Glioblastoma

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Seema Nagpal, MD
Stanford University
Palo Alto, CA
24 regimens on this page
40 variants on this page

Contents


Guidelines

ASCO

EANO

ESMO

NCCN

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

Preceding treatment

Chemotherapy

Radiotherapy

Subsequent treatment

References

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

Chemotherapy

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
2. Carmustine & Hydrea/Procarbazine & VM-26 & RT Did not meet primary endpoint of OS

Preceding treatment

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

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

  1. BTSG 69-01: Walker MD, Alexander E Jr, Hunt WE, MacCarty CS, Mahaley MS Jr, Mealey J Jr, Norrell HA, Owens G, Ransohoff J, Wilson CB, Gehan EA, Strike TA. Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas: a cooperative clinical trial. J Neurosurg. 1978 Sep;49(3):333-43. link to original article PubMed
  2. BTSG 72-01: Walker MD, Green SB, Byar DP, Alexander E Jr, Batzdorf U, Brooks WH, Hunt WE, MacCarty CS, Mahaley MS Jr, Mealey J Jr, Owens G, Ransohoff J 2nd, Robertson JT, Shapiro WR, Smith KR Jr, Wilson CB, Strike TA. Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N Engl J Med. 1980 Dec 4;303(23):1323-9. link to original article PubMed
  3. SWOG S7703: Eyre HJ, Eltringham JR, Gehan EA, Vogel FS, Al-Sarraf M, Talley RW, Costanzi JJ, Athens JW, Oishi N, Fletcher WS. Randomized comparisons of radiotherapy and carmustine versus procarbazine versus dacarbazine for the treatment of malignant gliomas following surgery: a Southwest Oncology Group Study. Cancer Treat Rep. 1986 Sep;70(9):1085-90. PubMed
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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

Chemotherapy

42-day cycle for up to 6 cycles

Radiotherapy

6- to 7-week course

References

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

Chemotherapy

Radiotherapy

References

  1. JCOG 0305: Shibui S, Narita Y, Mizusawa J, Beppu T, Ogasawara K, Sawamura Y, Kobayashi H, Nishikawa R, Mishima K, Muragaki Y, Maruyama T, Kuratsu J, Nakamura H, Kochi M, Minamida Y, Yamaki T, Kumabe T, Tominaga T, Kayama T, Sakurada K, Nagane M, Kobayashi K, Nakamura H, Ito T, Yazaki T, Sasaki H, Tanaka K, Takahashi H, Asai A, Todo T, Wakabayashi T, Takahashi J, Takano S, Fujimaki T, Sumi M, Miyakita Y, Nakazato Y, Sato A, Fukuda H, Nomura K. Randomized trial of chemoradiotherapy and adjuvant chemotherapy with nimustine (ACNU) versus nimustine plus procarbazine for newly diagnosed anaplastic astrocytoma and glioblastoma (JCOG0305). Cancer Chemother Pharmacol. 2013 Feb;71(2):511-21. Epub 2012 Dec 11. link to original article 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
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

Radiotherapy

References

  1. Urtasun R, Band P, Chapman JD, Feldstein ML, Mielke B, Fryer C. Radiation and high-dose metronidazole in supratentorial glioblastomas. N Engl J Med. 1976 Jun 17;294(25):1364-7. link to original article PubMed
  2. BTSG 69-01: Walker MD, Alexander E Jr, Hunt WE, MacCarty CS, Mahaley MS Jr, Mealey J Jr, Norrell HA, Owens G, Ransohoff J, Wilson CB, Gehan EA, Strike TA. Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas: a cooperative clinical trial. J Neurosurg. 1978 Sep;49(3):333-43. link to original article PubMed
  3. BTSG 72-01: Walker MD, Green SB, Byar DP, Alexander E Jr, Batzdorf U, Brooks WH, Hunt WE, MacCarty CS, Mahaley MS Jr, Mealey J Jr, Owens G, Ransohoff J 2nd, Robertson JT, Shapiro WR, Smith KR Jr, Wilson CB, Strike TA. Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N Engl J Med. 1980 Dec 4;303(23):1323-9. link to original article PubMed
  4. EORTC 22981/26981; NCIC CTG CE.3: Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; 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

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

Radiotherapy

  • Concurrent radiation therapy, 2 Gy fractions x 30 fractions, for a total dose of 60 Gy

6-week course

Subsequent treatment

References

  1. EORTC 22981/26981; NCIC CTG CE.3: Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; 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
  2. RTOG 0525: Gilbert MR, Wang M, Aldape KD, Stupp R, Hegi ME, Jaeckle KA, Armstrong TS, Wefel JS, Won M, Blumenthal DT, Mahajan A, Schultz CJ, Erridge S, Baumert B, Hopkins KI, Tzuk-Shina T, Brown PD, Chakravarti A, Curran WJ Jr, Mehta MP. Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol. 2013 Nov 10;31(32):4085-91. Epub 2013 Oct 7. link to original article link to PMC article contains verified protocol PubMed
  3. RTOG 0825: Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, Colman H, Chakravarti A, Pugh S, Won M, Jeraj R, Brown PD, Jaeckle KA, Schiff D, Stieber VW, Brachman DG, Werner-Wasik M, Tremont-Lukats IW, Sulman EP, Aldape KD, Curran WJ Jr, Mehta MP. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014 Feb 20;370(8):699-708. link to original article link to PMC article PubMed
  4. AVAglio: Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, Carpentier AF, Hoang-Xuan K, Kavan P, Cernea D, Brandes AA, Hilton M, Abrey L, Cloughesy T. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014 Feb 20;370(8):709-22. link to original article contains protocol PubMed
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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

References

  1. 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
2. Temozolomide Did not meet primary endpoint of OS

Preceding treatment

Radiotherapy

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

Radiotherapy

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

Radiotherapy

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
2. Temozolomide Inferior OS

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

Preceding treatment

Radiotherapy

6-week course

References

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

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
2. Standard RT Superior OS

Preceding treatment

Chemotherapy

28-day cycle for up to 6 cycles

References

  1. Malmström A, Grønberg BH, Marosi C, Stupp R, Frappaz D, Schultz H, Abacioglu U, Tavelin B, Lhermitte B, Hegi ME, Rosell J, Henriksson R; Nordic Clinical Brain Tumour Study Group (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

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

References

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

Chemotherapy

References

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

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

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

Chemotherapy

28-day cycle for up to 12 cycles

References

  1. EORTC 22981/26981; NCIC CTG CE.3: Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; 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
  2. RTOG 0525: Gilbert MR, Wang M, Aldape KD, Stupp R, Hegi ME, Jaeckle KA, Armstrong TS, Wefel JS, Won M, Blumenthal DT, Mahajan A, Schultz CJ, Erridge S, Baumert B, Hopkins KI, Tzuk-Shina T, Brown PD, Chakravarti A, Curran WJ Jr, Mehta MP. Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol. 2013 Nov 10;31(32):4085-91. Epub 2013 Oct 7. link to original article link to PMC article contains verified protocol PubMed
  3. RTOG 0825: Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, Colman H, Chakravarti A, Pugh S, Won M, Jeraj R, Brown PD, Jaeckle KA, Schiff D, Stieber VW, Brachman DG, Werner-Wasik M, Tremont-Lukats IW, Sulman EP, Aldape KD, Curran WJ Jr, Mehta MP. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014 Feb 20;370(8):699-708. link to original article link to PMC article PubMed
  4. AVAglio: Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, Carpentier AF, Hoang-Xuan K, Kavan P, Cernea D, Brandes AA, Hilton M, Abrey L, Cloughesy T. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014 Feb 20;370(8):709-22. link to original article contains protocol PubMed
  5. EF-14: Stupp R, Taillibert S, Kanner AA, Kesari S, Steinberg DM, Toms SA, Taylor LP, Lieberman F, Silvani A, Fink KL, Barnett GH, Zhu JJ, Henson JW, Engelhard HH, Chen TC, Tran DD, Sroubek J, Tran ND, Hottinger AF, Landolfi J, Desai R, Caroli M, Kew Y, Honnorat J, Idbaih A, Kirson ED, Weinberg U, Palti Y, Hegi ME, Ram Z. Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma: a randomized clinical trial. JAMA. 2015 Dec 15;314(23):2535-43. link to original article contains 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
  6. GLARIUS: Herrlinger U, Schäfer N, Steinbach JP, Weyerbrock A, Hau P, Goldbrunner R, Friedrich F, Rohde V, Ringel F, Schlegel U, Sabel M, Ronellenfitsch MW, Uhl M, Maciaczyk J, Grau S, Schnell O, Hänel M, Krex D, Vajkoczy P, Gerlach R, Kortmann RD, Mehdorn M, Tüttenberg J, Mayer-Steinacker R, Fietkau R, Brehmer S, Mack F, Stuplich M, Kebir S, Kohnen R, Dunkl E, Leutgeb B, Proescholdt M, Pietsch T, Urbach H, Belka C, Stummer W, Glas M. Bevacizumab plus irinotecan versus temozolomide in newly diagnosed O6-methylguanine-DNA methyltransferase nonmethylated glioblastoma: the randomized GLARIUS trial. J Clin Oncol. 2016 May 10;34(14):1611-9. Epub 2016 Mar 14. link to original article PubMed
  7. 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
  8. NCIC CTG CE.6: Perry JR, Laperriere N, O'Callaghan CJ, Brandes AA, Menten J, Phillips C, Fay M, Nishikawa R, Cairncross JG, Roa W, Osoba D, Rossiter JP, Sahgal A, Hirte H, Laigle-Donadey F, Franceschi E, Chinot O, Golfinopoulos V, Fariselli L, Wick A, Feuvret L, Back M, Tills M, Winch C, Baumert BG, Wick W, Ding K, Mason WP; Trial Investigators. Short-course radiation plus temozolomide in elderly patients with glioblastoma. N Engl J Med. 2017 Mar 16;376(11):1027-1037. link to original article contains verified protocol PubMed
  9. ACT IV: Weller M, Butowski N, Tran DD, Recht LD, Lim M, Hirte H, Ashby L, Mechtler L, Goldlust SA, Iwamoto F, Drappatz J, O'Rourke DM, Wong M, Hamilton MG, Finocchiaro G, Perry J, Wick W, Green J, He Y, Turner CD, Yellin MJ, Keler T, Davis TA, Stupp R, Sampson JH; ACT IV trial investigators. Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial. Lancet Oncol. 2017 Oct;18(10):1373-1385. Epub 2017 Aug 23. link to original article contains protocol PubMed
  10. 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

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

Up to to 24-month course

References

  1. EF-14: Stupp R, Taillibert S, Kanner AA, Kesari S, Steinberg DM, Toms SA, Taylor LP, Lieberman F, Silvani A, Fink KL, Barnett GH, Zhu JJ, Henson JW, Engelhard HH, Chen TC, Tran DD, Sroubek J, Tran ND, Hottinger AF, Landolfi J, Desai R, Caroli M, Kew Y, Honnorat J, Idbaih A, Kirson ED, Weinberg U, Palti Y, Hegi ME, Ram Z. Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma: a randomized clinical trial. JAMA. 2015 Dec 15;314(23):2535-43. link to original article 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

Supportive medications

8-week cycle for up to 6 cycles

References

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

References

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

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

References

  1. 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

Continued indefinitely

References

  1. Dresemann G. Imatinib and hydroxyurea in pretreated progressive glioblastoma multiforme: a patient series. Ann Oncol. 2005 Oct;16(10):1702-8. Epub 2005 Jul 20. link to original article contains verified protocol PubMed
  2. 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

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

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

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

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

  1. Bleehen NM, Freedman LS, Stenning SP. A randomized study of CCNU with and without benznidazole in the treatment of recurrent grades 3 and 4 astrocytoma: report to the Medical Research Council by the Brain Tumor Working Party. Int J Radiat Oncol Biol Phys. 1989 Apr;16(4):1077-81. link to SD article PubMed
  2. JCBF: Wick W, Puduvalli VK, Chamberlain MC, van den Bent MJ, Carpentier AF, Cher LM, Mason W, Weller M, Hong S, Musib L, Liepa AM, Thornton DE, Fine HA. Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma. J Clin Oncol. 2010 Mar 1;28(7):1168-74. Epub 2010 Feb 1. link to original article contains verified protocol link to PMC article PubMed
  3. 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
  4. BELOB: Taal W, Oosterkamp HM, Walenkamp AM, Dubbink HJ, Beerepoot LV, Hanse MC, Buter J, Honkoop AH, Boerman D, de Vos FY, Dinjens WN, Enting RH, Taphoorn MJ, van den Berkmortel FW, Jansen RL, Brandsma D, Bromberg JE, van Heuvel I, Vernhout RM, van der Holt B, van den Bent MJ. Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial. Lancet Oncol. 2014 Aug;15(9):943-53. Epub 2014 Jul 15. link to original article 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
  5. EORTC 26101: Wick W, Gorlia T, Bendszus M, Taphoorn M, Sahm F, Harting I, Brandes AA, Taal W, Domont J, Idbaih A, Campone M, Clement PM, Stupp R, Fabbro M, Le Rhun E, Dubois F, Weller M, von Deimling A, Golfinopoulos V, Bromberg JC, Platten M, Klein M, van den Bent MJ. Lomustine and bevacizumab in progressive glioblastoma. N Engl J Med. 2017 Nov 16;377(20):1954-1963. link to original article 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

  1. BELOB: Taal W, Oosterkamp HM, Walenkamp AM, Dubbink HJ, Beerepoot LV, Hanse MC, Buter J, Honkoop AH, Boerman D, de Vos FY, Dinjens WN, Enting RH, Taphoorn MJ, van den Berkmortel FW, Jansen RL, Brandsma D, Bromberg JE, van Heuvel I, Vernhout RM, van der Holt B, van den Bent MJ. Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial. Lancet Oncol. 2014 Aug;15(9):943-53. Epub 2014 Jul 15. link to original article 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
  2. EORTC 26101: Wick W, Gorlia T, Bendszus M, Taphoorn M, Sahm F, Harting I, Brandes AA, Taal W, Domont J, Idbaih A, Campone M, Clement PM, Stupp R, Fabbro M, Le Rhun E, Dubois F, Weller M, von Deimling A, Golfinopoulos V, Bromberg JC, Platten M, Klein M, van den Bent MJ. Lomustine and bevacizumab in progressive glioblastoma. N Engl J Med. 2017 Nov 16;377(20):1954-1963. link to original article 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

References

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

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

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

42-day cycle for up to 6 cycles

References

  1. Levin VA, Edwards MS, Wright DC, Seager ML, Schimberg TP, Townsend JJ, Wilson CB. Modified procarbazine, CCNU, and vincristine (PCV 3) combination chemotherapy in the treatment of malignant brain tumors. Cancer Treat Rep. 1980 Feb-Mar;64(2-3):237-44. contains protocol PubMed
  2. 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

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

28-day cycles

Subsequent treatment

References

  1. NCI 06-C-0064E: Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, Garren N, Mackey M, Butman JA, Camphausen K, Park J, Albert PS, Fine HA. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009 Feb 10;27(5):740-5. Epub 2008 Dec 29. link to original article contains verified protocol link to PMC article PubMed
  2. AVF3708g: Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, Yung WK, Paleologos N, Nicholas MK, Jensen R, Vredenburgh J, Huang J, Zheng M, Cloughesy T. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009 Oct 1;27(28):4733-40. Epub 2009 Aug 31. link to original article contains verified protocol PubMed
  3. BELOB: Taal W, Oosterkamp HM, Walenkamp AM, Dubbink HJ, Beerepoot LV, Hanse MC, Buter J, Honkoop AH, Boerman D, de Vos FY, Dinjens WN, Enting RH, Taphoorn MJ, van den Berkmortel FW, Jansen RL, Brandsma D, Bromberg JE, van Heuvel I, Vernhout RM, van der Holt B, van den Bent MJ. Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial. Lancet Oncol. 2014 Aug;15(9):943-53. Epub 2014 Jul 15. link to original article PubMed
    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

14-day cycles

Variant #2, q4wk bevacizumab

Study Evidence
Thompson et al. 2010 Retrospective

Chemotherapy

28-day cycles

References

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

  1. 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

Supportive medications

28-day cycles

References

  1. Chamberlain MC, Tsao-Wei DD. Salvage chemotherapy with cyclophosphamide for recurrent, temozolomide-refractory glioblastoma multiforme. Cancer. 2004 Mar 15;100(6):1213-20. link to original article 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

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

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

Supportive medications

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

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

References

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

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

  1. Yung WK, Albright RE, Olson J, Fredericks R, Fink K, Prados MD, Brada M, Spence A, Hohl RJ, Shapiro W, Glantz M, Greenberg H, Selker RG, Vick NA, Rampling R, Friedman H, Phillips P, Bruner J, Yue N, Osoba D, Zaknoen S, Levin VA. A phase II study of temozolomide vs procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer. 2000 Sep;83(5):588-93. link to original article contains verified protocol link to PMC article PubMed
  2. 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
  3. RESCUE: Perry JR, Rizek P, Cashman R, Morrison M, Morrison T. Temozolomide rechallenge in recurrent malignant glioma by using a continuous temozolomide schedule: the "rescue" approach. Cancer. 2008 Oct 15;113(8):2152-7. link to original article 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