Difference between revisions of "Glioblastoma"
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![[Levels_of_Evidence#Efficacy|Efficacy]] | ![[Levels_of_Evidence#Efficacy|Efficacy]] | ||
|- | |- | ||
− | |[http://www.nejm.org/doi/full/10.1056/NEJMoa043330 Stupp et al. 2005 (EORTC 22981/26981;NCIC CTG CE.3)] | + | |[http://www.nejm.org/doi/full/10.1056/NEJMoa043330 Stupp et al. 2005 (EORTC 22981/26981; NCIC CTG CE.3)] |
|style="background-color:#1a9851"|Phase III | |style="background-color:#1a9851"|Phase III | ||
|[[Complex_multipart_regimens#EORTC_22981.2F26981.3B_NCIC_CTG_CE.3|See link]] | |[[Complex_multipart_regimens#EORTC_22981.2F26981.3B_NCIC_CTG_CE.3|See link]] | ||
|[[Complex_multipart_regimens#EORTC_22981.2F26981.3B_NCIC_CTG_CE.3|See link]] | |[[Complex_multipart_regimens#EORTC_22981.2F26981.3B_NCIC_CTG_CE.3|See link]] | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3816958/ Gilbert et al. 2013 (RTOG 0525)] | ||
+ | | style="background-color:#91cf61" |Non-randomized portion of RCT | ||
+ | | style="background-color:#d3d3d3" | | ||
+ | | style="background-color:#d3d3d3" | | ||
|- | |- | ||
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201043/ Gilbert et al. 2014 (RTOG 0825)] | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201043/ Gilbert et al. 2014 (RTOG 0825)] | ||
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|- | |- | ||
|} | |} | ||
+ | ====Preceding treatment==== | ||
+ | *Surgical biopsy, partial resection, or total resection | ||
====Chemoradiotherapy==== | ====Chemoradiotherapy==== | ||
*[[Temozolomide (Temodar)]] 75 mg/m<sup>2</sup> PO once per day, used starting the first day of radiation therapy until the last day of radiation therapy, and no longer than 49 days | *[[Temozolomide (Temodar)]] 75 mg/m<sup>2</sup> PO once per day, used starting the first day of radiation therapy until the last day of radiation therapy, and no longer than 49 days | ||
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'''One course''' | '''One course''' | ||
====Subsequent treatment==== | ====Subsequent treatment==== | ||
− | *[[#Temozolomide_monotherapy_2|Temozolomide]] | + | *Most protocols: [[#Temozolomide_monotherapy_2|Temozolomide maintenance]], 4 weeks after completion of radiation therapy |
+ | *RTOG 0525: [[#Temozolomide_monotherapy_2|Temozolomide]] versus dose-dense temozolomide maintenance | ||
===References=== | ===References=== | ||
# Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987-96. [http://www.nejm.org/doi/full/10.1056/NEJMoa043330 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15758009 PubMed] | # Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987-96. [http://www.nejm.org/doi/full/10.1056/NEJMoa043330 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15758009 PubMed] | ||
## '''Subgroup analysis:''' Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005 Mar 10;352(10):997-1003. [http://www.nejm.org/doi/full/10.1056/NEJMoa043331 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15758010 PubMed] | ## '''Subgroup analysis:''' Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005 Mar 10;352(10):997-1003. [http://www.nejm.org/doi/full/10.1056/NEJMoa043331 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15758010 PubMed] | ||
+ | # '''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. [http://ascopubs.org/doi/full/10.1200/JCO.2013.49.6968 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3816958/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24101040 PubMed] | ||
# '''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. [http://www.nejm.org/doi/full/10.1056/NEJMoa1308573 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201043/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24552317 PubMed] | # '''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. [http://www.nejm.org/doi/full/10.1056/NEJMoa1308573 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201043/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24552317 PubMed] | ||
# Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, Carpentier AF, Hoang-Xuan K, Kavan P, Cernea D, Brandes AA, Hilton M, Abrey L, Cloughesy T. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014 Feb 20;370(8):709-22. [http://www.nejm.org/doi/full/10.1056/NEJMoa1308345 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24552318 PubMed] | # Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, Carpentier AF, Hoang-Xuan K, Kavan P, Cernea D, Brandes AA, Hilton M, Abrey L, Cloughesy T. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014 Feb 20;370(8):709-22. [http://www.nejm.org/doi/full/10.1056/NEJMoa1308345 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24552318 PubMed] | ||
Line 460: | Line 469: | ||
!Comparator | !Comparator | ||
![[Levels_of_Evidence#Efficacy|Efficacy]] | ![[Levels_of_Evidence#Efficacy|Efficacy]] | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3816958/ Gilbert et al. 2013 (RTOG 0525)] | ||
+ | | style="background-color:#1a9851" |Phase III (C) | ||
+ | |Dose-dense Temozolomide | ||
+ | | style="background-color:#ffffbf" |Seems not superior | ||
|- | |- | ||
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1611977 Perry et al. 2017 (NCIC CTG CE.6)] | |[http://www.nejm.org/doi/full/10.1056/NEJMoa1611977 Perry et al. 2017 (NCIC CTG CE.6)] | ||
Line 474: | Line 488: | ||
''Note: treatment in ACT IV was given for a minimum of 6 cycles.'' | ''Note: treatment in ACT IV was given for a minimum of 6 cycles.'' | ||
====Preceding treatment==== | ====Preceding treatment==== | ||
− | *NCIC CTG CE.6: [[#Temozolomide_.26_low-dose_RT| | + | *RTOG 0525: Surgery, then [[#Temozolomide_.26_RT|adjuvant temozolomide & RT]] |
+ | *NCIC CTG CE.6: Surgery, then [[#Temozolomide_.26_low-dose_RT|adjuvant temozolomide & low-dose RT]] | ||
*ACT IV: Resection | *ACT IV: Resection | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
Line 484: | Line 499: | ||
# '''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. [http://www.nejm.org/doi/full/10.1056/NEJMoa043330 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15758009 PubMed] | # '''EORTC 22981/26981; NCIC CTG CE.3:''' Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987-96. [http://www.nejm.org/doi/full/10.1056/NEJMoa043330 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15758009 PubMed] | ||
## '''Subgroup analysis:''' Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005 Mar 10;352(10):997-1003. [http://www.nejm.org/doi/full/10.1056/NEJMoa043331 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15758010 PubMed] | ## '''Subgroup analysis:''' Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005 Mar 10;352(10):997-1003. [http://www.nejm.org/doi/full/10.1056/NEJMoa043331 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15758010 PubMed] | ||
− | # '''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. [http://ascopubs.org/doi/full/10.1200/JCO.2013.49.6968 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3816958/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24101040 PubMed] | + | # '''RTOG 0525:''' Gilbert MR, Wang M, Aldape KD, Stupp R, Hegi ME, Jaeckle KA, Armstrong TS, Wefel JS, Won M, Blumenthal DT, Mahajan A, Schultz CJ, Erridge S, Baumert B, Hopkins KI, Tzuk-Shina T, Brown PD, Chakravarti A, Curran WJ Jr, Mehta MP. Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol. 2013 Nov 10;31(32):4085-91. Epub 2013 Oct 7. [http://ascopubs.org/doi/full/10.1200/JCO.2013.49.6968 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3816958/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24101040 PubMed] |
# '''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. [http://www.nejm.org/doi/full/10.1056/NEJMoa1308573 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201043/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24552317 PubMed] | # '''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. [http://www.nejm.org/doi/full/10.1056/NEJMoa1308573 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201043/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24552317 PubMed] | ||
# '''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. [http://www.nejm.org/doi/full/10.1056/NEJMoa1308345 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24552318 PubMed] | # '''AVAglio:''' Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, Carpentier AF, Hoang-Xuan K, Kavan P, Cernea D, Brandes AA, Hilton M, Abrey L, Cloughesy T. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014 Feb 20;370(8):709-22. [http://www.nejm.org/doi/full/10.1056/NEJMoa1308345 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24552318 PubMed] |
Revision as of 22:26, 30 June 2018
Section editor | |
---|---|
Seema Nagpal, MD Palo Alto, CA |
27 regimens on this page
41 variants on this page
|
Guidelines
ASCO
- 2016: Radiation therapy for glioblastoma: American Society of Clinical Oncology Clinical Practice Guideline endorsement of the American Society for Radiation Oncology Guideline PubMed
EANO
- 2017: European Association for Neuro-Oncology (EANO) guidelines for palliative care in adults with glioma PubMed
- 2014: EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma PubMed
ESMO
- 2014: High-grade glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up (2014) PubMed
NCCN
Adjuvant therapy, standard patients
Bevacizumab & RT
back to top |
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
Subsequent treatment
References
- 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
back to top |
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
- 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)
One course, followed by:
Chemotherapy
- Carmustine (BiCNU) 80 mg/m2 IV over 30 to 60 minutes once per day on days 1 to 3
Supportive care
- Pulmonary function tests (PFTs) checked before start of therapy, and then when cumulative dose of Carmustine (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
- 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
Radiation therapy
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Stupp et al. 2005 (EORTC 22981/26981;NCIC CTG CE.3) | Phase III (C) | Temozolomide & RT, then Temozolomide | Inferior OS |
Adjuvant radiotherapy alone; used as a comparator arm in the referenced trials.
Preceding treatment
- Surgical resection
Radiotherapy
References
- Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987-96. link to original article contains verified protocol PubMed
Temozolomide & RT
back to top |
RT: Radiation Therapy
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Stupp et al. 2005 (EORTC 22981/26981; NCIC CTG CE.3) | Phase III | See link | See link |
Gilbert et al. 2013 (RTOG 0525) | Non-randomized portion of RCT | ||
Gilbert et al. 2014 (RTOG 0825) | Phase III | See link | See link |
Chinot et al. 2014 (AVAglio) | Phase III | See link | See link |
Kong et al. 2017 | Phase III | Temozolomide & RT with CIK cells | Seems to have inferior PFS |
Preceding treatment
- Surgical biopsy, partial resection, or total resection
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
- PCP prophylaxis with ONE of the following:
- Trimethoprim/Sulfamethoxazole (Bactrim)
- Pentamidine (Nebupent) 300 mg nebulized inhaled
- Metoclopramide (Reglan) or 5-HT3 antagonist recommended before the initial doses of radiation therapy & temozolomide
One course
Subsequent treatment
- Most protocols: Temozolomide maintenance, 4 weeks after completion of radiation therapy
- RTOG 0525: Temozolomide versus dose-dense temozolomide maintenance
References
- Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987-96. link to original article contains verified protocol PubMed
- 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
- RTOG 0525: Gilbert MR, Wang M, Aldape KD, Stupp R, Hegi ME, Jaeckle KA, Armstrong TS, Wefel JS, Won M, Blumenthal DT, Mahajan A, Schultz CJ, Erridge S, Baumert B, Hopkins KI, Tzuk-Shina T, Brown PD, Chakravarti A, Curran WJ Jr, Mehta MP. Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol. 2013 Nov 10;31(32):4085-91. Epub 2013 Oct 7. link to original article link to PMC article contains verified protocol PubMed
- RTOG 0825: Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, Colman H, Chakravarti A, Pugh S, Won M, Jeraj R, Brown PD, Jaeckle KA, Schiff D, Stieber VW, Brachman DG, Werner-Wasik M, Tremont-Lukats IW, Sulman EP, Aldape KD, Curran WJ Jr, Mehta MP. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014 Feb 20;370(8):699-708. link to original article link to PMC article PubMed
- 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
- GLARIUS: Herrlinger U, Schäfer N, Steinbach JP, Weyerbrock A, Hau P, Goldbrunner R, Friedrich F, Rohde V, Ringel F, Schlegel U, Sabel M, Ronellenfitsch MW, Uhl M, Maciaczyk J, Grau S, Schnell O, Hänel M, Krex D, Vajkoczy P, Gerlach R, Kortmann RD, Mehdorn M, Tüttenberg J, Mayer-Steinacker R, Fietkau R, Brehmer S, Mack F, Stuplich M, Kebir S, Kohnen R, Dunkl E, Leutgeb B, Proescholdt M, Pietsch T, Urbach H, Belka C, Stummer W, Glas M. Bevacizumab plus irinotecan versus temozolomide in newly diagnosed O6-methylguanine-DNA methyltransferase nonmethylated glioblastoma: The randomized GLARIUS trial. J Clin Oncol. 2016 May 10;34(14):1611-9. Epub 2016 Mar 14. link to original article PubMed
- Kong DS, Nam DH, Kang SH, Lee JW, Chang JH, Kim JH, Lim YJ, Koh YC, Chung YG, Kim JM, Kim CH. Phase III randomized trial of autologous cytokine-induced killer cell immunotherapy for newly diagnosed glioblastoma in Korea. Oncotarget. 2017 Jan 24;8(4):7003-7013. link to original article link to PMC article contains verified protocol PubMed
- HERBY: Grill J, Massimino M, Bouffet E, Azizi AA, McCowage G, Cañete A, Saran F, Le Deley MC, Varlet P, Morgan PS, Jaspan T, Jones C, Giangaspero F, Smith H, Garcia J, Elze MC, Rousseau RF, Abrey L, Hargrave D, Vassal G. Phase II, Open-label, randomized, multicenter trial (HERBY) of bevacizumab in pediatric patients with newly diagnosed high-grade glioma. J Clin Oncol. 2018 Apr 1;36(10):951-958. Epub 2018 Feb 7. link to original article PubMed
Adjuvant therapy, elderly or poor performance status patients
Best supportive care
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Keime-Guibert et al. 2007 | Phase III (C) | RT x 50 Gy | Inferior OS |
No antineoplastic therapy after primary surgery.
Preceding treatment
- Surgery
References
- Keime-Guibert F, Chinot O, Taillandier L, Cartalat-Carel S, Frenay M, Kantor G, Guillamo JS, Jadaud E, Colin P, Bondiau PY, Meneï P, Loiseau H, Bernier V, Honnorat J, Barrié M, Mokhtari K, Mazeron JJ, Bissery A, Delattre JY; Association of French-Speaking Neuro-Oncologists. Radiotherapy for glioblastoma in the elderly. N Engl J Med. 2007 Apr 12;356(15):1527-35. link to original article contains protocol PubMed
Radiation therapy
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Variant #1, hypofractionated (34 Gy)
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Malmström et al. 2012 | Phase III (E) | Standard radiotherapy | Seems not superior |
Temozolomide | Seems not superior |
Preceding treatment
- Surgery
Radiotherapy
- External beam radiotherapy 10 x 3.40 Gy fractions, five days per week, for a total dose of 34 Gy
2-week course
Variant #2, abbreviated course (40 Gy)
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Roa et al. 2004 | Randomized Phase II (E) | Standard RT (60 Gy) | Seems not superior |
Perry et al. 2017 (NCIC CTG CE.6) | Phase III (C) | Temozolomide & LDRT | Inferior OS |
Note: Roa et al. 2004 was closed early due to poor accrual.
Preceding treatment
- Surgery
Radiotherapy
- External beam radiotherapy 15 x 2.67 Gy fractions, five days per week, for a total dose of 40.05 Gy
3-week course
Variant #3, standard course (50.4 Gy)
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Keime-Guibert et al. 2007 | Phase III (E) | Best supportive care | Superior OS |
Preceding treatment
- Surgery
Radiotherapy
- External beam radiotherapy 28 x 1.80 Gy fractions, five days per week, for a total dose of 50.4 Gy
5.5-week course
Variant #4, standard course (60 Gy)
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Roa et al. 2004 | Randomized Phase II | Abbreviated RT (40 Gy) | Seems not superior |
Malmström et al. 2012 | Phase III (C) | Hypofractionated RT | Seems not superior |
Temozolomide | Inferior OS |
Note: Roa et al. 2004 was closed early due to poor accrual.
Preceding treatment
- Surgery
Radiotherapy
- External beam radiotherapy 30 x 2.00 Gy fractions, five days per week, for a total dose of 60 Gy
6-week course
References
- Roa W, Brasher PM, Bauman G, Anthes M, Bruera E, Chan A, Fisher B, Fulton D, Gulavita S, Hao C, Husain S, Murtha A, Petruk K, Stewart D, Tai P, Urtasun R, Cairncross JG, Forsyth P. Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: a prospective randomized clinical trial. J Clin Oncol. 2004 May 1;22(9):1583-8. Epub 2004 Mar 29. link to original article contains protocol PubMed
- Keime-Guibert F, Chinot O, Taillandier L, Cartalat-Carel S, Frenay M, Kantor G, Guillamo JS, Jadaud E, Colin P, Bondiau PY, Meneï P, Loiseau H, Bernier V, Honnorat J, Barrié M, Mokhtari K, Mazeron JJ, Bissery A, Delattre JY; Association of French-Speaking Neuro-Oncologists. Radiotherapy for glioblastoma in the elderly. N Engl J Med. 2007 Apr 12;356(15):1527-35. link to original article contains protocol PubMed
- Malmström A, Grønberg BH, Marosi C, Stupp R, Frappaz D, Schultz H, Abacioglu U, Tavelin B, Lhermitte B, Hegi ME, Rosell J, Henriksson R; Nordic Clinical Brain Tumour Study Group (NCBTSG). Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncol. 2012 Sep;13(9):916-26. link to original article contains protocol PubMed
- NCIC CTG CE.6: Perry JR, Laperriere N, O'Callaghan CJ, Brandes AA, Menten J, Phillips C, Fay M, Nishikawa R, Cairncross JG, Roa W, Osoba D, Rossiter JP, Sahgal A, Hirte H, Laigle-Donadey F, Franceschi E, Chinot O, Golfinopoulos V, Fariselli L, Wick A, Feuvret L, Back M, Tills M, Winch C, Baumert BG, Wick W, Ding K, Mason WP; Trial Investigators. Short-course radiation plus temozolomide in elderly patients with glioblastoma. N Engl J Med. 2017 Mar 16;376(11):1027-1037. link to original article PubMed
- 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 | Phase III (E) | Hypofractionated radiotherapy | Seems not superior |
Standard radiotherapy | Superior OS |
Preceding treatment
- Surgery
Chemotherapy
- Temozolomide (Temodar) 200 mg/m2 PO once per day on days 1 to 5
28-day cycle for up to 6 cycles
References
- Malmström A, Grønberg BH, Marosi C, Stupp R, Frappaz D, Schultz H, Abacioglu U, Tavelin B, Lhermitte B, Hegi ME, Rosell J, Henriksson R; Nordic Clinical Brain Tumour Study Group (NCBTSG). Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncol. 2012 Sep;13(9):916-26. link to original article contains verified protocol PubMed
Temozolomide & low-dose RT
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LDRT: Low-Dose Radiation Therapy
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Perry et al. 2017 (NCIC CTG CE.6) | Phase III (E) | 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
Subsequent treatment
References
- NCIC CTG CE.6: Perry JR, Laperriere N, O'Callaghan CJ, Brandes AA, Menten J, Phillips C, Fay M, Nishikawa R, Cairncross JG, Roa W, Osoba D, Rossiter JP, Sahgal A, Hirte H, Laigle-Donadey F, Franceschi E, Chinot O, Golfinopoulos V, Fariselli L, Wick A, Feuvret L, Back M, Tills M, Winch C, Baumert BG, Wick W, Ding K, Mason WP; Trial Investigators. Short-course radiation plus temozolomide in elderly patients with glioblastoma. N Engl J Med. 2017 Mar 16;376(11):1027-1037. link to original article contains verified protocol PubMed
Maintenance after first-line therapy
Irinotecan & Bevacizumab
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Regimen
Study | Evidence |
---|---|
Herrlinger et al. 2016 (GLARIUS) | Non-randomized portion of RCT |
To be completed
Preceding treatment
Chemotherapy
References
- GLARIUS: Herrlinger U, Schäfer N, Steinbach JP, Weyerbrock A, Hau P, Goldbrunner R, Friedrich F, Rohde V, Ringel F, Schlegel U, Sabel M, Ronellenfitsch MW, Uhl M, Maciaczyk J, Grau S, Schnell O, Hänel M, Krex D, Vajkoczy P, Gerlach R, Kortmann RD, Mehdorn M, Tüttenberg J, Mayer-Steinacker R, Fietkau R, Brehmer S, Mack F, Stuplich M, Kebir S, Kohnen R, Dunkl E, Leutgeb B, Proescholdt M, Pietsch T, Urbach H, Belka C, Stummer W, Glas M. Bevacizumab plus irinotecan versus temozolomide in newly diagnosed O6-methylguanine-DNA methyltransferase nonmethylated glioblastoma: the randomized GLARIUS trial. J Clin Oncol. 2016 May 10;34(14):1611-9. Epub 2016 Mar 14. link to original article PubMed
Temozolomide monotherapy
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Variant #1, 6 cycles
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Stupp et al. 2005 (EORTC 22981/26981; NCIC CTG CE.3) |
Phase III | See link | See link |
Gilbert et al. 2014 (RTOG 0825) | Phase III | See link | See link |
Chinot et al. 2014 (AVAglio) | Phase III | See link | See link |
Stupp et al. 2015 (EF-14) | Phase III | Temozolomide & TTFields | 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
- Metoclopramide (Reglan) or 5-HT3 antagonist required
28-day cycle for 6 cycles
Variant #2, 12 cycles
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Gilbert et al. 2013 (RTOG 0525) | Phase III (C) | Dose-dense Temozolomide | Seems not superior |
Perry et al. 2017 (NCIC CTG CE.6) | Non-randomized portion of RCT | ||
Weller et al. 2017 (ACT IV) | Phase III (C) | Rindopepimut & Temozolomide | Seems not superior |
Note: treatment in ACT IV was given for a minimum of 6 cycles.
Preceding treatment
- RTOG 0525: Surgery, then adjuvant temozolomide & RT
- NCIC CTG CE.6: Surgery, then adjuvant temozolomide & low-dose RT
- ACT IV: Resection
Chemotherapy
- Temozolomide (Temodar) 150 to 200 mg/m2 PO once per day on days 1 to 5
28-day cycle for up to 12 cycles
References
- EORTC 22981/26981; NCIC CTG CE.3: Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987-96. link to original article contains verified protocol PubMed
- 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
- RTOG 0525: Gilbert MR, Wang M, Aldape KD, Stupp R, Hegi ME, Jaeckle KA, Armstrong TS, Wefel JS, Won M, Blumenthal DT, Mahajan A, Schultz CJ, Erridge S, Baumert B, Hopkins KI, Tzuk-Shina T, Brown PD, Chakravarti A, Curran WJ Jr, Mehta MP. Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol. 2013 Nov 10;31(32):4085-91. Epub 2013 Oct 7. link to original article link to PMC article contains verified protocol PubMed
- RTOG 0825: Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, Colman H, Chakravarti A, Pugh S, Won M, Jeraj R, Brown PD, Jaeckle KA, Schiff D, Stieber VW, Brachman DG, Werner-Wasik M, Tremont-Lukats IW, Sulman EP, Aldape KD, Curran WJ Jr, Mehta MP. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014 Feb 20;370(8):699-708. link to original article link to PMC article PubMed
- AVAglio: Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, Carpentier AF, Hoang-Xuan K, Kavan P, Cernea D, Brandes AA, Hilton M, Abrey L, Cloughesy T. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014 Feb 20;370(8):709-22. link to original article contains protocol PubMed
- EF-14: Stupp R, Taillibert S, Kanner AA, Kesari S, Steinberg DM, Toms SA, Taylor LP, Lieberman F, Silvani A, Fink KL, Barnett GH, Zhu JJ, Henson JW, Engelhard HH, Chen TC, Tran DD, Sroubek J, Tran ND, Hottinger AF, Landolfi J, Desai R, Caroli M, Kew Y, Honnorat J, Idbaih A, Kirson ED, Weinberg U, Palti Y, Hegi ME, Ram Z. Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma: a randomized clinical trial. JAMA. 2015 Dec 15;314(23):2535-43. link to original article contains protocol PubMed
- 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, Burna J, Hirte H, Weller M, Palti Y, Hegi ME, Ram Z. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial. JAMA. 2017 Dec 19;318(23):2306-2316. link to original article PubMed
- GLARIUS: Herrlinger U, Schäfer N, Steinbach JP, Weyerbrock A, Hau P, Goldbrunner R, Friedrich F, Rohde V, Ringel F, Schlegel U, Sabel M, Ronellenfitsch MW, Uhl M, Maciaczyk J, Grau S, Schnell O, Hänel M, Krex D, Vajkoczy P, Gerlach R, Kortmann RD, Mehdorn M, Tüttenberg J, Mayer-Steinacker R, Fietkau R, Brehmer S, Mack F, Stuplich M, Kebir S, Kohnen R, Dunkl E, Leutgeb B, Proescholdt M, Pietsch T, Urbach H, Belka C, Stummer W, Glas M. Bevacizumab plus irinotecan versus temozolomide in newly diagnosed O6-methylguanine-DNA methyltransferase nonmethylated glioblastoma: The randomized GLARIUS trial. J Clin Oncol. 2016 May 10;34(14):1611-9. Epub 2016 Mar 14. link to original article PubMed
- Kong DS, Nam DH, Kang SH, Lee JW, Chang JH, Kim JH, Lim YJ, Koh YC, Chung YG, Kim JM, Kim CH. Phase III randomized trial of autologous cytokine-induced killer cell immunotherapy for newly diagnosed glioblastoma in Korea. Oncotarget. 2017 Jan 24;8(4):7003-7013. link to original article link to PMC article contains verified protocol PubMed
- NCIC CTG CE.6: Perry JR, Laperriere N, O'Callaghan CJ, Brandes AA, Menten J, Phillips C, Fay M, Nishikawa R, Cairncross JG, Roa W, Osoba D, Rossiter JP, Sahgal A, Hirte H, Laigle-Donadey F, Franceschi E, Chinot O, Golfinopoulos V, Fariselli L, Wick A, Feuvret L, Back M, Tills M, Winch C, Baumert BG, Wick W, Ding K, Mason WP; Trial Investigators. Short-course radiation plus temozolomide in elderly patients with glioblastoma. N Engl J Med. 2017 Mar 16;376(11):1027-1037. link to original article contains verified protocol PubMed
- ACT IV: Weller M, Butowski N, Tran DD, Recht LD, Lim M, Hirte H, Ashby L, Mechtler L, Goldlust SA, Iwamoto F, Drappatz J, O'Rourke DM, Wong M, Hamilton MG, Finocchiaro G, Perry J, Wick W, Green J, He Y, Turner CD, Yellin MJ, Keler T, Davis TA, Stupp R, Sampson JH; ACT IV trial investigators. Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial. Lancet Oncol. 2017 Oct;18(10):1373-1385. Epub 2017 Aug 23. link to original article contains protocol PubMed
- HERBY: Grill J, Massimino M, Bouffet E, Azizi AA, McCowage G, Cañete A, Saran F, Le Deley MC, Varlet P, Morgan PS, Jaspan T, Jones C, Giangaspero F, Smith H, Garcia J, Elze MC, Rousseau RF, Abrey L, Hargrave D, Vassal G. Phase II, Open-label, randomized, multicenter trial (HERBY) of bevacizumab in pediatric patients with newly diagnosed high-grade glioma. J Clin Oncol. 2018 Apr 1;36(10):951-958. Epub 2018 Feb 7. link to original article PubMed
Temozolomide & TTFields
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Stupp et al. 2015 (EF-14) | Phase III | 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
- NovoTTF-100A system (Optune) for at least 18 hours per day
28-day cycle for 6 cycles; TTFields could be continued up to 24 months
References
- 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
- 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, Burna 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 salvage therapy
Bevacizumab monotherapy
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Variant #1
Study | Evidence |
---|---|
Friedman et al. 2009 | Phase II |
Chemotherapy
- Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1, 15, 29
42-day cycle for up to 104 weeks, until progression of disease, or unacceptable toxicity
Variant #2
Study | Evidence |
---|---|
Kreisl et al. 2008 | Phase II |
Chemotherapy
- Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1 & 15
28-day cycles
Subsequent treatment
- Upon progression: Irinotecan & Bevacizumab
References
- Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, Garren N, Mackey M, Butman JA, Camphausen K, Park J, Albert PS, Fine HA. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009 Feb 10;27(5):740-5. Epub 2008 Dec 29. link to original article contains verified protocol link to PMC article PubMed
- Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, Yung WK, Paleologos N, Nicholas MK, Jensen R, Vredenburgh J, Huang J, Zheng M, Cloughesy T. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009 Oct 1;27(28):4733-40. Epub 2009 Aug 31. link to original article contains verified protocol PubMed
- BELOB: Taal W, Oosterkamp HM, Walenkamp AM, Dubbink HJ, Beerepoot LV, Hanse MC, Buter J, Honkoop AH, Boerman D, de Vos FY, Dinjens WN, Enting RH, Taphoorn MJ, van den Berkmortel FW, Jansen RL, Brandsma D, Bromberg JE, van Heuvel I, Vernhout RM, van der Holt B, van den Bent MJ. Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial. Lancet Oncol. 2014 Aug;15(9):943-53. Epub 2014 Jul 15. link to original article PubMed
- 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
Study | Evidence |
---|---|
Thompson et al. 2010 | Retrospective |
Chemotherapy
- Carboplatin (Paraplatin) AUC 5 IV once on day 1
- Bevacizumab (Avastin) 10 mg/kg IV once on day 1
28-day cycles
Variant #2
Study | Evidence |
---|---|
Norden et al. 2008 | Retrospective |
Chemotherapy
- Carboplatin (Paraplatin) AUC 5 to 6 IV (reference does not list schedule of carboplatin)
- Bevacizumab (Avastin) 10 mg/kg IV once every 2 weeks
References
- Retrospective: Norden AD, Young GS, Setayesh K, Muzikansky A, Klufas R, Ross GL, Ciampa AS, Ebbeling LG, Levy B, Drappatz J, Kesari S, Wen PY. Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence. Neurology. 2008 Mar 4;70(10):779-87. link to original article PubMed
- Retrospective: Thompson EM, Dosa E, Kraemer DF, Neuwelt EA. Treatment with bevacizumab plus carboplatin for recurrent malignant glioma. Neurosurgery. 2010 Jul;67(1):87-93. link to original article link to PMC article PubMed
Carmustine monotherapy
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Regimen
Study | Evidence |
---|---|
Brandes et al. 2004 | Phase II |
Chemotherapy
- Carmustine (BiCNU) 80 mg/m2 IV once per day on days 1 to 3
Supportive medications
- Antiemesis prophylaxis with Ondansetron (Zofran)
- Steroids at lowest dose necessary
8-week cycle for up to 6 cycles
References
- 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
- Phase I: O'Rourke DM, Nasrallah MP, Desai A, Melenhorst JJ, Mansfield K, Morrissette JJD, Martinez-Lage M, Brem S, Maloney E, Shen A, Isaacs R, Mohan S, Plesa G, Lacey SF, Navenot JM, Zheng Z, Levine BL, Okada H, June CH, Brogdon JL, Maus MV. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci Transl Med. 2017 Jul 19;9(399). PubMed link to original article
Cyclophosphamide monotherapy
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Regimen
Study | Evidence |
---|---|
Chamberlain & Tsao-Wei, 2004 | Phase II |
Chemotherapy
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV over 30 minutes once per day on days 1 & 2
Supportive medications
- Dexamethasone (Decadron) allowed for control of neurologic symptoms
- Ondansetron (Zofran) 0.15 mg/kg IV once prior to cyclophosphamide
- Dexamethasone (Decadron) 4 mg IV once prior to cyclophosphamide
- 1 liter normal saline IV over 2 hours prior to cyclophosphamide
- Prochlorperazine (Compazine) (dose/schedule not specified) prn nausea/vomiting
28-day cycles
References
- Chamberlain MC, Tsao-Wei DD. Salvage chemotherapy with cyclophosphamide for recurrent, temozolomide-refractory glioblastoma multiforme. Cancer. 2004 Mar 15;100(6):1213-20. link to original article contains verified protocol PubMed
Hydroxyurea & Imatinib
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Regimen
Study | Evidence |
---|---|
Dresemann et al. 2005 | Non-randomized |
Chemotherapy
- Imatinib (Gleevec) 400 mg PO once per day
- Hydroxyurea (Hydrea) 500 mg PO BID
Given until progression of disease
References
- Dresemann G. Imatinib and hydroxyurea in pretreated progressive glioblastoma multiforme: a patient series. Ann Oncol. 2005 Oct;16(10):1702-8. Epub 2005 Jul 20. link to original article contains verified protocol PubMed
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
References
- Friedman HS, Petros WP, Friedman AH, Schaaf LJ, Kerby T, Lawyer J, Parry M, Houghton PJ, Lovell S, Rasheed K, Cloughsey T, Stewart ES, Colvin OM, Provenzale JM, McLendon RE, Bigner DD, Cokgor I, Haglund M, Rich J, Ashley D, Malczyn J, Elfring GL, Miller LL. Irinotecan therapy in adults with recurrent or progressive malignant glioma. J Clin Oncol. 1999 May;17(5):1516-25. link to original article contains verified protocol PubMed
Irinotecan & Bevacizumab
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Variant #1, q2wk bev
Study | Evidence |
---|---|
Chen et al. 2007 | Pilot, >20 pts |
Vredenburgh et al. 2007 | Phase II |
Norden et al. 2008 | Phase II |
Kreisl et al. 2008 | 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 or 350 mg/m2 (Chen et al. 2007) IV over 90 minutes once on day 1, given first
- Bevacizumab (Avastin) 10 mg/kg IV once on day 1, given second, 90 minutes after the start of irinotecan
- Infusion times for bevacizumab are 90 minutes for the first dose, then if tolerated, 60 minutes for the second dose, and 30 minutes for the third dose and later
Supportive medications
- Steroids were generally maintained at the same dose
14-day cycles
Variant #2, q3wk bev
Study | Evidence |
---|---|
Vredenburgh et al. 2007 | Phase II, <20 pts |
Chemotherapy
- Irinotecan (Camptosar) 125 mg/m2 IV over 90 minutes once per day on days 1, 8, 22, 29, given first
- Patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) are treated with a higher dose: 350 mg/m2 IV over 90 minutes once per day on days 1, 8, 22, 29, given first
- Bevacizumab (Avastin) 15 mg/kg IV once per day on days 1 & 22, given second, 90 minutes after the start of irinotecan
- Infusion time is 90 minutes for the first dose, then if tolerated, 60 minutes for the second dose, and 30 minutes for the third dose and later
Supportive medications
- Steroids were generally maintained at the same dose
42-day cycles
References
- Chen W, Delaloye S, Silverman DH, Geist C, Czernin J, Sayre J, Satyamurthy N, Pope W, Lai A, Phelps ME, Cloughesy T. Predicting treatment response of malignant gliomas to bevacizumab and irinotecan by imaging proliferation with [18F] fluorothymidine positron emission tomography: a pilot study. J Clin Oncol. 2007 Oct 20;25(30):4714-21. link to original article contains verified protocol PubMed
- Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Marcello J, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Sampson J, Wagner M, Bailey L, Bigner DD, Friedman AH, Friedman HS. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol. 2007 Oct 20;25(30):4722-9. link to original article contains verified protocol PubMed
- Norden AD, Young GS, Setayesh K, Muzikansky A, Klufas R, Ross GL, Ciampa AS, Ebbeling LG, Levy B, Drappatz J, Kesari S, Wen PY. Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence. Neurology. 2008 Mar 4;70(10):779-87. link to original article contains verified protocol PubMed
- 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
- 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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Variant #1, uncapped
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Batchelor et al. 2013 | Phase III (C) | Cediranib Cediranib & Lomustine |
Seems not superior |
Chemotherapy
- Lomustine (Ceenu) 110 mg/m2 PO once on day 1
42-day cycles
Variant #2, capped
Study | Evidence | Comparator | 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 | Seems not superior |
Chemotherapy
- Lomustine (Ceenu) 110 mg/m2 (maximum dose of 200 mg) PO once on day 1
42-day cycles
Variant #3, with range
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Wick et al. 2010 | Phase III (C) | Enzastaurin | Seems not superior |
Chemotherapy
- Lomustine (Ceenu) 100 to 130 mg/m2 PO once on day 1
Supportive medications
- Enzyme-inducing antiepileptic drugs (EIAEDs) needed to be discontinued 14 days before enrolling in the trial
42-day cycles
References
- Wick W, Puduvalli VK, Chamberlain MC, van den Bent MJ, Carpentier AF, Cher LM, Mason W, Weller M, Hong S, Musib L, Liepa AM, Thornton DE, Fine HA. Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma. J Clin Oncol. 2010 Mar 1;28(7):1168-74. Epub 2010 Feb 1. link to original article contains verified protocol link to PMC article PubMed
- Batchelor TT, Mulholland P, Neyns B, Nabors LB, Campone M, Wick A, Mason W, Mikkelsen T, Phuphanich S, Ashby LS, Degroot J, Gattamaneni R, Cher L, Rosenthal M, Payer F, Jürgensmeier JM, Jain RK, Sorensen AG, Xu J, Liu Q, van den Bent M. Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. J Clin Oncol. 2013 Sep 10;31(26):3212-8. Epub 2013 Aug 12. link to original article contains verified protocol link to PMC article PubMed
- BELOB: Taal W, Oosterkamp HM, Walenkamp AM, Dubbink HJ, Beerepoot LV, Hanse MC, Buter J, Honkoop AH, Boerman D, de Vos FY, Dinjens WN, Enting RH, Taphoorn MJ, van den Berkmortel FW, Jansen RL, Brandsma D, Bromberg JE, van Heuvel I, Vernhout RM, van der Holt B, van den Bent MJ. Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial. Lancet Oncol. 2014 Aug;15(9):943-53. Epub 2014 Jul 15. link to original article contains verified protocol PubMed
- HRQoL analysis: Dirven L, van den Bent MJ, Bottomley A, van der Meer N, van der Holt B, Vos MJ, Walenkamp AM, Beerepoot LV, Hanse MC, Reijneveld JC, Otten A, de Vos FY, Smits M, Bromberg JE, Taal W, Taphoorn MJ; Dutch Neuro-Oncology Group (LWNO). The impact of bevacizumab on health-related quality of life in patients treated for recurrent glioblastoma: results of the randomised controlled phase 2 BELOB trial. Eur J Cancer. 2015 Jul;51(10):1321-30. Epub 2015 Apr 17. PubMed
- EORTC 26101: Wick W, Gorlia T, Bendszus M, Taphoorn M, Sahm F, Harting I, Brandes AA, Taal W, Domont J, Idbaih A, Campone M, Clement PM, Stupp R, Fabbro M, Le Rhun E, Dubois F, Weller M, von Deimling A, Golfinopoulos V, Bromberg JC, Platten M, Klein M, van den Bent MJ. Lomustine and bevacizumab in progressive glioblastoma. N Engl J Med. 2017 Nov 16;377(20):1954-1963. link to original article contains verified protocol PubMed
PCV
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PCV: Procarbazine, CCNU (Lomustine), Vincristine
Regimen
Study | Evidence |
---|---|
Levin et al. 1980 | Non-randomized |
Chemotherapy
- Procarbazine (Matulane) 60 mg/m2 PO once per day on days 8 to 21
- Lomustine (Ceenu) 110 mg/m2 PO once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once per day on days 8 & 29
42-day cycles
References
- Levin VA, Edwards MS, Wright DC, Seager ML, Schimberg TP, Townsend JJ, Wilson CB. Modified procarbazine, CCNU, and vincristine (PCV 3) combination chemotherapy in the treatment of malignant brain tumors. Cancer Treat Rep. 1980 Feb-Mar;64(2-3):237-44. contains protocol PubMed
Procarbazine monotherapy
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Variant #1, 125 mg/m2
Study | Evidence |
---|---|
Yung et al. 2000 | Phase II |
Note: this is the starting dose for patients who previously received chemotherapy; no instructions for dose escalation are given.
Chemotherapy
- Procarbazine (Matulane) 125 mg/m2 PO once per day on days 1 to 28
Supportive medications
- Steroids at lowest dose necessary
8-week cycles for up to 2 years, progression of disease, or unacceptable toxicity
Variant #2, 150 mg/m2
Study | Evidence |
---|---|
Yung et al. 2000 | Phase II |
Note: this dosing is intended for patients who have never previously received chemotherapy.
Chemotherapy
- Procarbazine (Matulane) 150 mg/m2 PO once per day on days 1 to 28
- Patients who previously received chemotherapy started with 125 mg/m2 PO once per day on days 1 to 28
Supportive medications
- Steroids at lowest dose necessary
8-week cycles for up to 2 years, progression of disease, or unacceptable toxicity
References
- Yung WK, Albright RE, Olson J, Fredericks R, Fink K, Prados MD, Brada M, Spence A, Hohl RJ, Shapiro W, Glantz M, Greenberg H, Selker RG, Vick NA, Rampling R, Friedman H, Phillips P, Bruner J, Yue N, Osoba D, Zaknoen S, Levin VA. A phase II study of temozolomide vs procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer. 2000 Sep;83(5):588-93. link to original article contains verified protocol link to PMC article PubMed
Temozolomide monotherapy
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Variant #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:
- Temozolomide (Temodar) 150 to 200 mg/m2 PO once per day on days 1 to 5
28-day cycles
Patients with progressive disease are changed to:
- Temozolomide (Temodar) 50 mg/m2 PO once per day, taken continuously without treatment break
Given until progression of disease or unacceptable toxicity
Patients who had recurrent/progressive disease after surgery and concurrent radiation and temozolomide are treated with:
- Temozolomide (Temodar) 50 mg/m2 PO once per day, taken continuously without treatment break
Given until progression of disease or unacceptable toxicity
Variant #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
Variant #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
- Yung WK, Albright RE, Olson J, Fredericks R, Fink K, Prados MD, Brada M, Spence A, Hohl RJ, Shapiro W, Glantz M, Greenberg H, Selker RG, Vick NA, Rampling R, Friedman H, Phillips P, Bruner J, Yue N, Osoba D, Zaknoen S, Levin VA. A phase II study of temozolomide vs procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer. 2000 Sep;83(5):588-93. link to original article contains verified protocol link to PMC article PubMed
- Nicholson HS, Kretschmar CS, Krailo M, Bernstein M, Kadota R, Fort D, Friedman H, Harris MB, Tedeschi-Blok N, Mazewski C, Sato J, Reaman GH. Phase 2 study of temozolomide in children and adolescents with recurrent central nervous system tumors: a report from the Children's Oncology Group. Cancer. 2007 Oct 1;110(7):1542-50. link to original article contains verified protocol PubMed
- 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
- 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