Glioblastoma

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16 regimens on this page
26 variants on this page

Contents


Guidelines

ASCO

EANO

ESMO

NCCN

Adjuvant therapy

Bevacizumab & RT

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RT: Radiation Therapy

Regimen

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

To be completed

Chemoradiotherapy

Treatment followed by irinotecan & bevacizumab maintenance.

References

  1. 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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RT: Radiation Therapy

Regimen

Study Evidence Comparator Efficacy
Shapiro et al. 1989 (BTCG 8001) Phase III Carmustine/Procarbazine & RT Seems not superior
Carmustine & Hydrea/Procarbazine & VM-26 & RT Seems not superior

Radiotherapy

  • Radiation therapy 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)

One course, followed by:

Chemotherapy

Supportive care

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

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

References

  1. Shapiro WR, Green SB, Burger PC, Mahaley MS Jr, Selker RG, VanGilder JC, Robertson JT, Ransohoff J, Mealey J Jr, Strike TA et al. Randomized trial of three chemotherapy regimens and two radiotherapy regimens and two radiotherapy regimens in postoperative treatment of malignant glioma. Brain Tumor Cooperative Group Trial 8001. J Neurosurg. 1989 Jul;71(1):1-9. link to original article contains verified protocol PubMed

Radiation therapy

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Regimen #1, standard radiotherapy

Study Evidence Comparator Efficacy
Stupp et al. 2005 Phase III Temozolomide & RT, then Temozolomide Inferior OS
Malmström et al. 2012 (NCBTSG) Phase III Hypofractionated radiotherapy Not reported
Temozolomide Inferior OS

Adjuvant radiotherapy alone; used as a comparator arm in the referenced trials.

Regimen #2, hypofractionated radiotherapy

Study Evidence Comparator Efficacy
Malmström et al. 2012 (NCBTSG) Phase III Standard radiotherapy Not reported
Temozolomide Seems not superior

Adjuvant radiotherapy alone; used as a comparator arm in the referenced trials.

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 articlePubMed
  2. 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
  3. 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 PubMed
  4. 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 PubMed
  5. 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
  6. Guedes de Castro D, Matiello J, Roa W, Ghosh S, Kepka L, Kumar N, Sinaika V, Lomidze D, Hentati D, Rosenblatt E, Fidarova E. Survival outcomes with short-course radiation therapy in elderly patients with glioblastoma: data from a randomized phase 3 trial. Int J Radiat Oncol Biol Phys. 2017 Jul 15;98(4):931-938. Epub 2017 Mar 30. PubMed

Temozolomide monotherapy

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Regimen

Study Evidence Comparator Efficacy
Malmström et al. 2012 (NCBTSG) Phase III Hypofractionated radiotherapy Seems not superior
Standard radiotherapy Superior OS

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
  2. 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
  3. 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 PubMed

Temozolomide & RT, then Temozolomide

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RT: Radiation Therapy

Regimen #1, low-dose RT

Study Evidence Comparator Efficacy
Perry et al. 2017 Phase III Radiotherapy Superior OS

Chemoradiotherapy

  • 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
  • Concurrent radiation therapy, 2.67 Gy fractions x 15 fractions given 5 days per week, for a total dose of 40.05 Gy

One course, followed by:

Chemotherapy

28-day cycle for up to 12 cycles or until disease progression

Regimen #2, high-dose RT

Study Evidence Comparator Efficacy
Stupp et al. 2005 Phase III Radiotherapy Superior OS
Gilbert et al. 2014 Phase III Bevacizumab, Temozolomide, RT Inferior PFS
Chinot et al. 2014 Phase III Bevacizumab, Temozolomide, RT Inferior PFS

Note: although this regimen had inferior PFS in Gilbert et al. 2014, the effect size did not reach the prespecified improvement target.

Chemoradiotherapy

  • Temozolomide (Temodar) 75 mg/m2 PO once per day, used starting the first day of radiation therapy until the last day of radiation therapy, and no longer than 49 days
  • Concurrent radiation therapy, 2 Gy fractions x 30 fractions given 5 days per week, for a total dose of 60 Gy

Supportive medications

One course

4 weeks after completion of radiation therapy, patients received additional therapy:

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

References

  1. 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. Subgroup analysis: Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005 Mar 10;352(10):997-1003. link to original article PubMed
  2. 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
  3. 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 PubMed
  4. 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
  5. 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

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. 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

Recurrent disease, non-curative salvage therapy

Bevacizumab monotherapy

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Regimen #1

Study Evidence
Friedman et al. 2009 Phase II

Chemotherapy

42-day cycle for up to 104 weeks, until progression of disease, or unacceptable toxicity

Regimen #2

Study Evidence
Kreisl et al. 2008 Phase II

Chemotherapy

28-day cycles, given until progression of disease, or unacceptable toxicity

Upon progression, patients received Irinotecan & Bevacizumab.

References

  1. 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. 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. 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. 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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Regimen #1

Study Evidence
Thompson et al. 2010 Retrospective

Chemotherapy

28-day cycles

Regimen #2

Study Evidence
Norden et al. 2008 Retrospective

Chemotherapy

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

Carmustine monotherapy

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Regimen

Study Evidence
Brandes et al. 2004 Phase II

Chemotherapy

Supportive medications

8-week cycle for up to 6 cycles

References

  1. 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

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

Hydroxyurea & Imatinib

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Regimen

Study Evidence
Dresemann et al. 2005 Non-randomized

Chemotherapy

Given until progression of disease

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

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 (6-week) cycles, given until progression of disease or unacceptable toxicity

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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Regimen #1, every 2 week schedule

Study Evidence
Chen et al. 2007 Pilot, >20 pts
Vredenburgh et al. 2007 Phase II
Norden et al. 2008 Phase II
Friedman et al. 2009 Phase II

Note: Friedman et al. 2009 described 6-week cycles in which treatment was every 2 weeks, given up to 104 weeks, and was otherwise identical, so its entry was consolidated with the other ones here.

Chemotherapy

  • Irinotecan (Camptosar) 125 mg/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 (Vredenburgh et al. 2007 & Norden et al. 2008) 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, given until progression of disease or unacceptable toxicity

Regimen #2

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 (6-week) cycles, given until progression of disease or unacceptable toxicity

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, 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. 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 PubMed
  5. 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

Lomustine monotherapy

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Regimen #1, capped

Study Evidence Comparator Efficacy
Wick et al. 2017 (EORTC 26101) Phase III Lomustine & Bevacizumab Seems not superior

Chemotherapy

42-day cycles

Regimen #2

Study Evidence Comparator Efficacy
Wick et al. 2010 Phase III Enzastaurin Seems not superior

Chemotherapy

Supportive medications

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

42-day cycles, given until progression of disease or unacceptable toxicity

References

  1. 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
  2. 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. 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
  3. 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

PCV

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PCV: Procarbazine, CCNU (Lomustine), Vincristine

Regimen #1

Study Evidence
Levin et al. 1980 Non-randomized

Chemotherapy

42-day cycles, given until progression of disease or unacceptable toxicity

Regimen #2, higher doses

Study Evidence
Cairncross et al. 1994 Phase II

Chemotherapy

42-day cycles, given until progression of disease or unacceptable toxicity

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

Procarbazine monotherapy

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Regimen

Study Evidence
Yung et al. 2000 Phase II

Chemotherapy

  • Procarbazine (Matulane) as follows:
    • Patients who had never previously received chemotherapy: 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 2 years, progression of disease, or unacceptable toxicity

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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Regimen #1, continuous therapy

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

Chemotherapy

Patients who have first recurrence after surgery and conventional external beam radiation:

28-day cycles

Patients with progressive disease are changed to:

Given until progression of disease or unacceptable toxicity

Patients who had recurrent/progressive disease after surgery and concurrent radiation and temozolomide are treated with:

Given until progression of disease or unacceptable toxicity

Regimen #2, traditional dosing

Study Evidence
Nicholson et al. 2007 Non-randomized

Chemotherapy

  • Temozolomide (Temodar) 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

Regimen #3

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 2 years, until progression of disease, or unacceptable toxicity

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. 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