Anaplastic glioma

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

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18 regimens on this page 36 variants on this page

Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

ASCO/SNO

• 2022: Mohile et al. Therapy for Diffuse Astrocytic and Oligodendroglial Tumors in Adults: ASCO-SNO Guideline PubMed

EANO

• 2017: European Association for Neuro-Oncology (EANO) guidelines for palliative care in adults with glioma (2017) PubMed

• 2014: EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma (2014) PubMed

ESMO

• High-grade glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up (2014) PubMed

NCCN

• NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - Central Nervous System Cancers and related JNCCN publications below.

Adjuvant therapy

Carmustine monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Chang et al. 1983	1974-1979	Phase 3 (E-esc)	RT alone	Did not meet primary endpoint of OS
Levin et al. 1985 (NCOG 6G61)	1977-1983	Phase 3 (C)	PCV	Seems to have inferior OS1
Halperin et al. 1996	1988-11 to 1991-12	Phase 3 (C)	Carmustine & Mercaptopurine	Did not meet endpoint of OS

¹Reported efficacy for NCOG 6G61 is based on the 1990 update.
Note: Chang et al. 1983 was technically a negative study, although the subgroup of patients aged 40 to 60 had superior survival in this arm.

Preceding treatment

• Chang et al. 1983: Surgery, then adjuvant RT
• NCOG 6G61: Surgery, then adjuvant Hydrea & WBRT

Chemotherapy

• Carmustine (BCNU) 200 mg/m² IV once on day 1

6-week cycles

References

1. Chang CH, Horton J, Schoenfeld D, Salazer O, Perez-Tamayo R, Kramer S, Weinstein A, Nelson JS, Tsukada Y; RTOG; ECOG. Comparison of postoperative radiotherapy and combined postoperative radiotherapy and chemotherapy in the multidisciplinary management of malignant gliomas: a joint Radiation Therapy Oncology Group and Eastern Cooperative Oncology Group study. Cancer. 1983 Sep 15;52(6):997-1007. link to original article PubMed
2. NCOG 6G61: Levin VA, Wara WM, Davis RL, Vestnys P, Resser KJ, Yatsko K, Nutik S, Gutin PH, Wilson CB. Phase III comparison of BCNU and the combination of procarbazine, CCNU, and vincristine administered after radiotherapy with hydroxyurea for malignant gliomas. J Neurosurg. 1985 Aug;63(2):218-23. link to original article dosing details in manuscript have been reviewed by our editors PubMed
   1. Update: Levin VA, Silver P, Hannigan J, Wara WM, Gutin PH, Davis RL, Wilson CB. Superiority of post-radiotherapy adjuvant chemotherapy with CCNU, procarbazine, and vincristine (PCV) over BCNU for anaplastic gliomas: NCOG 6G61 final report. Int J Radiat Oncol Biol Phys. 1990 Feb;18(2):321-4. link to original article PubMed
3. Halperin EC, Herndon J, Schold SC, Brown M, Vick N, Cairncross JG, Macdonald DR, Gaspar L, Fischer B, Dropcho E, Rosenfeld S, Morowitz R, Piepmeier J, Hait W, Byrne T, Salter M, Imperato J, Khandekar J, Paleologos N, Burger P, Bentel GC, Friedman A; CNS Cancer Consortium. A phase III randomized prospective trial of external beam radiotherapy, mitomycin C, carmustine, and 6-mercaptopurine for the treatment of adults with anaplastic glioma of the brain. Int J Radiat Oncol Biol Phys. 1996 Mar 1;34(4):793-802. link to original article dosing details in abstract have been reviewed by our editors PubMed

PCV

PCV: Procarbazine, CCNU, Vincristine

Regimen variant #1, 60/110/1.4 (capped)

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Levin et al. 2003	1992-1999	Phase 3 (C)	PCV & DMFO	Did not meet primary endpoint of OS1
van den Bent et al. 2006 (EORTC 26951)	1996-2002	Phase 3 (E-esc)	No further treatment	Seems to have superior OS2 (primary endpoint) Median OS: 3.5 vs 2.6 y (HR 0.78, 95% CI 0.63-0.98)

¹Levin et al. 2003 had a complex hazard function; see paper for details.
²Reported efficacy for EORTC 26951 is based on the 2022 update.
Chemotherapy begins within 4 weeks after completion of radiation therapy:

Biomarker eligibility criteria

• 1p/19q co-deletion: As of WHO 2016 IDH mutated, 1p/19q co-deleted tumors are classified as oligodendroglioma
• EORTC 26951: van den Bent et al. 2013 noted that 1p/19q co-deleted tumors received the more benefit from adjuvant PCV as compared to tumors without 1p/19q co-deletion.

Preceding treatment

• Surgery, then adjuvant RT x 4500 cGy with 1440 cGy boost

Chemotherapy

• Procarbazine (Matulane) 60 mg/m² PO once per day on days 8 to 21
• Lomustine (CCNU) 110 mg/m² PO once on day 1
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once per day on days 8 & 29

Supportive therapy

• Antiemetics for lomustine: "Domperidone (Motilium) or Metoclopramide (Reglan), and if necessary, Ondansetron (Zofran) or a similar agent"
• Corticosteroids kept at lowest possible dose

42-day cycle for 6 cycles (EORTC 26951) or 7 cycles (Levin et al. 2003)

Regimen variant #2, 60/110/1.4 (no cap)

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Levin et al. 1985 (NCOG 6G61)	1977-1983	Phase 3 (E-esc)	BCNU	Seems to have superior OS1

¹Reported efficacy is based on the 1990 update.
Note: the total number of cycles is not specified in this protocol.

Preceding treatment

• Surgery, then adjuvant Hydrea & WBRT

Chemotherapy

• Procarbazine (Matulane) 60 mg/m² PO once per day on days 8 to 21
• Lomustine (CCNU) 110 mg/m² PO once on day 1
• Vincristine (Oncovin) 1.4 mg/m² IV once per day on days 8 & 29

6- to 8-week cycles

Regimen variant #3, 60/110/2 x 4

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Wick et al. 2009 (NOA-04)	1999-2005	Phase 3 (E-esc)	1. RT	Did not meet primary endpoint of TTF
			2. Temozolomide	Did not meet primary endpoint of TTF

Preceding treatment

• Surgery

Chemotherapy

• Procarbazine (Matulane) 60 mg/m² PO once per day on days 8 to 21
• Lomustine (CCNU) 110 mg/m² PO once on day 1
• Vincristine (Oncovin) 2 mg IV once per day on days 8 & 29

8-week cycle for 4 cycles

Subsequent treatment

• NOA-04, patients with stable disease or better: PCV continuation x 2 (6 total)
• NOA-04, at time of disease progression: Salvage RT

Regimen variant #4, 75/130/1.4 (no cap) x 4

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Prados et al. 1999 (RTOG 9404)	1991-1997	Phase 3 (C)	PCV & BUdR	Did not meet co-primary endpoints of TTP/OS
Cairncross et al. 2006 (RTOG 9402)	1994-2002	Phase 3 (E-esc)	No chemotherapy	Might have superior OS1 (primary endpoint) Median OS: 4.8 vs 4.8 y (HR 0.79, 95% CI 0.61-1.03)

¹Reported efficacy for RTOG 9402 is based on the 2022 update.
Note: the abstract of Prados et al. 2004 does not have dosing details.

Biomarker eligibility criteria

• 1p/19q co-deletion: As of WHO 2016 IDH mutated, 1p/19q co-deleted tumors are classified as oligodendroglioma
• RTOG 9402: a survival benefit was noted in the population with 1p/19q co-deleted tumors

Preceding treatment

• Surgery

Chemotherapy

• Procarbazine (Matulane) 75 mg/m² PO once per day on days 8 to 21
• Lomustine (CCNU) 130 mg/m² PO once on day 1
• Vincristine (Oncovin) 1.4 mg/m² IV once per day on days 8 & 29

6-week cycle for 4 cycles

Subsequent treatment

• Adjuvant RT x 5040 cGy + 900 cGy boost

Regimen variant #5, 100/100/1.5 (capped) x 12

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Thomas et al. 2001 (MRC BR05)	1988-1997	Phase 3 (E-esc)	No further treatment	Did not meet primary endpoint of OS24

Chemotherapy begins 3 to 4 weeks after completion of radiation therapy.

Preceding treatment

• Surgery, then adjuvant RT x 4500 cGy or RT x 6000 cGy

Chemotherapy

• Procarbazine (Matulane) 100 mg/m² PO once per day on days 1 to 10
• Lomustine (CCNU) 100 mg/m² PO once on day 1
• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once on day 1

Supportive therapy

• Corticosteroid use was left up to physician discretion. It was recommended to not discontinue steroids until at least 6 weeks after radiation therapy. If it was to be discontinued, it should be tapered down gradually over several weeks, or could be titrated down to the lowest tolerated dose.

42-day cycle for up to 12 cycles

References

1. NCOG 6G61: Levin VA, Wara WM, Davis RL, Vestnys P, Resser KJ, Yatsko K, Nutik S, Gutin PH, Wilson CB. Phase III comparison of BCNU and the combination of procarbazine, CCNU, and vincristine administered after radiotherapy with hydroxyurea for malignant gliomas. J Neurosurg. 1985 Aug;63(2):218-23. link to original article dosing details in manuscript have been reviewed by our editors PubMed
   1. Update: Levin VA, Silver P, Hannigan J, Wara WM, Gutin PH, Davis RL, Wilson CB. Superiority of post-radiotherapy adjuvant chemotherapy with CCNU, procarbazine, and vincristine (PCV) over BCNU for anaplastic gliomas: NCOG 6G61 final report. Int J Radiat Oncol Biol Phys. 1990 Feb;18(2):321-4. link to original article PubMed
2. MRC BR05: Thomas D, Brada M, Stenning S; Medical Research Council Brain Tumor Working Party. Randomized trial of procarbazine, lomustine, and vincristine in the adjuvant treatment of high-grade astrocytoma: a Medical Research Council trial. J Clin Oncol. 2001 Jan 15;19(2):509-18. link to original article dosing details in manuscript have been reviewed by our editors PubMed
3. Levin VA, Hess KR, Choucair A, Flynn PJ, Jaeckle KA, Kyritsis AP, Yung WK, Prados MD, Bruner JM, Ictech S, Gleason MJ, Kim HW. Phase III randomized study of postradiotherapy chemotherapy with combination alpha-difluoromethylornithine-PCV versus PCV for anaplastic gliomas. Clin Cancer Res. 2003 Mar;9(3):981-90. link to original article dosing details in manuscript have been reviewed by our editors PubMed
4. RTOG 9404: Prados MD, Scott C, Sandler H, Buckner JC, Phillips T, Schultz C, Urtasun R, Davis R, Gutin P, Cascino TL, Greenberg HS, Curran WJ Jr. A phase 3 randomized study of radiotherapy plus procarbazine, CCNU, and vincristine (PCV) with or without BUdR for the treatment of anaplastic astrocytoma: a preliminary report of RTOG 9404. Int J Radiat Oncol Biol Phys. 1999 Dec 1;45(5):1109-15. link to original article PubMed
   1. Update: Prados MD, Seiferheld W, Sandler HM, Buckner JC, Phillips T, Schultz C, Urtasun R, Davis R, Gutin P, Cascino TL, Greenberg HS, Curran WJ Jr. Phase III randomized study of radiotherapy plus procarbazine, lomustine, and vincristine with or without BUdR for treatment of anaplastic astrocytoma: final report of RTOG 9404. Int J Radiat Oncol Biol Phys. 2004 Mar 15;58(4):1147-52. link to original article PubMed
5. RTOG 9402: Cairncross G, Berkey B, Shaw E, Jenkins R, Scheithauer B, Brachman D, Buckner J, Fink K, Souhami L, Laperierre N, Mehta M, Curran W. Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402. J Clin Oncol. 2006 Jun 20;24(18):2707-14. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00002569
   1. Update: Cairncross G, Wang M, Shaw E, Jenkins R, Brachman D, Buckner J, Fink K, Souhami L, Laperriere N, Curran W, Mehta M. Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J Clin Oncol. 2013 Jan 20;31(3):337-43. Epub 2012 Oct 15. link to original article link to PMC article PubMed
   2. Pooled update: Lassman AB, Hoang-Xuan K, Polley MC, Brandes AA, Cairncross JG, Kros JM, Ashby LS, Taphoorn MJB, Souhami L, Dinjens WNM, Laack NN, Kouwenhoven MCM, Fink KL, French PJ, Macdonald DR, Lacombe D, Won M, Gorlia T, Mehta MP, van den Bent MJ. Joint Final Report of EORTC 26951 and RTOG 9402: Phase III Trials With Procarbazine, Lomustine, and Vincristine Chemotherapy for Anaplastic Oligodendroglial Tumors. J Clin Oncol. 2022 Aug 10;40(23):2539-2545. Epub 2022 Jun 22. link to original article link to PMC article PubMed
6. EORTC 26951: van den Bent MJ, Carpentier AF, Brandes AA, Sanson M, Taphoorn MJ, Bernsen HJ, Frenay M, Tijssen CC, Grisold W, Sipos L, Haaxma-Reiche H, Kros JM, van Kouwenhoven MC, Vecht CJ, Allgeier A, Lacombe D, Gorlia T. Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III trial. J Clin Oncol. 2006 Jun 20;24(18):2715-22. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00002840
   1. Update: van den Bent MJ, Brandes AA, Taphoorn MJ, Kros JM, Kouwenhoven MC, Delattre JY, Bernsen HJ, Frenay M, Tijssen CC, Grisold W, Sipos L, Enting RH, French PJ, Dinjens WN, Vecht CJ, Allgeier A, Lacombe D, Gorlia T, Hoang-Xuan K. Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. J Clin Oncol. 2013 Jan 20;31(3):344-50. Epub 2012 Oct 15. link to original article PubMed
   2. Pooled update: Lassman AB, Hoang-Xuan K, Polley MC, Brandes AA, Cairncross JG, Kros JM, Ashby LS, Taphoorn MJB, Souhami L, Dinjens WNM, Laack NN, Kouwenhoven MCM, Fink KL, French PJ, Macdonald DR, Lacombe D, Won M, Gorlia T, Mehta MP, van den Bent MJ. Joint Final Report of EORTC 26951 and RTOG 9402: Phase III Trials With Procarbazine, Lomustine, and Vincristine Chemotherapy for Anaplastic Oligodendroglial Tumors. J Clin Oncol. 2022 Aug 10;40(23):2539-2545. Epub 2022 Jun 22. link to original article link to PMC article PubMed
7. NOA-04: Wick W, Hartmann C, Engel C, Stoffels M, Felsberg J, Stockhammer F, Sabel MC, Koeppen S, Ketter R, Meyermann R, Rapp M, Meisner C, Kortmann RD, Pietsch T, Wiestler OD, Ernemann U, Bamberg M, Reifenberger G, von Deimling A, Weller M. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol. 2009 Dec 10;27(35):5874-80. Epub 2009 Nov 9. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00717210
   1. Update: Wick W, Roth P, Hartmann C, Hau P, Nakamura M, Stockhammer F, Sabel MC, Wick A, Koeppen S, Ketter R, Vajkoczy P, Eyupoglu I, Kalff R, Pietsch T, Happold C, Galldiks N, Schmidt-Graf F, Bamberg M, Reifenberger G, Platten M, von Deimling A, Meisner C, Wiestler B, Weller M; Neuro-oncology Working Group of the German Cancer Society. Long-term analysis of the NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with PCV or temozolomide. Neuro Oncol. 2016 Nov;18(11):1529-1537. Epub 2016 Jul 1. Erratum in: Neuro Oncol. 2016 Nov;18(11):e1. link to original article link to PMC article PubMed

Radiation therapy

Regimen variant #1, 4500 cGy

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Bleehen et al. 1991 (MRC BR02)	1983-1988	Phase 3 (C)	RT x 6000 cGy	Inferior OS
Thomas et al. 2001 (MRC BR05)	1988-1997	Non-randomized part of phase 3 RCT

Radiation therapy starts preferably within 3, but no more than 6, weeks after neurosurgery.

Preceding treatment

• Surgery

Radiotherapy

• External beam radiotherapy 225 cGy fractions x 20 fractions (total dose of 4500 cGy)

4-week course

Subsequent treatment

• MRC BR05: Adjuvant PCV versus no further treatment

Regimen variant #2, 4500 cGy with 1440 cGy boost

Study	Dates of enrollment	Evidence
van den Bent et al. 2006 (EORTC 26951)	1996-2002	Non-randomized part of phase 3 RCT

Radiation therapy starts within 6 weeks after surgery.

Preceding treatment

• Surgery

Radiotherapy

• External beam radiotherapy, 180 cGy fractions x 25 fractions, total dose of 4500 cGy to the planning target volume (PTV-1); then a boost of 180 cGy fractions x 8 fractions, total boost dose of 1440 cGy to the PTV-2, for a total cumulative dose of 5940 cGy

6.5-week course

Subsequent treatment

• Adjuvant PCV versus no further treatment

Regimen variant #3, 5040 cGy with 900 cGy boost

Study	Dates of enrollment	Evidence
Cairncross et al. 2006 (RTOG 9402)	1994-2002	Non-randomized part of phase 3 RCT

Radiation therapy starts within 6 weeks after surgery or chemotherapy.

Preceding treatment

• Surgery versus PCV induction x 6

Radiotherapy

• External beam radiotherapy, 180 cGy fractions x 28 fractions, total dose of 5040 cGy to the planning target volume (PTV-1); then a boost of 180 cGy fractions x 5 fractions, total boost dose of 900 cGy to the PTV-2, for a total cumulative dose of 5940 cGy

6.5-week course

Regimen variant #4, 6000 cGy

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Bleehen et al. 1991 (MRC BR02)	1983-1988	Phase 3 (E-esc)	RT x 4500 cGy	Superior OS
Thomas et al. 2001 (MRC BR05)	1988-1997	Phase 3 (C)	RT, then PCV	Did not meet primary endpoint of OS24
Hildebrand et al. 2008 (EORTC 26882)	1988-2000	Phase 3 (C)	BCNU, DBD, RT	Did not meet primary endpoint of OS
van den Bent et al. 2006 (EORTC 26951)	1996-2002	Non-randomized part of phase 3 RCT
Wick et al. 2009 (NOA-04)	1999-2005	Phase 3 (C)	1. PCV	Did not meet primary endpoint of TTF
			2. Temozolomide	Did not meet primary endpoint of TTF

Note: dosing details are not described in the abstract of Hildebrand et al. 2008.

Preceding treatment

• Surgery

Radiotherapy

• External beam radiotherapy with 180 to 200 cGy fractions for a total dose of 6000 cGy

6-week course

Subsequent treatment

• MRC BR05 & EORTC 26951: Adjuvant PCV versus no further treatment
• NOA-04, upon progression: Salvage PCV versus temozolomide

References

1. MRC BR02: Bleehen NM, Stenning SP; Medical Research Council Brain Tumour Working Party. A Medical Research Council trial of two radiotherapy doses in the treatment of grades 3 and 4 astrocytoma. Br J Cancer. 1991 Oct;64(4):769-74. link to original article link to PMC article dosing details in abstract have been reviewed by our editors PubMed
2. MRC BR05: Thomas D, Brada M, Stenning S; Medical Research Council Brain Tumor Working Party. Randomized trial of procarbazine, lomustine, and vincristine in the adjuvant treatment of high-grade astrocytoma: a Medical Research Council trial. J Clin Oncol. 2001 Jan 15;19(2):509-18. link to original article dosing details in manuscript have been reviewed by our editors PubMed
3. RTOG 9402: Cairncross G, Berkey B, Shaw E, Jenkins R, Scheithauer B, Brachman D, Buckner J, Fink K, Souhami L, Laperierre N, Mehta M, Curran W. Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402. J Clin Oncol. 2006 Jun 20;24(18):2707-14. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00002569
   1. Update: Cairncross G, Wang M, Shaw E, Jenkins R, Brachman D, Buckner J, Fink K, Souhami L, Laperriere N, Curran W, Mehta M. Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J Clin Oncol. 2013 Jan 20;31(3):337-43. Epub 2012 Oct 15. link to original article link to PMC article PubMed
   2. Pooled update: Lassman AB, Hoang-Xuan K, Polley MC, Brandes AA, Cairncross JG, Kros JM, Ashby LS, Taphoorn MJB, Souhami L, Dinjens WNM, Laack NN, Kouwenhoven MCM, Fink KL, French PJ, Macdonald DR, Lacombe D, Won M, Gorlia T, Mehta MP, van den Bent MJ. Joint Final Report of EORTC 26951 and RTOG 9402: Phase III Trials With Procarbazine, Lomustine, and Vincristine Chemotherapy for Anaplastic Oligodendroglial Tumors. J Clin Oncol. 2022 Aug 10;40(23):2539-2545. Epub 2022 Jun 22. link to original article link to PMC article PubMed
4. EORTC 26951: van den Bent MJ, Carpentier AF, Brandes AA, Sanson M, Taphoorn MJ, Bernsen HJ, Frenay M, Tijssen CC, Grisold W, Sipos L, Haaxma-Reiche H, Kros JM, van Kouwenhoven MC, Vecht CJ, Allgeier A, Lacombe D, Gorlia T. Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III trial. J Clin Oncol. 2006 Jun 20;24(18):2715-22. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00002840
   1. Update: van den Bent MJ, Brandes AA, Taphoorn MJ, Kros JM, Kouwenhoven MC, Delattre JY, Bernsen HJ, Frenay M, Tijssen CC, Grisold W, Sipos L, Enting RH, French PJ, Dinjens WN, Vecht CJ, Allgeier A, Lacombe D, Gorlia T, Hoang-Xuan K. Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. J Clin Oncol. 2013 Jan 20;31(3):344-50. Epub 2012 Oct 15. link to original article PubMed
   2. Pooled update: Lassman AB, Hoang-Xuan K, Polley MC, Brandes AA, Cairncross JG, Kros JM, Ashby LS, Taphoorn MJB, Souhami L, Dinjens WNM, Laack NN, Kouwenhoven MCM, Fink KL, French PJ, Macdonald DR, Lacombe D, Won M, Gorlia T, Mehta MP, van den Bent MJ. Joint Final Report of EORTC 26951 and RTOG 9402: Phase III Trials With Procarbazine, Lomustine, and Vincristine Chemotherapy for Anaplastic Oligodendroglial Tumors. J Clin Oncol. 2022 Aug 10;40(23):2539-2545. Epub 2022 Jun 22. link to original article link to PMC article PubMed
5. EORTC 26882: Hildebrand J, Gorlia T, Kros JM, Afra D, Frenay M, Omuro A, Stupp R, Lacombe D, Allgeier A, van den Bent MJ; EORTC Brain Tumour Group. Adjuvant dibromodulcitol and BCNU chemotherapy in anaplastic astrocytoma: results of a randomised European Organisation for Research and Treatment of Cancer phase III study (EORTC study 26882). Eur J Cancer. 2008 Jun;44(9):1210-6. Epub 2008 Jan 14. link to original article PubMed NCT00002620
6. NOA-04: Wick W, Hartmann C, Engel C, Stoffels M, Felsberg J, Stockhammer F, Sabel MC, Koeppen S, Ketter R, Meyermann R, Rapp M, Meisner C, Kortmann RD, Pietsch T, Wiestler OD, Ernemann U, Bamberg M, Reifenberger G, von Deimling A, Weller M. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol. 2009 Dec 10;27(35):5874-80. Epub 2009 Nov 9. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00717210
   1. Update: Wick W, Roth P, Hartmann C, Hau P, Nakamura M, Stockhammer F, Sabel MC, Wick A, Koeppen S, Ketter R, Vajkoczy P, Eyupoglu I, Kalff R, Pietsch T, Happold C, Galldiks N, Schmidt-Graf F, Bamberg M, Reifenberger G, Platten M, von Deimling A, Meisner C, Wiestler B, Weller M; Neuro-oncology Working Group of the German Cancer Society. Long-term analysis of the NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with PCV or temozolomide. Neuro Oncol. 2016 Nov;18(11):1529-1537. Epub 2016 Jul 1. Erratum in: Neuro Oncol. 2016 Nov;18(11):e1. link to original article link to PMC article PubMed
7. NOA-08: Wick W, Platten M, Meisner C, Felsberg J, Tabatabai G, Simon M, Nikkhah G, Papsdorf K, Steinbach JP, Sabel M, Combs SE, Vesper J, Braun C, Meixensberger J, Ketter R, Mayer-Steinacker R, Reifenberger G, Weller M; Neuro-oncology Working Group of German Cancer Society. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol. 2012 Jul;13(7):707-15. Epub 2012 May 10. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01502241

RT, then Carmustine

Regimen variant #1, WBRT

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Shapiro et al. 1989 (BTCG 8001)	1980-1983	Phase 3 (C)	1. Carmustine/Procarbazine & RT	Did not meet primary endpoint of OS
			2. Carmustine & Hydrea/Procarbazine, VM-26, RT	Did not meet primary endpoint of OS

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

Preceding treatment

• Surgery, within 3 weeks

Radiotherapy

• Whole-brain External beam radiotherapy, 172 cGy (rads) fractions x 35 fractions, given over 7 weeks for a total dose of 6020 cGy (6020 rads/~1700 rets)

7-week course, followed by:

Chemotherapy

• Carmustine (BCNU) 80 mg/m² IV over 30 to 60 minutes once per day on days 1 to 3

8-week cycle for up to 18 cycles (a maximum cumulative carmustine dose of 1500 mg/m²)

Regimen variant #2, WBRT with cone-down

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Shapiro et al. 1989 (BTCG 8001)	1980-1983	Phase 3 (C)	1. Carmustine/Procarbazine & RT	Did not meet primary endpoint of OS
			2. Carmustine & Hydrea/Procarbazine, VM-26, RT	Did not meet primary endpoint of OS

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

Preceding treatment

• Surgery, within 3 weeks

Radiotherapy

• Whole-brain External beam radiotherapy, 172 cGy (rads) fractions x 25 fractions, given over 5 weeks for a total dose of 4300 cGy (4300 rads), then coned-down boost of 172 cGy (rads) fractions x 10 fractions, given over 2 weeks for a dose of 1720 cGy (rads), and a total cumulative dose of 6020 cGy (rads)

7-week course, followed by:

Chemotherapy

• Carmustine (BCNU) 80 mg/m² IV over 30 to 60 minutes once per day on days 1 to 3

8-week cycle for up to 18 cycles (a maximum cumulative carmustine dose of 1500 mg/m²)

References

1. 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 dosing details in manuscript have been reviewed by our editors PubMed

RT, then Temozolomide

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
van den Bent et al. 2017 (CATNON)	2007-2015	Phase 3 (E-RT-esc)	1. RT 2. Temozolomide & RT	Superior OS (primary endpoint) OS60: 55.9% vs 44.1% (HR 0.65, 99.145% CI 0.45-0.93)
			3. Temozolomide & RT, then Temozolomide	Not reported

Biomarker eligibility criteria

This study excluded patients with 1p19q codeletions. As of WHO 2016 IDH mutated, 1p19q co-deleted tumors are classified as oligodendroglioma . This study is of Anaplastic Astrocytoma and included patients with both IDH mutant and IDH wild-type astrocytomas.

Preceding treatment

• Surgery

Radiotherapy

• External beam radiotherapy as follows:
  • Cycle 1: 180 cGy x 33 fractions (total dose of 5940 cGy)

Chemotherapy

• Temozolomide (Temodar) as follows:
  • Cycle 2: 150 mg/m² PO once per day on days 1 to 5, taken on an empty stomach
  • Cycles 3 to 13: 200 mg/m² PO once per day on days 1 to 5, taken on an empty stomach

11-week course, then 28-day cycle for 12 cycles

References

1. CATNON: van den Bent MJ, Baumert B, Erridge SC, Vogelbaum MA, Nowak AK, Sanson M, Brandes AA, Clement PM, Baurain JF, Mason WP, Wheeler H, Chinot OL, Gill S, Griffin M, Brachman DG, Taal W, Rudà R, Weller M, McBain C, Reijneveld J, Enting RH, Weber DC, Lesimple T, Clenton S, Gijtenbeek A, Pascoe S, Herrlinger U, Hau P, Dhermain F, van Heuvel I, Stupp R, Aldape K, Jenkins RB, Dubbink HJ, Dinjens WNM, Wesseling P, Nuyens S, Golfinopoulos V, Gorlia T, Wick W, Kros JM; EORTC. Interim results from the CATNON trial (EORTC study 26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: a phase 3, randomised, open-label intergroup study. Lancet. 2017 Oct 7;390(10103):1645-1653. Epub 2017 Aug 8. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00626990

Temozolomide monotherapy

Regimen variant #1, 100 mg/m², 7 out of 14 days

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Wick et al. 2012 (NOA-08)	2005-05-15 to 2009-11-02	Phase 3 (E-switch-ooc)	Radiation therapy	Seems to have non-inferior OS (primary endpoint) Median OS: 8.6 vs 9.6 mo (HR 1.09, 95% CI 0.84-1.42)

Preceding treatment

• Surgery

Chemotherapy

• Temozolomide (Temodar) 100 mg/m² PO once per day on days 1 to 7

14-day cycles

Regimen variant #2, 200 mg/m², 5 out of 28 days x 8 cycles

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Wick et al. 2009 (NOA-04)	1999-2005	Phase 3 (E-esc)	1. PCV	Did not meet primary endpoint of TTF
			2. Radiation therapy	Did not meet primary endpoint of TTF

Preceding treatment

• Surgery

Chemotherapy

• Temozolomide (Temodar) 200 mg/m² PO once per day on days 1 to 5

28-day cycle for 8 cycles

Subsequent treatment

• NOA-04, SD or better: Temozolomide continuation x 4 (12 total)
• NOA-04, upon progression: Salvage RT

Regimen variant #3, 200 mg/m², 5 out of 28 days x 2y

Study	Dates of enrollment	Evidence
Taliansky-Aronov et al. 2006	Not reported	Non-randomized

Preceding treatment

• Surgery

Chemotherapy

• Temozolomide (Temodar) 200 mg/m² PO once per day on days 1 to 5

Supportive therapy

• Corticosteroids could be continued at same dose or reduced, but not increased while on study

28-day cycle for up to 26 cycles (2 years)

Regimen variant #4, 5 out of 28 days, with dose-escalation, indefinite

Study	Dates of enrollment	Evidence
Mikkelsen et al. 2009	Not reported	Non-randomized

Biomarker eligibility criteria

• 1p/19q loss of heterozygosity (LOH)

Preceding treatment

• Surgery

Chemotherapy

• Temozolomide (Temodar) as follows:
  • Cycles 1 & 2: 150 mg/m² PO once per day on days 1 to 5, taken on an empty stomach
  • Cycle 3 onwards (if no myelosuppression): 200 mg/m² PO once per day on days 1 to 5, taken on an empty stomach

28-day cycles

References

1. Taliansky-Aronov A, Bokstein F, Lavon I, Siegal T. Temozolomide treatment for newly diagnosed anaplastic oligodendrogliomas: a clinical efficacy trial. J Neurooncol. 2006 Sep;79(2):153-7. Epub 2006 Jul 20. link to original article dosing details in manuscript have been reviewed by our editors PubMed
2. Mikkelsen T, Doyle T, Anderson J, Margolis J, Paleologos N, Gutierrez J, Croteau D, Hasselbach L, Avedissian R, Schultz L. Temozolomide single-agent chemotherapy for newly diagnosed anaplastic oligodendroglioma. J Neurooncol. 2009 Mar;92(1):57-63. Epub 2008 Nov 15. link to original article dosing details in manuscript have been reviewed by our editors PubMed content property of HemOnc.org
3. NOA-04: Wick W, Hartmann C, Engel C, Stoffels M, Felsberg J, Stockhammer F, Sabel MC, Koeppen S, Ketter R, Meyermann R, Rapp M, Meisner C, Kortmann RD, Pietsch T, Wiestler OD, Ernemann U, Bamberg M, Reifenberger G, von Deimling A, Weller M. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol. 2009 Dec 10;27(35):5874-80. Epub 2009 Nov 9. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00717210
   1. Update: Wick W, Roth P, Hartmann C, Hau P, Nakamura M, Stockhammer F, Sabel MC, Wick A, Koeppen S, Ketter R, Vajkoczy P, Eyupoglu I, Kalff R, Pietsch T, Happold C, Galldiks N, Schmidt-Graf F, Bamberg M, Reifenberger G, Platten M, von Deimling A, Meisner C, Wiestler B, Weller M; Neuro-oncology Working Group of the German Cancer Society. Long-term analysis of the NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with PCV or temozolomide. Neuro Oncol. 2016 Nov;18(11):1529-1537. Epub 2016 Jul 1. Erratum in: Neuro Oncol. 2016 Nov;18(11):e1. link to original article link to PMC article PubMed
4. NOA-08: Wick W, Platten M, Meisner C, Felsberg J, Tabatabai G, Simon M, Nikkhah G, Papsdorf K, Steinbach JP, Sabel M, Combs SE, Vesper J, Braun C, Meixensberger J, Ketter R, Mayer-Steinacker R, Reifenberger G, Weller M; Neuro-oncology Working Group of German Cancer Society. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol. 2012 Jul;13(7):707-15. Epub 2012 May 10. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01502241

Temozolomide, then Temozolomide & RT, then Temozolomide

Protocol

Study	Dates of enrollment	Evidence
Mikkelsen et al. 2009	Not reported	Non-randomized

Biomarker eligibility criteria

• This protocol is meant for patients without 1p/19q loss of heterozygosity (LOH).

Preceding treatment

• Surgery

Chemotherapy, pre-radiation portion

• Temozolomide (Temodar) as follows:
  • Cycles 1 & 2: 150 mg/m² PO once per day on days 1 to 5, taken on an empty stomach
  • Cycles 3 & 4 (if no myelosuppression): 200 mg/m² PO once per day on days 1 to 5, taken on an empty stomach

28-day cycle for 2 to 4 cycles, followed by:

Chemotherapy, concurrent radiation portion

• Temozolomide (Temodar) 75 mg/m² PO once per day during radiation therapy

Radiotherapy, concurrent radiation portion

• Concurrent radiation therapy: a total dose of 6000 cGy

One course, followed by:

Chemotherapy, maintenance portion

• Temozolomide (Temodar) 150 to 200 mg/m² PO once per day on days 1 to 5, taken on an empty stomach

28-day cycles

References

1. Mikkelsen T, Doyle T, Anderson J, Margolis J, Paleologos N, Gutierrez J, Croteau D, Hasselbach L, Avedissian R, Schultz L. Temozolomide single-agent chemotherapy for newly diagnosed anaplastic oligodendroglioma. J Neurooncol. 2009 Mar;92(1):57-63. Epub 2008 Nov 15. link to original article dosing details in manuscript have been reviewed by our editors PubMed content property of HemOnc.org

Temozolomide & RT

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
van den Bent et al. 2017 (CATNON)	2007-2015	Phase 3 (E-RT-esc)	1. RT	Not reported
			2. Temozolomide & RT, then Temozolomide 3. RT, then Temozolomide	Inferior OS (primary endpoint)

Biomarker eligibility criteria

This study excluded patients with 1p19q codeletions. As of WHO 2016 IDH mutated, 1p19q co-deleted tumors are classified as oligodendroglioma. This study is of Anaplastic Astrocytoma and included patients with both IDH mutant and IDH wild-type astrocytomas.

Preceding treatment

• Surgery

Chemotherapy

• Temozolomide (Temodar) 75 mg/m² PO once per day on days 1 to 45

Radiotherapy

• Concurrent radiation therapy 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33, 36 to 40, 43 to 45 (33 fractions; total dose of 5940 cGy)

45-day course

References

1. CATNON: van den Bent MJ, Baumert B, Erridge SC, Vogelbaum MA, Nowak AK, Sanson M, Brandes AA, Clement PM, Baurain JF, Mason WP, Wheeler H, Chinot OL, Gill S, Griffin M, Brachman DG, Taal W, Rudà R, Weller M, McBain C, Reijneveld J, Enting RH, Weber DC, Lesimple T, Clenton S, Gijtenbeek A, Pascoe S, Herrlinger U, Hau P, Dhermain F, van Heuvel I, Stupp R, Aldape K, Jenkins RB, Dubbink HJ, Dinjens WNM, Wesseling P, Nuyens S, Golfinopoulos V, Gorlia T, Wick W, Kros JM; EORTC. Interim results from the CATNON trial (EORTC study 26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: a phase 3, randomised, open-label intergroup study. Lancet. 2017 Oct 7;390(10103):1645-1653. Epub 2017 Aug 8. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00626990

Temozolomide & RT, then Temozolomide

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Chang et al. 2017 (RTOG 9813)	2002-2007	Phase 3 (E-switch-ic)	1a. Carmustine & RT 1b. Lomustine & RT	Did not meet primary endpoint of OS Median OS: 3.9 vs 3.8 yrs (HR 0.94, 95% CI 0.67-1.32)

Note: This was an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority.

Preceding treatment

• Surgery

Chemotherapy

• Temozolomide (Temodar) as follows:
  • Cycle 1 (chemoradiation): 200 mg/m² PO once per day on days 1 to 5, 29 to 33
  • Cycles 2 to 11: 200 mg/m² PO once per day on days 1 to 5

Radiotherapy

• Concurrent radiation therapy as follows:
  • Cycle 1 (chemoradiation): 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33, 36 to 40, 43 to 45 (33 fractions; total dose of 5940 cGy)

8-week course, then 28-day cycle for 10 cycles

Regimen variant #2

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
van den Bent et al. 2017 (CATNON)	2007-2015	Phase 3 (E-RT-esc)	1. RT 2. Temozolomide & RT	Superior OS (primary endpoint)
			3. RT, then Temozolomide	Not reported

Biomarker eligibility criteria

This study excluded patients with 1p19q codeletions. As of WHO 2016 IDH mutated, 1p19q co-deleted tumors are classified as oligodendroglioma . This study is of Anaplastic Astrocytoma and included patients with both IDH mutant and IDH wild-type astrocytomas.

Preceding treatment

• Surgery

Chemotherapy

• Temozolomide (Temodar) as follows:
  • Cycle 1 (chemoradiation): 75 mg/m² PO once per day on days 1 to 45, given during radiation therapy, including non-treatment weekend days
  • Cycle 2: 150 mg/m² PO once per day on days 1 to 5, taken on an empty stomach
  • Cycles 3 to 13: 200 mg/m² PO once per day on days 1 to 5, taken on an empty stomach

Radiotherapy

• Concurrent radiation therapy 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33, 36 to 40, 43 to 45 (33 fractions; total dose of 5940 cGy)

11-week course, then 28-day cycle for 12 cycles

References

1. RTOG 9813: Chang S, Zhang P, Cairncross JG, Gilbert MR, Bahary JP, Dolinskas CA, Chakravarti A, Aldape KD, Bell EH, Schiff D, Jaeckle K, Brown PD, Barger GR, Werner-Wasik M, Shih H, Brachman D, Penas-Prado M, Robins HI, Belanger K, Schultz C, Hunter G, Mehta M. Phase III randomized study of radiation and temozolomide versus radiation and nitrosourea therapy for anaplastic astrocytoma: results of NRG Oncology RTOG 9813. Neuro Oncol. 2017 Feb 1;19(2):252-258. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00004259
2. CATNON: van den Bent MJ, Baumert B, Erridge SC, Vogelbaum MA, Nowak AK, Sanson M, Brandes AA, Clement PM, Baurain JF, Mason WP, Wheeler H, Chinot OL, Gill S, Griffin M, Brachman DG, Taal W, Rudà R, Weller M, McBain C, Reijneveld J, Enting RH, Weber DC, Lesimple T, Clenton S, Gijtenbeek A, Pascoe S, Herrlinger U, Hau P, Dhermain F, van Heuvel I, Stupp R, Aldape K, Jenkins RB, Dubbink HJ, Dinjens WNM, Wesseling P, Nuyens S, Golfinopoulos V, Gorlia T, Wick W, Kros JM; EORTC. Interim results from the CATNON trial (EORTC study 26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: a phase 3, randomised, open-label intergroup study. Lancet. 2017 Oct 7;390(10103):1645-1653. Epub 2017 Aug 8. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00626990

Recurrent disease, salvage therapy

Bevacizumab monotherapy

Regimen

Study	Dates of enrollment	Evidence
Chamberlain et al. 2008a	2005-01 to 2008-03	Retrospective

Targeted therapy

• Bevacizumab (Avastin) 10 mg/kg IV over 30 minutes once on day 1

Supportive therapy

• Use of steroids allowed for control of neurologic signs and symptoms

14-day cycles

References

1. Retrospective: Chamberlain MC, Johnston S. Salvage chemotherapy with bevacizumab for recurrent alkylator-refractory anaplastic astrocytoma. J Neurooncol. 2009 Feb;91(3):359-67. Epub 2008 Oct 25. J Neurooncol. 2009 Feb;91(3):359-67. Epub 2008 Oct 25. link to original article dosing details in manuscript have been reviewed by our editors PubMed
2. Retrospective: Chamberlain MC, Johnston S. Bevacizumab for recurrent alkylator-refractory anaplastic oligodendroglioma. Cancer. 2009 Apr 15;115(8):1734-43. link to original article PubMed

Carboplatin & Bevacizumab

Regimen variant #1, q2wk bevacizumab

Study	Dates of enrollment	Evidence
Norden et al. 2008	2005-06 to 2007-03	Retrospective

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 to 6 IV (reference does not list schedule of carboplatin) once on day 1

Targeted therapy

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

14-day cycles

Regimen variant #2, q4wk bevacizumab

Study	Dates of enrollment	Evidence
Thompson et al. 2010	2006-2008	Retrospective

Chemotherapy

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

Targeted therapy

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

28-day cycles

References

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 dosing details in abstract have been reviewed by our editors PubMed

Cyclophosphamide monotherapy

Regimen

Study	Dates of enrollment	Evidence
Chamberlain et al. 2006	1999-2004	Phase 2

Prior treatment criteria

• Temozolomide exposure

Chemotherapy

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

Supportive therapy

• Dexamethasone (Decadron) allowed for control of neurologic symptoms
• Ondansetron (Zofran) 0.15 mg/kg IV once per day on days 1 & 2, prior to cyclophosphamide
• Dexamethasone (Decadron) 4 mg IV once per day on days 1 & 2, prior to cyclophosphamide
• 1 liter normal saline IV over 2 hours once per day on days 1 & 2, prior to cyclophosphamide
• Prochlorperazine (Compazine) (dose/schedule not specified) prn nausea/vomiting

28-day cycles

References

1. Chamberlain MC, Tsao-Wei DD, Groshen S. Salvage chemotherapy with cyclophosphamide for recurrent temozolomide-refractory anaplastic astrocytoma. Cancer. 2006 Jan 1;106(1):172-9. link to original article dosing details in manuscript have been reviewed by our editors PubMed

Etoposide monotherapy

Regimen

Study	Dates of enrollment	Evidence
Fulton et al. 1996	1991-1994	Phase 2

Chemotherapy

• Etoposide (Vepesid) 50 mg PO once per day

Continued indefinitely

References

1. Fulton D, Urtasun R, Forsyth P. Phase II study of prolonged oral therapy with etoposide (VP16) for patients with recurrent malignant glioma. J Neurooncol. 1996 Feb;27(2):149-55. link to original article dosing details in manuscript have been reviewed by our editors PubMed

Irinotecan monotherapy

Regimen variant #1, 125 mg/m², 4 out of 6 weeks

Study	Dates of enrollment	Evidence
Friedman et al. 1999	1996-1997	Phase 2

Chemotherapy

• Irinotecan (Camptosar) 125 mg/m² IV once per day on days 1, 8, 15, 22

Supportive therapy

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

42-day cycles

Dose and schedule modifications

• If tolerated, irinotecan dose could be increased to 150 mg/m²

Regimen variant #2, 350 mg/m² q3wk

Study	Dates of enrollment	Evidence
Chamberlain et al. 2008b	2000-2007	Phase 2

Chemotherapy

• Irinotecan (Camptosar) 350 mg/m² IV over 2 hours once on day 1

Supportive therapy

• As described by Chamberlain et al. 2008b:
• Dexamethasone (Decadron) allowed for control of neurologic symptoms
• 500 mL normal saline IV over 60 minutes once on day 1, prior to irinotecan
• One of the following serotonin 5-HT3 antagonists:
  • Ondansetron (Zofran) IV (dose not specified) once on day 1, prior to irinotecan
  • Granisetron IV (dose not specified) once on day 1, prior to irinotecan
  • Dolasetron (Anzemet) IV (dose not specified) once on day 1, prior to irinotecan
• Dexamethasone (Decadron) 20 mg IV once on day 1, prior to irinotecan
• Atropine (Atropen) 0.5 mg IV once on day 1, prior to irinotecan
• Prochlorperazine (Compazine) (dose/schedule not specified) prn nausea/vomiting
• Loperamide (Imodium) (dose/schedule not specified) prn diarrhea

21-day cycles

Regimen variant #3, 600 mg/m² q3wk

Study	Dates of enrollment	Evidence
Chamberlain 2002	Not reported	Phase 1
Chamberlain et al. 2008b	2000-2007	Phase 2

Note: this is the dose recommended for patients receiving enzyme-inducing antiepileptic drugs (EIAEDs).

Prior treatment criteria

• Chamberlain et al. 2008b: Temozolomide exposure

Chemotherapy

• Irinotecan (Camptosar) 600 mg/m² IV over 2 hours once on day 1

Supportive therapy

• As described by Chamberlain et al. 2008b:
• Dexamethasone (Decadron) allowed for control of neurologic symptoms
• 500 mL normal saline IV over 60 minutes, prior to irinotecan
• One of the following serotonin 5-HT3 antagonists:
  • Ondansetron (Zofran) IV (dose not specified) once on day 1, prior to irinotecan
  • Granisetron IV (dose not specified) once on day 1, prior to irinotecan
  • Dolasetron (Anzemet) IV (dose not specified) once on day 1, prior to irinotecan
• Dexamethasone (Decadron) 20 mg IV once on day 1, prior to irinotecan
• Atropine (Atropen) 0.5 mg IV once on day 1, prior to irinotecan
• Prochlorperazine (Compazine) (dose/schedule not specified) prn nausea/vomiting
• Loperamide (Imodium) (dose/schedule not specified) prn diarrhea

21-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 dosing details in manuscript have been reviewed by our editors PubMed
2. Phase 1: Chamberlain MC. Salvage chemotherapy with CPT-11 for recurrent oligodendrogliomas. J Neurooncol. 2002 Sep;59(2):157-63. link to original article dosing details in abstract have been reviewed by our editors PubMed
3. Chamberlain MC, Wei-Tsao DD, Blumenthal DT, Glantz MJ. Salvage chemotherapy with CPT-11 for recurrent temozolomide-refractory anaplastic astrocytoma. Cancer. 2008 May 1;112(9):2038-45. link to original article dosing details in manuscript have been reviewed by our editors PubMed

Irinotecan & Bevacizumab

Regimen

Study	Dates of enrollment	Evidence
Vredenburgh et al. 2007	Not reported	Phase 2

Note: Vredenburgh et al. 2007 described 6-week cycles in which treatment was every 2 weeks and was otherwise identical, so its entry was consolidated with Taillibert et al. 2009.

Chemotherapy

• Irinotecan (Camptosar) 125 mg/m² IV over 90 minutes once on day 1, given first

Targeted therapy

• Bevacizumab (Avastin) 10 mg/kg IV once on day 1, given second
  • Infusion time is 90 minutes for the first dose, then if tolerated, 60 minutes for the second dose, and 30 minutes for the third dose and later

Supportive therapy

• "Appropriate antiemetics"

14-day cycles

Dose and schedule modifications

• Patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) are treated with a higher dose of irinotecan: 340 mg/m²

References

1. 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 dosing details in manuscript have been reviewed by our editors 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 dosing details in manuscript have been reviewed by our editors PubMed
2. Retrospective: Taillibert S, Vincent LA, Granger B, Marie Y, Carpentier C, Guillevin R, Bellanger A, Mokhtari K, Rousseau A, Psimaras D, Dehais C, Sierra del Rio M, Meng Y, Laigle-Donadey F, Hoang-Xuan K, Sanson M, Delattre JY. Bevacizumab and irinotecan for recurrent oligodendroglial tumors. Neurology. 2009 May 5;72(18):1601-6. link to original article PubMed

PCV

PCV: Procarbazine, CCNU (Lomustine), Vincristine

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Wick et al. 2009 (NOA-04)	1999-2005	Phase 3 (E-esc)	Temozolomide	Did not meet primary endpoint of TTF

Preceding treatment

• RT or salvage temozolomide or salvage RT, with progression

Chemotherapy

• Procarbazine (Matulane) 60 mg/m² PO once per day on days 8 to 21
• Lomustine (CCNU) 110 mg/m² PO once on day 1
• Vincristine (Oncovin) 2 mg IV once per day on days 8 & 29

8-week cycles

Subsequent treatment

• NOA-04, upon progression, patients who had not previously received temozolomide: Salvage temozolomide

Regimen variant #2

Study	Dates of enrollment	Evidence
Levin et al. 1980	Not reported in abstract	Non-randomized

Chemotherapy

• Procarbazine (Matulane) 60 mg/m² PO once per day on days 8 to 21
• Lomustine (CCNU) 110 mg/m² PO once on day 1
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once per day on days 8 & 29

42-day cycles

Regimen variant #3, higher doses

Study	Dates of enrollment	Evidence
Cairncross et al. 1994	1989-1992	Phase 2

Chemotherapy

• Procarbazine (Matulane) 75 mg/m² PO once per day on days 8 to 21
• Lomustine (CCNU) 130 mg/m² PO once on day 1
• Vincristine (Oncovin) 1.4 mg/m² IV once per day on days 8 & 29

42-day 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. dosing details in abstract have been reviewed by our editors PubMed
2. Cairncross G, Macdonald D, Ludwin S, Lee D, Cascino T, Buckner J, Fulton D, Dropcho E, Stewart D, Schold C Jr, Wainman N, Eisenhauer E; National Cancer Institute of Canada Clinical Trials Group. Chemotherapy for anaplastic oligodendroglioma. J Clin Oncol. 1994 Oct;12(10):2013-21. link to original article dosing details in manuscript have been reviewed by our editors PubMed
3. Retrospective: Kappelle AC, Postma TJ, Taphoorn MJ, Groeneveld GJ, van den Bent MJ, van Groeningen CJ, Zonnenberg BA, Sneeuw KC, Heimans JJ. PCV chemotherapy for recurrent glioblastoma multiforme. Neurology. 2001 Jan 9;56(1):118-20. link to original article PubMed
4. NOA-04: Wick W, Hartmann C, Engel C, Stoffels M, Felsberg J, Stockhammer F, Sabel MC, Koeppen S, Ketter R, Meyermann R, Rapp M, Meisner C, Kortmann RD, Pietsch T, Wiestler OD, Ernemann U, Bamberg M, Reifenberger G, von Deimling A, Weller M. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol. 2009 Dec 10;27(35):5874-80. Epub 2009 Nov 9. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00717210
   1. Update: Wick W, Roth P, Hartmann C, Hau P, Nakamura M, Stockhammer F, Sabel MC, Wick A, Koeppen S, Ketter R, Vajkoczy P, Eyupoglu I, Kalff R, Pietsch T, Happold C, Galldiks N, Schmidt-Graf F, Bamberg M, Reifenberger G, Platten M, von Deimling A, Meisner C, Wiestler B, Weller M; Neuro-oncology Working Group of the German Cancer Society. Long-term analysis of the NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with PCV or temozolomide. Neuro Oncol. 2016 Nov;18(11):1529-1537. Epub 2016 Jul 1. Erratum in: Neuro Oncol. 2016 Nov;18(11):e1. link to original article link to PMC article PubMed

Radiation therapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Wick et al. 2009 (NOA-04)	1999-2005	Phase 3 (C)	1. PCV	Did not meet primary endpoint of TTF
			2. Temozolomide	Did not meet primary endpoint of TTF

Preceding treatment

• Adjuvant PCV versus temozolomide, with progression

Radiotherapy

• External beam radiotherapy with 1.8 to 200 cGy fractions for a total dose of 6000 cGy

6-week course

Subsequent treatment

• NOA-04, at progression: Salvage PCV if they had previously received temozolomide or temozolomide if they had previously received PCV

References

1. NOA-04: Wick W, Hartmann C, Engel C, Stoffels M, Felsberg J, Stockhammer F, Sabel MC, Koeppen S, Ketter R, Meyermann R, Rapp M, Meisner C, Kortmann RD, Pietsch T, Wiestler OD, Ernemann U, Bamberg M, Reifenberger G, von Deimling A, Weller M. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol. 2009 Dec 10;27(35):5874-80. Epub 2009 Nov 9. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00717210
   1. Update: Wick W, Roth P, Hartmann C, Hau P, Nakamura M, Stockhammer F, Sabel MC, Wick A, Koeppen S, Ketter R, Vajkoczy P, Eyupoglu I, Kalff R, Pietsch T, Happold C, Galldiks N, Schmidt-Graf F, Bamberg M, Reifenberger G, Platten M, von Deimling A, Meisner C, Wiestler B, Weller M; Neuro-oncology Working Group of the German Cancer Society. Long-term analysis of the NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with PCV or temozolomide. Neuro Oncol. 2016 Nov;18(11):1529-1537. Epub 2016 Jul 1. Erratum in: Neuro Oncol. 2016 Nov;18(11):e1. link to original article link to PMC article PubMed

Temozolomide monotherapy

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Wick et al. 2009 (NOA-04)	1999-2005	Phase 3 (E-de-esc)	PCV	Did not meet primary endpoint of TTF

Preceding treatment

• RT or salvage PCV or salvage RT, with progression

Chemotherapy

• Temozolomide (Temodar) 200 mg/m² PO once per day on days 1 to 5

28-day cycles

Subsequent treatment

• NOA-04, upon progression, patients who had not previously received PCV: Salvage PCV

Regimen variant #2, continuous therapy

Study	Dates of enrollment	Evidence
Perry et al. 2008 (RESCUE)	2001-01 to 2005-07	Retrospective

Note: Patients who undergo conventional temozolomide therapy, have surgery and radiation therapy, and then relapse receive:

Chemotherapy

• Temozolomide (Temodar) 150 to 200 mg/m² PO once per day on days 1 to 5

28-day cycles

Subsequent treatment

• RESCUE, upon progression: Salvage temozolomide; 50 mg/m² PO once per day

Regimen variant #3

Study	Dates of enrollment	Evidence
Yung et al. 1999 (MK-7365-006)	Not reported	Phase 2 (RT)

Chemotherapy

• Temozolomide (Temodar) by the following exposure-based criteria:
  • Patients who had never previously received chemotherapy: 200 mg/m² PO once per day on days 1 to 5
  • Patients who previously received chemotherapy: 150 mg/m² PO once per day on days 1 to 5

Supportive therapy

• Prophylactic antiemetics as needed
• Lowest dose of corticosteroids necessary to maintain neurologic stability

28-day cycle for up to 26 cycles (2 years)

Dose and schedule modifications

• If tolerated in patients who previously received chemotherapy, temozolomide dose could be increased to 200 mg/m²

References

1. MK-7365-006: Yung WK, Prados MD, Yaya-Tur R, Rosenfeld SS, Brada M, Friedman HS, Albright R, Olson J, Chang SM, O'Neill AM, Friedman AH, Bruner J, Yue N, Dugan M, Zaknoen S, Levin VA; Temodal Brain Tumor Group. Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. J Clin Oncol. 1999 Sep;17(9):2762-71. link to original article dosing details in manuscript have been reviewed by our editors PubMed
2. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT00392171
   1. Update: Perry JR, Bélanger K, Mason WP, Fulton D, Kavan P, Easaw J, Shields C, Kirby S, Macdonald DR, Eisenstat DD, Thiessen B, Forsyth P, Pouliot JF. Phase II trial of continuous dose-intense temozolomide in recurrent malignant glioma: RESCUE study. J Clin Oncol. 2010 Apr 20;28(12):2051-7. Epub 2010 Mar 22. link to original article dosing details in manuscript have been reviewed by our editors PubMed
3. NOA-04: Wick W, Hartmann C, Engel C, Stoffels M, Felsberg J, Stockhammer F, Sabel MC, Koeppen S, Ketter R, Meyermann R, Rapp M, Meisner C, Kortmann RD, Pietsch T, Wiestler OD, Ernemann U, Bamberg M, Reifenberger G, von Deimling A, Weller M. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol. 2009 Dec 10;27(35):5874-80. Epub 2009 Nov 9. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00717210
   1. Update: Wick W, Roth P, Hartmann C, Hau P, Nakamura M, Stockhammer F, Sabel MC, Wick A, Koeppen S, Ketter R, Vajkoczy P, Eyupoglu I, Kalff R, Pietsch T, Happold C, Galldiks N, Schmidt-Graf F, Bamberg M, Reifenberger G, Platten M, von Deimling A, Meisner C, Wiestler B, Weller M; Neuro-oncology Working Group of the German Cancer Society. Long-term analysis of the NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with PCV or temozolomide. Neuro Oncol. 2016 Nov;18(11):1529-1537. Epub 2016 Jul 1. Erratum in: Neuro Oncol. 2016 Nov;18(11):e1. link to original article link to PMC article PubMed