Low-grade glioma

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

7 regimens on this page 10 variants on this page

Guidelines

EANO

• European Association for Neuro-Oncology (EANO) guideline on the diagnosis and treatment of adult astrocytic and oligodendroglial gliomas (2017) PubMed
• European Association for Neuro-Oncology (EANO) guidelines for palliative care in adults with glioma (2017) PubMed

NCCN

• NCCN Guidelines - Central Nervous System Cancers

Adjuvant therapy

Carboplatin & Vincristine

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CV: Carboplatin & Vincristine
VC: Vincristine & Carboplatin

Variant #1, 175/1.5 (capped vincristine)

Study	Evidence	Comparator	Comparative Efficacy
Packer et al. 1993	Non-randomized
Ater et al. 2012 (COG A9952)	Phase III (C)	TPCV	Seems not superior

Note that the cycle begins on day 0.

Preceding treatment

• Biopsy or incomplete resection

Chemotherapy

• Carboplatin (Paraplatin) 175 mg/m² IV once per day on days 0, 7, 14, 21, 42, 49, 56, 63 (8 doses)
• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once per day on days 0, 7, 14, 21, 28, 35, 42, 49, 56, 63 (10 doses)

10-week course

Subsequent treatment

• CV maintenance

Variant #2, 550/1.5 (uncapped vincristine)

Study	Evidence	Comparator	Comparative Efficacy
Gnekow et al. 2017 (SIOP-LCG 2004)	Phase III (C)	VCE	Seems not superior

Preceding treatment

• Biopsy or incomplete resection

Chemotherapy

• Carboplatin (Paraplatin) 550 mg/m² IV over 60 minutes once on day 1
• Vincristine (Oncovin) as follows:
  • Cycles 1 to 4: 1.5 mg/m² IV once per week (10 total doses)
  • Cycles 5 to 7: 1.5 mg/m² IV once on day 1

21-day cycle for 4 cycles, then 28-day cycle for 3 cycles

Subsequent treatment

• VC consolidation

References

1. Packer RJ, Lange B, Ater J, Nicholson HS, Allen J, Walker R, Prados M, Jakacki R, Reaman G, Needles MN, Phillips PC, Ryan J, Boyett JM, Geyer R, Finlay J. Carboplatin and vincristine for recurrent and newly diagnosed low-grade gliomas of childhood. J Clin Oncol. 1993 May;11(5):850-6. link to original article contains verified protocol PubMed
2. COG A9952: Ater JL, Zhou T, Holmes E, Mazewski CM, Booth TN, Freyer DR, Lazarus KH, Packer RJ, Prados M, Sposto R, Vezina G, Wisoff JH, Pollack IF. Randomized study of two chemotherapy regimens for treatment of low-grade glioma in young children: a report from the Children's Oncology Group. J Clin Oncol. 2012 Jul 20;30(21):2641-7. Epub 2012 Jun 4. link to original article link to PMC article contains verified protocol PubMed
3. SIOP-LGG 2004: Gnekow AK, Walker DA, Kandels D, Picton S, Perilongo G, Grill J, Stokland T, Sandstrom PE, Warmuth-Metz M, Pietsch T, Giangaspero F, Schmidt R, Faldum A, Kilmartin D, De Paoli A, De Salvo GL; of the Low Grade Glioma Consortium and the participating centers. A European randomised controlled trial of the addition of etoposide to standard vincristine and carboplatin induction as part of an 18-month treatment programme for childhood (≤16 years) low grade glioma - a final report. Eur J Cancer. 2017 Aug;81:206-225. Epub 2017 Jun 22. Erratum in: Eur J Cancer. 2017 Dec 13;:. link to original article link to PMC article contains verified protocol PubMed

Observation

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Shaw et al. 2012 (RTOG 9802)	Phase III (C)	PCV	Inferior OS (*)

Efficacy is based on the 2016 update.

Preceding treatment

• RT x 54 Gy

References

1. RTOG 9802: Shaw EG, Wang M, Coons SW, Brachman DG, Buckner JC, Stelzer KJ, Barger GR, Brown PD, Gilbert MR, Mehta MP. Randomized trial of radiation therapy plus procarbazine, lomustine, and vincristine chemotherapy for supratentorial adult low-grade glioma: initial results of RTOG 9802. J Clin Oncol. 2012 Sep 1;30(25):3065-70. link to original article contains verified protocol link to PMC article PubMed
   1. Update: Buckner JC, Shaw EG, Pugh SL, Chakravarti A, Gilbert MR, Barger GR, Coons S, Ricci P, Bullard D, Brown PD, Stelzer K, Brachman D, Suh JH, Schultz CJ, Bahary JP, Fisher BJ, Kim H, Murtha AD, Bell EH, Won M, Mehta MP, Curran WJ Jr. Radiation plus procarbazine, CCNU, and vincristine in low-grade glioma. N Engl J Med. 2016 Apr 7;374(14):1344-55. link to original article link to PMC article PubMed

PCV

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PCV: Procarbazine, CCNU (Lomustine), Vincristine

Regimen

Study	Evidence	Comparator	Comparative Efficacy
Shaw et al. 2012 (RTOG 9802)	Phase III (E)	Observation	Superior OS (*)

Efficacy is based on the 2016 update.

Preceding treatment

• RT x 54 Gy

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

8-week cycle for 6 cycles

References

1. RTOG 9802: Shaw EG, Wang M, Coons SW, Brachman DG, Buckner JC, Stelzer KJ, Barger GR, Brown PD, Gilbert MR, Mehta MP. Randomized trial of radiation therapy plus procarbazine, lomustine, and vincristine chemotherapy for supratentorial adult low-grade glioma: initial results of RTOG 9802. J Clin Oncol. 2012 Sep 1;30(25):3065-70. link to original article contains verified protocol link to PMC article PubMed
   1. Update: Buckner JC, Shaw EG, Pugh SL, Chakravarti A, Gilbert MR, Barger GR, Coons S, Ricci P, Bullard D, Brown PD, Stelzer K, Brachman D, Suh JH, Schultz CJ, Bahary JP, Fisher BJ, Kim H, Murtha AD, Bell EH, Won M, Mehta MP, Curran WJ Jr. Radiation plus procarbazine, CCNU, and vincristine in low-grade glioma. N Engl J Med. 2016 Apr 7;374(14):1344-55. link to original article link to PMC article PubMed

Radiation therapy

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Shaw et al. 2012 (RTOG 9802)	Non-randomized portion of RCT
Baumert et al. 2016 (EORTC 22033-26033)	Phase III (C)	Temozolomide	Seems not superior

Details here are from RTOG 9802.

Radiotherapy

• External beam radiotherapy with 1.8 Gy fractions given in 30 fractions over 6 weeks, for a total dose of 54 Gy

One course

Subsequent treatment

• RTOG 9802: Observation versus PCV x 6

References

1. RTOG 9802: Shaw EG, Wang M, Coons SW, Brachman DG, Buckner JC, Stelzer KJ, Barger GR, Brown PD, Gilbert MR, Mehta MP. Randomized trial of radiation therapy plus procarbazine, lomustine, and vincristine chemotherapy for supratentorial adult low-grade glioma: initial results of RTOG 9802. J Clin Oncol. 2012 Sep 1;30(25):3065-70. link to original article contains verified protocol link to PMC article PubMed
   1. Update: Buckner JC, Shaw EG, Pugh SL, Chakravarti A, Gilbert MR, Barger GR, Coons S, Ricci P, Bullard D, Brown PD, Stelzer K, Brachman D, Suh JH, Schultz CJ, Bahary JP, Fisher BJ, Kim H, Murtha AD, Bell EH, Won M, Mehta MP, Curran WJ Jr. Radiation plus procarbazine, CCNU, and vincristine in low-grade glioma. N Engl J Med. 2016 Apr 7;374(14):1344-55. link to original article link to PMC article PubMed
2. EORTC 22033-26033: Baumert BG, Hegi ME, van den Bent MJ, von Deimling A, Gorlia T, Hoang-Xuan K, Brandes AA, Kantor G, Taphoorn MJ, Hassel MB, Hartmann C, Ryan G, Capper D, Kros JM, Kurscheid S, Wick W, Enting R, Reni M, Thiessen B, Dhermain F, Bromberg JE, Feuvret L, Reijneveld JC, Chinot O, Gijtenbeek JM, Rossiter JP, Dif N, Balana C, Bravo-Marques J, Clement PM, Marosi C, Tzuk-Shina T, Nordal RA, Rees J, Lacombe D, Mason WP, Stupp R. Temozolomide chemotherapy versus radiotherapy in high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study. Lancet Oncol. 2016 Nov;17(11):1521-1532. link to original article contains protocol link to PMC article PubMed

Temozolomide monotherapy

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Baumert et al. 2016 (EORTC 22033-26033)	Phase III (E)	Radiotherapy	Seems not superior

Chemotherapy

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

28-day cycle for up to 12 cycles

References

1. Baumert BG, Hegi ME, van den Bent MJ, von Deimling A, Gorlia T, Hoang-Xuan K, Brandes AA, Kantor G, Taphoorn MJ, Hassel MB, Hartmann C, Ryan G, Capper D, Kros JM, Kurscheid S, Wick W, Enting R, Reni M, Thiessen B, Dhermain F, Bromberg JE, Feuvret L, Reijneveld JC, Chinot O, Gijtenbeek JM, Rossiter JP, Dif N, Balana C, Bravo-Marques J, Clement PM, Marosi C, Tzuk-Shina T, Nordal RA, Rees J, Lacombe D, Mason WP, Stupp R. Temozolomide chemotherapy versus radiotherapy in high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study. Lancet Oncol. 2016 Nov;17(11):1521-1532. link to original article contains protocol link to PMC article PubMed

Recurrent or progressive, non-curative therapy

Carboplatin monotherapy

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Regimen

Study	Evidence
Moghrabi et al. 1998	Phase II

Chemotherapy

• Carboplatin (Paraplatin) 560 mg/m² IV over 60 minutes once on day 1
  • Mixed in D5 1/2 NS

Supportive medications

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

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

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

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Regimen

Study	Evidence
Brandes et al. 2003	Phase II

Chemotherapy

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

Supportive medications

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

28-day cycle for up to 10 cycles

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

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Regimen

Study	Evidence
Massimino et al. 2010	Non-randomized

Note: In children less than 1 year old or less than 10 kg, "doses were adjusted to their weight"--reference does not say exactly how doses are adjusted.

Chemotherapy

• 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

Supportive medications

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

28-day cycle for 4 cycles, then 35-day cycle for 3 cycles, then 42-day cycle for 3 cycles

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

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PCV: Procarbazine, CCNU (Lomustine), Vincristine

Regimen

Study	Evidence
Brandes et al. 2004	Phase II

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 medications

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

42-day cycle for up to 6 cycles

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. Retrospective: 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 monotherapy

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Variant #1, low dose

Study	Evidence
Pouratian et al. 2006	Retrospective

Chemotherapy

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

Supportive medications

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

28-day cycle for 12 to 15 cycles

Variant #2, low dose, longer cycles

Study	Evidence
Kesari et al. 2009	Phase II

Chemotherapy

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

Supportive medications

• PCP prophylaxis with Trimethoprim/Sulfamethoxazole (Bactrim)

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

Variant #3, traditional initial dosing, then continuous therapy

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

At first recurrence/progression:

Chemotherapy

• 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

Variant #4, traditional dosing

Study	Evidence
Chinot et al. 2001	Phase II
Nicholson et al. 2007	Non-randomized

Chemotherapy

• 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 180 mg/m² PO once per day on days 1 to 5

28-day cycle for 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. Retrospective: 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. RESCUE: Perry JR, Rizek P, Cashman R, Morrison M, Morrison T. Temozolomide rechallenge in recurrent malignant glioma by using a continuous temozolomide schedule: the "rescue" approach. Cancer. 2008 Oct 15;113(8):2152-7. link to original article contains verified protocol PubMed
   1. Update: Perry JR, Bélanger K, Mason WP, Fulton D, Kavan P, Easaw J, Shields C, Kirby S, Macdonald DR, Eisenstat DD, Thiessen B, Forsyth P, Pouliot JF. Phase II trial of continuous dose-intense temozolomide in recurrent malignant glioma: RESCUE study. J Clin Oncol. 2010 Apr 20;28(12):2051-7. Epub 2010 Mar 22. link to original article contains verified protocol PubMed
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