Anaplastic glioma

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Anaplastic glioma - adjuvant therapy

PCV, deferred RT

PCV: Procarbazine, CCNU, Vincristine

Regimen, Wick et al. 2009 (NOA-04)

Level of Evidence: Phase III

• 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) 2 mg IV once per day on days 8 & 29

8-week cycles x 4 cycles

At time of disease progression after completion of the above treatment:

• Retreat with 2 cycles of PCV as described above

With further disease progression:

• Radiation therapy with 1.8 to 2 Gy fractions given over 6 weeks for a total dose of 60 Gy

References

1. 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 contains verified protocol PubMed

Radiation

Regimen

Level of Evidence: Phase III

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

References

1. 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 contains verified protocol PubMed
2. 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 contains verified protocol PubMed
   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. doi: 10.1200/JCO.2012.43.2229. Epub 2012 Oct 15. link to original article PubMed

Radiation & Carmustine (BiCNU)

• Regimen is the same as Radiation & Carmustine (BiCNU) adjuvant regimen in Glioblastoma multiforme, Shapiro et al. 1989

Radiation -> PCV

PCV: Procarbazine, CCNU, Vincristine

Regimen #1, Medical Research Council, 2001

Level of Evidence: Phase III

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

• Radiation therapy with either:
  • 2.25 Gy fractions x 20 fractions, given 5 days per week over 4 weeks, total dose of 45 Gy
  • or 2 Gy fractions x 30 fractions, given 5 days per week over 6 weeks, total dose of 60 Gy

Chemotherapy begins 3-4 weeks after completion of radiation therapy:

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

6-week cycles x up to 12 cycles

Supportive medications:

• 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.

Regimen #2, van den Bent et al. 2006 & 2013 (EORTC 26951)

Level of Evidence: Phase III

van den Bent et al. 2013 noted that 1p/19q-codeleted tumors received the more benefit from adjuvant PCV as compared to tumors without 1p/19q codeletion.

Radiation therapy starts within 6 weeks after surgery.

• Radiation therapy, 1.8 Gy fractions x 25 fractions, given 5 days per week, total dose of 45 Gy to the planning target volume (PTV-1); then a boost of 1.8 Gy fractions x 8 fractions, given 5 days per week, total boost dose of 14.4 Gy to the PTV-2, for a total cumulative dose of 59.4 Gy

Chemotherapy begins within 4 weeks after completion of radiation therapy:

• 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

6-week cycles x 6 cycles

Supportive medications:

• Antiemetics for lomustine: "domperidone or metoclopramide, and if necessary, ondansetron or a similar agent"
• Corticosteroids kept at lowest possible dose

Regimen #3,

Level of Evidence: Phase III

• Radiation therapy with 1.8-2 Gy fractions given over 6 weeks for a total dose of 60 Gy

At completion of radiation therapy or disease progression, treat patients with:

• • 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) 2 mg IV once per day on days 8 & 29

8-week cycles x 4 cycles

References

1. 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. PubMed
2. 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 contains verified protocol PubMed
3. 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 contains verified protocol PubMed
   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. doi: 10.1200/JCO.2012.43.2229. Epub 2012 Oct 15. link to original article PubMed
4. 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 contains verified protocol PubMed

Radiation therapy -> Temozolomide (Temodar)

Regimen

Level of Evidence: Phase III

• Radiation therapy with 1.8-2 Gy fractions given over 6 weeks for a total dose of 60 Gy

At completion of radiation therapy or disease progression, treat patients with:

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

28-day cycles x 8 cycles

References

1. 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 contains verified protocol PubMed

Temozolomide (Temodar) +/- radiation

Regimen #1, Wick et al. 2009 - deferred RT

Level of Evidence: Phase III

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

28-day cycles x 8 cycles

At time of disease progression after completion of the above treatment:

• Retreat with 4 cycles of Temozolomide (Temodar) as described above

With further disease progression:

• Radiation therapy with 1.8-2 Gy fractions given over 6 weeks for a total dose of 60 Gy

Regimen #2, Mikkelsen et al. 2009

Level of Evidence: Non-randomized

Patients with 1p/19q loss of heterozygosity (LOH):

• Temozolomide (Temodar) 150 mg/m2 PO once per day on days 1 to 5 during cycles 1 & 2, on empty stomach; then, if there is myelosuppression, dosage is increased for cycles 3 and on to Temozolomide (Temodar) 200 mg/m2 PO once per day on days 1 to 5, on empty stomach

28-day cycles

Patients without 1p/19q loss of heterozygosity (LOH):

• Temozolomide (Temodar) 150 mg/m2 PO once per day on days 1 to 5 during cycles 1 & 2, on empty stomach; then, if there is myelosuppression, dosage is increased for cycles 3 and on to Temozolomide (Temodar) 200 mg/m2 PO once per day on days 1 to 5, on empty stomach

28-day cycles x 2 to 4 cycles, then

• Concurrent tadiation therapy with a total dose of 60 Gy
• Temozolomide (Temodar) 75 mg/m2 PO once per day during radiation therapy

After radiation therapy:

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

28-day cycles

Regimen #3, Taliansky-Aronov et al. 2006

Level of Evidence: Non-randomized

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

28-day cycles, given until progression of disease or, in patients with stable disease, up to 24 months

Supportive medications:

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

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 contains verified protocol 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 contains verified protocol PubMed content property of HemOnc.org
3. 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 contains verified protocol PubMed

Anaplastic glioma - recurrent disease, salvage therapy

Bevacizumab (Avastin)

Regimen

Level of Evidence: Non-randomized

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

14-day cycles

Supportive medications:

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

References

1. 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 contains verified protocol PubMed
2. Chamberlain MC, Johnston S. Bevacizumab for recurrent alkylator-refractory anaplastic oligodendroglioma. Cancer. 2009 Apr 15;115(8):1734-43. link to original article contains verified protocol PubMed

Bevacizumab & Carboplatin

• Regimen is the same as Carboplatin (Paraplatin) & Bevacizumab (Avastin) salvage therapy in glioblastoma multiforme, Regimen #1, Thompson et al. 2010 and Regimen #2, Norden et al. 2008

Bevacizumab & Irinotecan

These regimens are essentially the same as Irinotecan (Camptosar) & Bevacizumab (Avastin) salvage therapy in glioblastoma multiforme, Regimen #1, Chen et al. 2007, Vredenburgh et al. 2007, Norden et al. 2008 - every 2 week schedule.

Regimen

Level of Evidence: Phase II

• Irinotecan (Camptosar) 125 mg/m2 IV once on day 1, given first, over 90 minutes before the start of bevacizumab
  • Patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) are treated with a higher dose: Irinotecan (Camptosar) 340 mg/m2 IV once on day 1, given first, over 90 minutes before the start of bevacizumab
• Bevacizumab (Avastin) 10 mg/kg IV once on day 1, given second, after 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

14-day cycles; 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

Supportive medications:

• "Appropriate antiemetics"

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 contains verified protocol PubMed
2. 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. doi: 10.1212/WNL.0b013e3181a413be. link to original article contains verified protocol PubMed

Cyclophosphamide (Cytoxan)

Regimen

Level of Evidence: Phase II

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

28-day cycles

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

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 contains verified protocol PubMed

Etoposide (Vepesid)

Regimen

Level of Evidence: Phase II

• Etoposide (Vepesid) 50 mg PO once per day

given until progression of disease or unacceptable toxicity

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 contains verified protocol PubMed

Irinotecan (Camptosar)

Another regimen can be found under Irinotecan (Camptosar) salvage therapy in glioblastoma multiforme, Friedman et al. 1999.

Regimen

Level of Evidence: Phase II

• Irinotecan (Camptosar) 350 mg/m2 IV over 120 minutes once on day 1
  • Patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) are treated with a higher dose: Irinotecan (Camptosar) 600 mg/m2 IV over 120 minutes once on day 1

21-day cycles

Supportive medications:

• Dexamethasone (Decadron) allowed for control of neurologic symptoms
• 500 mL normal saline IV over 1 hour prior to irinotecan
• Intravenous ondansetron (Zofran), granisetron (Kytril), or dolasetron (Anzemet) as antiemetic prior to irinotecan
• Dexamethasone (Decadron) 20 mg IV once prior to irinotecan
• Atropine 0.5 mg IV once prior to irinotecan
• Prochlorperazine (Compazine) (dose/schedule not specified) prn nausea/vomiting
• Loperamide (Imodium) (dose/schedule not specified) prn diarrhea

References

1. Chamberlain MC. Salvage chemotherapy with CPT-11 for recurrent oligodendrogliomas. J Neurooncol. 2002 Sep;59(2):157-63. link to original article PubMed
2. 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. doi: 10.1002/cncr.23404. link to original article contains verified protocol PubMed

Lomustine (Ceenu)

• Note: The NCCN, Central Nervous System Cancers version 1.2013 lists this regimen (Wick et al. 2010) with Lomustine (Ceenu) salvage therapy in glioblastoma multiforme as an option for treatment of anaplastic gliomas. This study only included patients who had histologically confirmed WHO grade 4 glioblastoma. The NCCN also listed the following phase II trial as a reference for use of Carmustine (BiCNU)/Lomustine (Ceenu) in recurrent malignant glioma, but the nitrosourea used was fotemustine (FTM): R. Soffietti, R. Rudà, E. Trevisan, E. Picco, D. Guarneri, M. Caroli, M. Fabrini, V. Scotti. Phase II study of bevacizumab and nitrosourea in patients with recurrent malignant glioma: A multicenter Italian study. CNS Tumors 2012 J Clin Oncol 27:15s, 2009 (suppl; abstr 2012). 2009 ASCO Annual Meeting abstract 2012. link to abstract

PCV

PCV: Procarbazine, CCNU, Vincristine

Regimen #1, Levin et al. 1980

Level of Evidence: Non-randomized

• 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

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

Regimen #2, Cairncross et al. 1994 - higher doses

Level of Evidence: Phase II

• Procarbazine (Matulane) 75 mg/m2 PO once per day on days 8 to 21
• Lomustine (Ceenu) 130 mg/m2 PO once on day 1
• Vincristine (Oncovin) 1.4 mg/m2 (dose not capped) IV once per day on days 8 & 29

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

References

1. Levin VA, Edwards MS, Wright DC, Seager ML, Schimberg TP, Townsend JJ, Wilson CB. Modified procarbazine, CCNU, and vincristine (PCV 3) combination chemotherapy in the treatment of malignant brain tumors. Cancer Treat Rep. 1980 Feb-Mar;64(2-3):237-44. contains protocol PubMed
2. Cairncross G, Macdonald D, Ludwin S, Lee D, Cascino T, Buckner J, Fulton D, Dropcho E, Stewart D, Schold C Jr et al. Chemotherapy for anaplastic oligodendroglioma. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1994 Oct;12(10):2013-21. link to original article contains verified protocol PubMed
3. 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

Temozolomide (Temodar)

Regimen #1, Perry et al. 2008 & Perry et al. 2010 - continuous therapy; RESCUE study

Level of Evidence: Phase II

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

• 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

Regimen #2, Nicholson et al. 2007 - traditional dosing

• Regimen is the same as Temozolomide (Temodar) in supratentorial astrocytoma or oligodendroglioma recurrent disease, Regimen #4, Nicholson et al. 2007 - traditional dosing

Regimen #3, Yung et al. 1999

Level of Evidence: Phase II

• Patients who had never previously received chemotherapy: Temozolomide (Temodar) 200 mg/m2 PO once per day on days 1 to 5
• Patients who previously received chemotherapy started with Temozolomide (Temodar) 150 mg/m2 PO once per day on days 1 to 5, which could be increased as tolerated to Temozolomide (Temodar) 200 mg/m2 PO once per day on days 1 to 5

28-day cycles x up to 2 years

Supportive medications:

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

References

1. 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. Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. Temodal Brain Tumor Group. J Clin Oncol. 1999 Sep;17(9):2762-71. link to original article contains verified protocol PubMed
2. 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
3. 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

Glioblastoma multiforme chemoradiation & adjuvant therapy

Radiation

Regimen

Level of Evidence: Phase III

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

References

1. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987-96. link to original article contains verified protocol PubMed

Radiation & Carmustine (BiCNU)

Regimen

Level of Evidence: Phase III

• Radiation therapy starting within 3 weeks after surgical resection, with one of the following:
  • Whole brain: 172 cGy (rads) fractions x 35 fractions, given over 7 weeks for a total dose of 6020 cGy (6020 rads/~1700 rets)
  • Whole brain & cone down: 172 cGy (rads) fractions x 25 fractions, given over 5 weeks for a total dose of 4300 cGy (4300 rads), then coned-down boost of 172 cGy (rads) fractions x 10 fractions, given over 2 weeks for a dose of 1720 cGy (rads), and a total cumulative dose of 6020 cGy (rads)

Then proceed to adjuvant chemotherapy:

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

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

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

References

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

Radiation & Temozolomide -> Temozolomide

Regimen

• Concurrent radiation therapy, 2 Gy fractions x 30 fractions given 5 days per week, for a total dose of 60 Gy
• 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

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

• Temozolomide (Temodar) 150 mg/m2 PO once per day on days 1 to 5 of cycle 1; if tolerated, in cycles 2 and on, the dose is increased to Temozolomide (Temodar) 200 mg/m2 PO once per day on days 1 to 5

28-day cycles x 6 cycles

Supportive medications:

• PCP prophylaxis during radiation therapy & temozolomide with one of the following:
  • Trimethoprim/Sulfamethoxazole (Bactrim)
  • Pentamidine (Nebupent) 300 mg nebulized inhaled
• Metoclopramide (Reglan) or 5-HT3 antagonist required during the adjuvant temozolomide-only period; their use was also recommended before the initial doses of radiation therapy & temozolomide

References

1. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987-96. link to original article contains verified protocol PubMed

Glioblastoma multiforme - recurrent disease, salvage therapy

Bevacizumab (Avastin)

Regimen #1, Friedman et al. 2009

Level of Evidence: Phase II

• Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1, 15, 29

6-week cycles x up to 104 weeks, until progression of disease, or unacceptable toxicity

Regimen #2, Kreisl et al. 2009

Level of Evidence: Phase II

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

4-week cycles, given until progression of disease, or unacceptable toxicity; upon progression, patients received Irinotecan (Camptosar) & Bevacizumab (Avastin)

References

1. Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, Garren N, Mackey M, Butman JA, Camphausen K, Park J, Albert PS, Fine HA. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009 Feb 10;27(5):740-5. doi: 10.1200/JCO.2008.16.3055. Epub 2008 Dec 29. link to original article contains verified protocol PubMed
2. Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, Yung WK, Paleologos N, Nicholas MK, Jensen R, Vredenburgh J, Huang J, Zheng M, Cloughesy T. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009 Oct 1;27(28):4733-40. doi: 10.1200/JCO.2008.19.8721. Epub 2009 Aug 31. link to original article contains verified protocol PubMed

Bevacizumab & Carboplatin

Regimen #1, Thompson et al. 2010

Level of Evidence: Retrospective

• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Bevacizumab (Avastin) 10 mg/kg IV once on day 1

28-day cycles

Regimen #2, Norden et al. 2008

Level of Evidence: Retrospective

• Carboplatin (Paraplatin) AUC 5-6 IV (reference does not list schedule of carboplatin)
• Bevacizumab (Avastin) 10 mg/kg IV once every 2 weeks

References

1. 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
2. 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 contains verified protocol PubMed

Bevacizumab & Irinotecan

Regimen #1, Chen et al. 2007; Vredenburgh et al. 2007; Norden et al. 2008; Friedman et al. 2009 - every 2 week schedule

Level of Evidence: Phase II

• Irinotecan (Camptosar) 125 mg/m2 IV over 90 minutes once on day 1, given first, before bevacizumab
  • Patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) are treated with a higher dose: Irinotecan (Camptosar) 340 mg/m2 (Vredenburgh et al. 2007 & Norden et al. 2008) or 350 mg/m2 (Chen et al. 2007) IV over 90 minutes once on day 1 given first, before bevacizumab
• 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

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

Supportive medications:

• Steroids were generally maintained at the same dose

Regimen #2, Vredenburgh et al. 2007

Level of Evidence: Phase II

• Irinotecan (Camptosar) 125 mg/m2 IV over 90 minutes once per day on days 1, 8, 22, 29, given first, before bevacizumab
  • Patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) are treated with a higher dose: Irinotecan (Camptosar) 350 mg/m2 IV over 90 minutes once per day on days 1, 8, 22, 29, given first, before bevacizumab
• Bevacizumab (Avastin) 15 mg/kg IV once per day on days 1 & 22, 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

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

Supportive medications:

• Steroids were generally maintained at the same dose

References

1. Chen W, Delaloye S, Silverman DH, Geist C, Czernin J, Sayre J, Satyamurthy N, Pope W, Lai A, Phelps ME, Cloughesy T. Predicting treatment response of malignant gliomas to bevacizumab and irinotecan by imaging proliferation with [18F] fluorothymidine positron emission tomography: a pilot study. J Clin Oncol. 2007 Oct 20;25(30):4714-21. link to original article contains verified protocol PubMed
2. Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Marcello J, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Sampson J, Wagner M, Bailey L, Bigner DD, Friedman AH, Friedman HS. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol. 2007 Oct 20;25(30):4722-9. link to original article contains verified protocol PubMed
3. Norden AD, Young GS, Setayesh K, Muzikansky A, Klufas R, Ross GL, Ciampa AS, Ebbeling LG, Levy B, Drappatz J, Kesari S, Wen PY. Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence. Neurology. 2008 Mar 4;70(10):779-87. link to original article contains verified protocol PubMed
4. 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. doi: 10.1200/JCO.2008.19.8721. Epub 2009 Aug 31. link to original article contains verified protocol PubMed

Carmustine (BiCNU)

Regimen

Level of Evidence: Phase II

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

8-week cycles x up to 6 cycles

Supportive medications:

• Antiemesis prophylaxis with Ondansetron (Zofran)
• Steroids at lowest dose necessary

References

1. Brandes AA, Tosoni A, Amistà P, Nicolardi L, Grosso D, Berti F, Ermani M. How effective is BCNU in recurrent glioblastoma in the modern era? A phase II trial. Neurology. 2004 Oct 12;63(7):1281-4. link to original article contains verified protocol PubMed

Cyclophosphamide (Cytoxan)

Regimen

Level of Evidence: Phase II

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

28-day cycles

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

References

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

Hydroxyurea & Imatinib

Regimen, Dresemann et al. 2005

Level of Evidence: Non-randomized

Dresemann et al. 2005 was a patient series.

• Imatinib (Gleevec) 400 mg PO once per day
• Hydroxyurea (Hydrea) 500 mg PO BID

given until progression of disease

References

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

Irinotecan (Camptosar)

Regimen

Level of Evidence: Phase II

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

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

Supportive medications:

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

References

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

Lomustine (Ceenu)

Regimen

Level of Evidence: Phase III

• Lomustine (Ceenu) 100 to 130 mg/m2 PO once on day 1

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

Supportive medications:

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

References

1. Wick W, Puduvalli VK, Chamberlain MC, van den Bent MJ, Carpentier AF, Cher LM, Mason W, Weller M, Hong S, Musib L, Liepa AM, Thornton DE, Fine HA. Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma. J Clin Oncol. 2010 Mar 1;28(7):1168-74. Epub 2010 Feb 1. link to original article contains verified protocol PubMed

PCV

PCV: Procarbazine, CCNU, Vincristine

• Regimens are the same as PCV in Anaplastic glioma - recurrent disease, salvage therapy, Regimen #1, Levin et al. 1980 and Regimen #2, Cairncross et al. 1994

Procarbazine (Matulane)

Regimen

Level of Evidence: Phase II

• Patients who had never previously received chemotherapy: Procarbazine (Matulane) 150 mg/m2 PO once per day on days 1 to 28
• Patients who previously received chemotherapy started with Procarbazine (Matulane) 125 mg/m2 PO once per day on days 1 to 28

8-week cycles x up to 2 years, progression of disease, or unacceptable toxicity

Supportive medications:

• Steroids at lowest dose necessary

References

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

Temozolomide (Temodar)

Regimen #1, Perry et al. 2008 & Perry et al. 2010 - continuous therapy; RESCUE study

Level of Evidence: Phase II

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

Regimen #2, Nicholson et al. 2007 - traditional dosing

• Regimen is the same as Temozolomide (Temodar) in supratentorial astrocytoma or oligodendroglioma recurrent disease, Regimen #4, Nicholson et al. 2007 - traditional dosing

Regimen #3, Yung et al. 2000

Level of Evidence: Phase II

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

28-day cycles x up to 2 years, until progression of disease, or unacceptable toxicity

References

1. Yung WK, Albright RE, Olson J, Fredericks R, Fink K, Prados MD, Brada M, Spence A, Hohl RJ, Shapiro W, Glantz M, Greenberg H, Selker RG, Vick NA, Rampling R, Friedman H, Phillips P, Bruner J, Yue N, Osoba D, Zaknoen S, Levin VA. A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer. 2000 Sep;83(5):588-93. link to original article contains verified protocol PubMed
2. 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
3. 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

Supratentorial astrocytoma or oligodendroglioma chemoradiation & adjuvant therapy

Temozolomide (Temodar)

Regimen

Note: The patients in the reference were treated for glioblastoma, but the NCCN, Central Nervous System Cancers version 1.2013 lists this as an acceptable regimen for supratentorial astrocytoma or oligodendroglioma. No primary reference could be found for this regimen in this disease.

• Concurrent radiation therapy, 2 Gy fractions x 30 fractions given 5 days per week, for a total dose of 60 Gy
• 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

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

• Temozolomide (Temodar) 150 mg/m2 PO once per day on days 1 to 5 of cycle 1; if tolerated, in cycles 2 and on, the dose is increased to Temozolomide (Temodar) 200 mg/m2 PO once per day on days 1 to 5

28-day cycles x 6 cycles

Supportive medications:

• PCP prophylaxis during radiation therapy & temozolomide with one of the following:
  • Trimethoprim/Sulfamethoxazole (Bactrim)
  • Pentamidine (Nebupent) 300 mg nebulized inhaled
• Metoclopramide (Reglan) or 5-HT3 antagonist required during the adjuvant temozolomide-only period; their use was also recommended before the initial doses of radiation therapy & temozolomide

References

1. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987-96. link to original article contains verified protocol PubMed

Supratentorial astrocytoma or oligodendroglioma - recurrent or progressive, low-grade disease

Carboplatin (Paraplatin)

Regimen

Level of Evidence: Phase II

• Carboplatin (Paraplatin) 560 mg/m2 IV over 1 hour once on day 1
  • Mixed in D5 1/2 NS

28-day cycles x up to 12 cycles beyond the maximum response, given until progression of disease, or unacceptable toxicity

Supportive medications:

• Hydration for 1 hour before chemotherapy, and for 1 hour after chemotherapy; total volume including carboplatin is 900 mL/m2

References

1. Moghrabi A, Friedman HS, Ashley DM, Bottom KS, Kerby T, Stewart E, Bruggers C, Provenzale JM, Champagne M, Hershon L, Watral M, Ryan J, Rasheed K, Lovell S, Korones D, Fuchs H, George T, McLendon RE, Friedman AH, Buckley E, Longee DC. Phase II study of carboplatin (CBDCA) in progressive low-grade gliomas. Neurosurg Focus. 1998 Apr 15;4(4):e3. link to original article contains verified protocol PubMed

Carboplatin & Teniposide

Regimen

Level of Evidence: Phase II

• Carboplatin (Paraplatin) 350 mg/m2 IV once on day 1
• Teniposide (Vumon) 50 mg/m2 IV once per day on days 1 to 3

28-day cycles x up to 10 cycles

Supportive medications:

• Prophylactic 5-HT3 antagonists routinely used
• Lowest dose of corticosteroids necessary to maintain neurologic stability
• Antiepileptic medications for all patients

References

1. Brandes AA, Basso U, Vastola F, Tosoni A, Pasetto LM, Jirillo A, Lonardi S, Paris MK, Koussis H, Monfardini S, Ermani M. Carboplatin and teniposide as third-line chemotherapy in patients with recurrent oligodendroglioma or oligoastrocytoma: a phase II study. Ann Oncol. 2003 Dec;14(12):1727-31. link to original article contains verified protocol PubMed

Cisplatin & Etoposide

Regimen

Level of Evidence: Non-randomized

• Cisplatin (Platinol) 25 mg/m2 IV over 2 hours once per day on days 1 to 3, given first
• Etoposide (Vepesid) 100 mg/m2 IV over 30 minutes once per day on days 1 to 3, given second
• In children <1 year old or <10 kg, "doses were adjusted to their weight"--reference does not say exactly how doses are adjusted

28-day cycles x 4 cycles, then 35-day cycles x 3 cycles, then 42-day cycles x 3 cycles

Supportive medications:

• Hydration for 2 hours before chemotherapy, and for 2 hours after chemotherapy

References

1. Massimino M, Spreafico F, Riva D, Biassoni V, Poggi G, Solero C, Gandola L, Genitori L, Modena P, Simonetti F, Potepan P, Casanova M, Meazza C, Clerici CA, Catania S, Sardi I, Giangaspero F. A lower-dose, lower-toxicity cisplatin-etoposide regimen for childhood progressive low-grade glioma. J Neurooncol. 2010 Oct;100(1):65-71. Epub 2010 Feb 12. link to original article contains verified protocol PubMed

PCV

PCV: Procarbazine, CCNU, Vincristine

Regimen, Brandes et al. 2004

Level of Evidence: Phase II

• 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

6-week cycles x up to 6 cycles

Supportive medications:

• Routine use of prophylactic 5-HT3 antagonists
• Steroids given at the lowest dose required by patient's neurologic status

References

1. Brandes AA, Tosoni A, Vastola F, Pasetto LM, Coria B, Danieli D, Iuzzolino P, Gardiman M, Talacchi A, Ermani M. Efficacy and feasibility of standard procarbazine, lomustine, and vincristine chemotherapy in anaplastic oligodendroglioma and oligoastrocytoma recurrent after radiotherapy. A Phase II study. Cancer. 2004 Nov 1;101(9):2079-85. link to original article contains verified protocol PubMed
2. Triebels VH, Taphoorn MJ, Brandes AA, Menten J, Frenay M, Tosoni A, Kros JM, Stege EB, Enting RH, Allgeier A, van Heuvel I, van den Bent MJ. Salvage PCV chemotherapy for temozolomide-resistant oligodendrogliomas. Neurology. 2004 Sep 14;63(5):904-6. link to original article PubMed

Temozolomide (Temodar)

Regimen #1, Pouratian et al. 2007 - low dose

Level of Evidence: Retrospective

• Temozolomide (Temodar) 75 mg/m2 PO once per day on days 1 to 21

28-day cycles x 12 to 15 cycles

Supportive medications:

• PCP prophylaxis with Trimethoprim/Sulfamethoxazole (Bactrim)
• Antiemetics and stool softeners used as needed

Regimen #2, Kesari et al. 2009 - low dose, longer cycles

Level of Evidence: Phase II

• Temozolomide (Temodar) 75 mg/m2 PO once per day on days 1 to 49

77-day cycles x up to 6 cycles, progression of disease, or unacceptable toxicity

Supportive medications:

• PCP prophylaxis with Trimethoprim/Sulfamethoxazole (Bactrim)

Regimen #3, Perry et al. 2008 - traditional initial dosing, then continuous therapy

Level of Evidence: Retrospective

At first recurrence/progression:

• 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

Regimen #4, Chinot et al. 2001 & Nicholson et al. 2007 - traditional dosing

Level of Evidence: Non-randomized

• Temozolomide (Temodar) 200 mg/m2 PO once per day on days 1 to 5
  • In Nicholson et al. 2007, patients who previously received craniospinal irradiation (CSI) instead received Temozolomide (Temodar) 180 mg/m2 PO once per day on days 1 to 5

28-day cycles x up to 24 months (in Chinot et al. 2001) or 11 cycles (in Nicholson et al. 2007)

References

1. Chinot OL, Honore S, Dufour H, Barrie M, Figarella-Branger D, Muracciole X, Braguer D, Martin PM, Grisoli F. Safety and efficacy of temozolomide in patients with recurrent anaplastic oligodendrogliomas after standard radiotherapy and chemotherapy. J Clin Oncol. 2001 May 1;19(9):2449-55. link to original article contains verified protocol PubMed
2. Pouratian N, Gasco J, Sherman JH, Shaffrey ME, Schiff D. Toxicity and efficacy of protracted low dose temozolomide for the treatment of low grade gliomas. J Neurooncol. 2007 May;82(3):281-8. Epub 2006 Nov 3. link to original article contains verified protocol PubMed
3. 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
4. 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
5. Kesari S, Schiff D, Drappatz J, LaFrankie D, Doherty L, Macklin EA, Muzikansky A, Santagata S, Ligon KL, Norden AD, Ciampa A, Bradshaw J, Levy B, Radakovic G, Ramakrishna N, Black PM, Wen PY. Phase II study of protracted daily temozolomide for low-grade gliomas in adults. Clin Cancer Res. 2009 Jan 1;15(1):330-7. link to original article contains verified protocol PubMed