January 2020

Guidelines

ASCO

EANO

ESMO

NCCN

Adjuvant therapy, standard patients

Bevacizumab & RT

Regimen

Preceding treatment

Chemotherapy

Radiotherapy

Subsequent treatment

References

Carmustine & RT

Variant #1, concurrent

Preceding treatment

Chemotherapy

Radiotherapy

Variant #2, sequential

Preceding treatment

Radiotherapy

Chemotherapy

Supportive care

References

Lomustine, Temozolomide, RT

Regimen

Preceding treatment

Chemotherapy

Radiotherapy

References

Nimustine & RT

Regimen

Preceding treatment

Chemotherapy

Radiotherapy

References

Radiation therapy

Regimen

Preceding treatment

Radiotherapy

References

Temozolomide & RT

Regimen

Preceding treatment

Chemotherapy

Supportive medications

Radiotherapy

Subsequent treatment

References

Adjuvant therapy, elderly or poor performance status patients

Best supportive care

Regimen

Preceding treatment

References

Radiation therapy

Variant #1, hypofractionated (34 Gy)

Preceding treatment

Radiotherapy

Variant #2, abbreviated course (40 Gy)

Preceding treatment

Radiotherapy

Variant #3, standard course (50.4 Gy)

Preceding treatment

Radiotherapy

Variant #4, standard course (60 Gy)

Preceding treatment

Radiotherapy

References

Temozolomide monotherapy

Regimen

Preceding treatment

Chemotherapy

References

Temozolomide & low-dose RT

Regimen

Preceding treatment

Chemotherapy

Radiotherapy

Variant #1, 100 mg/m²

Variant #2, 110 mg/m², uncapped

Variant #3, 110 mg/m², capped

Variant #4, 130 mg/m²