Medulloblastoma - historical

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 Nicole M. Wood, DO
University of Missouri
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The purpose of this page is to provide references to regimens that are obsolete, outdated, or of historical interest only. As a general rule, this includes the inferior arm(s) of a randomized study, unless said regimens continue to be recommended by trustworthy sources such as the NCCN Guidelines. Is there a regimen missing from this list? See the main medulloblastoma page for current regimens.

4 regimens on this page
5 variants on this page


Pediatric Historic Therapy Older Children

COG ACNS0331 Reduced Dose CSRT with Reduced Volume Boost to Tumor Bed

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Michalski et al. 2021 (COG ACNS0331) 2004-04-30 to 2014-01-06 Phase 3 (E-de-esc) COG ACNS0331 Protocol for Standard Dose CSRT with Reduced Volume Boost Inferior EFS (primary endpoint)
  • Ages 3-7 Randomized
  • All patients must begin therapy within 31 days of surgery.

Induction

Radiotherapy

Chemotherapy

  • Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV push over 1 minute or IV infusion (per institution) once per day on days 8, 15, 22, 29, 36, 43 (Once a week starting one week after CSRT begins)
    • Round vincristine down to the nearest 0.1 mg

7-week course


Maintenance

Chemotherapy, first portion (cycles 1, 2, 4, 5, 7, 8; "Part A")

  • Cisplatin (Platinol) 75 mg/m2 IV once on day 1
  • Lomustine (CCNU) 75 mg/m2 PO once on day 1, taken on an empty stomach (at least 2 hours after food) preferably at bedtime (reduce N/V)
  • Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15
    • Dose rounded down to the nearest 0.1 mg
    • Can be given IV push over 1-minute or by infusion via minibag as per institution policy

Chemotherapy, second portion (cycles 3, 6, 9; "Part B")

  • Cyclophosphamide (Cytoxan) 1000 mg/m2 IV over 60 minutes once per day on days 1 & 2
  • Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1 & 8
    • Dose rounded down to the nearest 0.1 mg
    • Can be given IV push over 1-minute or by infusion via minibag as per institution policy

Supportive therapy, second portion (cycles 3, 6, 9; "Part B")

  • Mesna (Mesnex) 360 mg/m2 IV over 15 to 30 minutes once per day on days 1 & 2
    • Dose is given at least 15 minutes prior to or at the same time as cyclophosphamide and repeated at 4 and 8 hours post cyclophosphamide
    • Can be given via continuous infusion starting 15 to 30 minutes before or at the same time as cyclophosphamide and finished no sooner than 8 hours after the end of the cyclophosphamide infusion

42-day cycle for 2 cycles, then 28-day course, then 42-day cycle for 2 cycles, then 28-day course, then 42-day cycle for 2 cycles, then 28-day course (9 cycles total; AAB-AAB-AAB)

References

  1. COG ACNS0331: Michalski JM, Janss AJ, Vezina LG, Smith KS, Billups CA, Burger PC, Embry LM, Cullen PL, Hardy KK, Pomeroy SL, Bass JK, Perkins SM, Merchant TE, Colte PD, Fitzgerald TJ, Booth TN, Cherlow JM, Muraszko KM, Hadley J, Kumar R, Han Y, Tarbell NJ, Fouladi M, Pollack IF, Packer RJ, Li Y, Gajjar A, Northcott PA. Children's Oncology Group Phase III Trial of Reduced-Dose and Reduced-Volume Radiotherapy With Chemotherapy for Newly Diagnosed Average-Risk Medulloblastoma. J Clin Oncol. 2021 Aug 20;39(24):2685-2697. link to original article link to PMC article PubMed NCT00085735

COG ACNS0331 Reduced Dose CSRT with Standard Volume Boost

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Michalski et al. 2021 (COG ACNS0331) 2004-04-30 to 2014-01-06 Phase 3 (E-de-esc) COG ACNS0331 Protocol for Standard Dose CSRT with Standard Volume Boost Inferior EFS (primary endpoint)
  • Ages 3-7
  • All patients must begin therapy within 31 days of surgery.

Induction

Radiotherapy

Chemotherapy

  • Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV push over 1 minute or IV infusion (per institution) once per day on days 8, 15, 22, 29, 36, 43 (Once a week starting one week after CSRT begins)
    • Round vincristine down to the nearest 0.1 mg

7-week course


Maintenance

Chemotherapy, first portion (cycles 1, 2, 4, 5, 7, 8; "Part A")

  • Cisplatin (Platinol) 75 mg/m2 IV once on day 1
  • Lomustine (CCNU) 75 mg/m2 PO once on day 1, taken on an empty stomach (at least 2 hours after food) preferably at bedtime (reduce N/V)
  • Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15
    • Dose rounded down to the nearest 0.1 mg
    • Can be given IV push over 1-minute or by infusion via minibag as per institution policy

Chemotherapy, second portion (cycles 3, 6, 9; "Part B")

  • Cyclophosphamide (Cytoxan) 1000 mg/m2 IV over 60 minutes once per day on days 1 & 2
  • Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1 & 8
    • Dose rounded down to the nearest 0.1 mg
    • Can be given IV push over 1-minute or by infusion via minibag as per institution policy

Supportive therapy, second portion (cycles 3, 6, 9; "Part B")

  • Mesna (Mesnex) 360 mg/m2 IV over 15 to 30 minutes once per day on days 1 & 2
    • Dose is given at least 15 minutes prior to or at the same time as cyclophosphamide and repeated at 4 and 8 hours post cyclophosphamide
    • Can be given via continuous infusion starting 15 to 30 minutes before or at the same time as cyclophosphamide and finished no sooner than 8 hours after the end of the cyclophosphamide infusion

42-day cycle for 2 cycles, then 28-day course, then 42-day cycle for 2 cycles, then 28-day course, then 42-day cycle for 2 cycles, then 28-day course (9 cycles total; AAB-AAB-AAB)

References

  1. COG ACNS0331: Michalski JM, Janss AJ, Vezina LG, Smith KS, Billups CA, Burger PC, Embry LM, Cullen PL, Hardy KK, Pomeroy SL, Bass JK, Perkins SM, Merchant TE, Colte PD, Fitzgerald TJ, Booth TN, Cherlow JM, Muraszko KM, Hadley J, Kumar R, Han Y, Tarbell NJ, Fouladi M, Pollack IF, Packer RJ, Li Y, Gajjar A, Northcott PA. Children's Oncology Group Phase III Trial of Reduced-Dose and Reduced-Volume Radiotherapy With Chemotherapy for Newly Diagnosed Average-Risk Medulloblastoma. J Clin Oncol. 2021 Aug 20;39(24):2685-2697. link to original article link to PMC article PubMed NCT00085735

COG ACNS0332 Regimen C

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Leary et al. 2021 (COG ACNS0332) 2007-03 to 2018-09 Phase 3 (E-esc) COG ACNS0332 Protocol A (no carboplatin) Not reported

Note: incomplete regimen - missing isotretinoin dosing; this arm was closed early for futility.

Induction, Chemoradiotherapy

Radiotherapy

For additional boost details, such as technique and location, please see full protocol as this depends on site of metastases and disease stage

Chemotherapy

  • Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV push over 1 minute or IV infusion (per institution) once per day on days 1, 8, 15, 22, 29, 36 (Once a week starting within one week of the start of CSRT)
    • Round vincristine down to the nearest 0.1 mg

6-week course, followed by:


Maintenance

Chemotherapy

28-day cycle for 6 cycles; begin next cycle on day 29 or when ANC at least 750/μL, platelets at least 75,000/μL, and the patient has been off of myeloid growth factor for at least 24 hours

References

  1. COG ACNS0332: Leary SES, Packer RJ, Li Y, Billups CA, Smith KS, Jaju A, Heier L, Burger P, Walsh K, Han Y, Embry L, Hadley J, Kumar R, Michalski J, Hwang E, Gajjar A, Pollack IF, Fouladi M, Northcott PA, Olson JM. Efficacy of Carboplatin and Isotretinoin in Children With High-risk Medulloblastoma: A Randomized Clinical Trial From the Children's Oncology Group. JAMA Oncol. 2021 Sep 1;7(9):1313-1321. link to original article link to PMC article PubMed NCT00392327

COG ACNS0332 Regimen D

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Leary et al. 2021 (COG ACNS0332) 2007-03 to 2018-09 Phase 3 (E-esc) COG ACNS0332 Protocol A (no carboplatin) Not reported

Note: incomplete regimen - missing isotretinoin dosing; this arm was closed early for futility.

Induction, Chemoradiotherapy

Radiotherapy

For additional boost details, such as technique and location, please see full protocol as this depends on site of metastases and disease stage

Chemotherapy

  • Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV push over 1 minute or IV infusion (per institution) once per day on days 1, 8, 15, 22, 29, 36 (Once a week starting within one week of the start of CSRT)
    • Round vincristine down to the nearest 0.1 mg
    • Administer prior to Carboplatin
  • Carboplatin (Paraplatin) 35 mg/m2 IV over 15 minutes once per day on radiation days, given 1 to 4 hours prior to radiation therapy (Total of 30 doses)

6-week course


Maintenance

Chemotherapy

28-day cycle for 6 cycles; begin each cycle on day 29 or when ANC at least 750/μL, platelets at least 75,000/μL, and the patient has been off of myeloid growth factor for at least 24 hours

References

  1. COG ACNS0332: Leary SES, Packer RJ, Li Y, Billups CA, Smith KS, Jaju A, Heier L, Burger P, Walsh K, Han Y, Embry L, Hadley J, Kumar R, Michalski J, Hwang E, Gajjar A, Pollack IF, Fouladi M, Northcott PA, Olson JM. Efficacy of Carboplatin and Isotretinoin in Children With High-risk Medulloblastoma: A Randomized Clinical Trial From the Children's Oncology Group. JAMA Oncol. 2021 Sep 1;7(9):1313-1321. link to original article link to PMC article PubMed NCT00392327

All lines of therapy, younger children

COG ACNS1221 Protocol

Study Dates of enrollment Evidence
Lafay-Cousin et al. 2019 (COG ACNS1221) 2013-12-12 to 2016-07-07 Phase 2

Induction, (Vincristine, Cyclophosphamide, MTX, Etoposide, Carboplatin)

Given for cycles 1, 2, & 3

Chemotherapy

  • Vincristine (Oncovin) by the following age-based criteria:
    • 0 to 6.99 months old: 1 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 15, 29
    • 7 to 12.99 months old: 1.2 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 15, 29
    • 13 months old or older: 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 15, 29
    • Can be given IV push over 1-minute or by infusion via minibag as per institution policy
  • Cyclophosphamide (Cytoxan) by the following age-based criteria:
    • 0 to 6.99 months old: 533 mg/m2 IV over 1 hour once per day on days 1 to 3
    • 7 to 12.99 months old: 640 mg/m2 IV over 1 hour once per day on days 1 to 3
    • 13 months old or older: 800 mg/m2 IV over 1 hour once per day on days 1 to 3

Supportive therapy

  • Mesna (Mesnex) by the following age-based criteria:
    • 0 to 6.99 months old: 533 mg/m2 IV over 1 hour once per day on days 1 to 3
    • 7 to 12.99 months old: 640 mg/m2 IV over 1 hour once per day on days 1 to 3
    • 13 months old or older: 800 mg/m2 IV over 1 hour once per day on days 1 to 3
    • Mesna (Mesnex) Dose can be given in 5 divided doses by short IV infusion over 15 to 30 minutes starting 15 minutes prior to cyclophosphamide with subsequent doses given at 3, 6, 9, & 12 hours after the start of cyclophosphamide
    • Can be given via continuous infusion starting 15 to 30 minutes before or at the same time as cyclophosphamide and finished no sooner than 12 hours after the end of the cyclophosphamide infusion

Chemotherapy

  • High Dose Methotrexate (MTX) 5000 mg/m2 IV over 24 hours on days 15 & 29
    • Methotrexate (MTX) 500 mg/m2 IV infused over 30 minutes, then 4500 mg/m2 given by continuous IV infusion over 23.5 hours

Supportive therapy

  • Leucovorin (Folinic acid) 15 mg/m2 IV or PO given at 42, 48 & 54 hours after start of methotrexate infusion on days 17 & 31
    • Leucovorin (Folinic acid) should be continued until serum methotrexate levels are less than 0.1 µM
    • Can be given as an IV push over a minimum of 3 minutes or by short infusion over 15 to 120 minutes
    • See full protocol for dose modifications based on methotrexate levels

Chemotherapy

  • Etoposide (Vepesid) 150 mg/m2 IV over 60 to 120 minutes (maximum rate of 300 mg/m2/hr) once per day on days 43 to 45, given before carboplatin
  • Carboplatin (Paraplatin) by the following age-based criteria:
    • 0 to 6.99 months old: 133 mg/m2 IV over 1 hour once per day on days 43 to 45
    • 7 to 12.99 months old: 160 mg/m2 IV over 1 hour once per day on days 43 to 45
    • 13 months old or older: 200 mg/m2 IV over 1 hour once per day on days 43 to 45

Supportive therapy

  • Filgrastim (Neupogen) 5 mcg/kg SC or IV once per day for at least 7 days or until ANC at least 750/μl, beginning on day 4 & 46
    • ANC at least 750/μl on or before day 7 of the cycle is not sufficient for discontinuing G-CSF

63-day cycle


Continuation, Therapy (Vincristine, CPM, Etoposide, Carboplatin)

Given for 2 cycles if residual disease noted after Induction

Chemotherapy

  • Vincristine (Oncovin) by the following age-based criteria:
    • 0 to 6.99 months old: 1 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 15, 29
    • 7 to 12.99 months old: 1.2 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 15, 29
    • 13 months old or older: 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 15, 29
    • Can be given IV push over 1-minute or by infusion via minibag as per institution policy
  • Cyclophosphamide (Cytoxan) by the following age-based criteria:
    • 0 to 6.99 months old: 533 mg/m2 IV over 1 hour once per day on days 1 to 3
    • 7 to 12.99 months old: 640 mg/m2 IV over 1 hour once per day on days 1 to 3
    • 13 months old or older: 800 mg/m2 IV over 1 hour once per day on days 1 to 3

Supportive therapy

  • Mesna (Mesnex) by the following age-based criteria:
    • 0 to 6.99 months old: 533 mg/m2 IV over 1 hour once per day on days 1 to 3
    • 7 to 12.99 months old: 640 mg/m2 IV over 1 hour once per day on days 1 to 3
    • 13 months old or older: 800 mg/m2 IV over 1 hour once per day on days 1 to 3
      • Dose can be given in 5 divided doses by short IV infusion over 15 to 30 minutes starting 15 minutes prior to cyclophosphamide with subsequent doses given at 3, 6, 9, & 12 hours after the start of cyclophosphamide
      • Dose can be given via continuous infusion starting 15 to 30 minutes before or at the same time as cyclophosphamide and finished no sooner than 12 hours after the end of the cyclophosphamide infusion

Chemotherapy

  • Etoposide (Vepesid) 150 mg/m2 IV over 60 to 120 minutes (maximum rate of 300 mg/m2/hr) once per day on days 21 to 23, given prior to carboplatin
  • Carboplatin (Paraplatin) by the following age-based criteria:
    • 0 to 6.99 months old: 133 mg/m2 IV over 1 hour once per day on days 21 to 23
    • 7 to 12.99 months old: 160 mg/m2 IV over 1 hour once per day on days 21 to 23
    • 13 months old or older: 200 mg/m2 IV over 1 hour once per day on days 21 to 23

Supportive therapy

  • Filgrastim (Neupogen) 5 mcg/kg SC or IV once per day for at least 7 days or until ANC at least 750/μl, beginning on days 4 & 24
    • ANC at least 750/μl on or before day 7 of the cycle is not sufficient for discontinuing G-CSF

42-day cycle

References

  1. COG ACNS1221: Lafay-Cousin L, Bouffet E, Strother D, Rudneva V, Hawkins C, Eberhart C, Horbinski C, Heier L, Souweidane M, Williams-Hughes C, Onar-Thomas A, Billups CA, Fouladi M, Northcott P, Robinson G, Gajjar A. Phase II Study of Nonmetastatic Desmoplastic Medulloblastoma in Children Younger Than 4 Years of Age: A Report of the Children's Oncology Group (ACNS1221). J Clin Oncol. 2020 Jan 20;38(3):223-231. Epub 2019 Nov 27. link to original article link to PMC article PubMed NCT02017964

Head Start III Regimen D

Study Dates of enrollment Evidence
Dhall et al. 2020 (Head Start III) 2003-05 to 2009-12 Non-randomized

Induction

Chemotherapy, first portion (cycles 1 & 3)

Supportive therapy, first portion (cycles 1 & 3)

Chemotherapy, second portion (cycles 2 & 4)

Chemotherapy, third portion (cycle 5)

Supportive therapy, third portion (cycle 5)

5 cycles


Consolidation, Myeloablative Chemotherapy with AuHCR

  • Patients with no evidence of disease (NED) after induction or second look surgery.

Chemotherapy

3-day course

References

  1. Head Start III: Dhall G, O'Neil SH, Ji L, Haley K, Whitaker AM, Nelson MD, Gilles F, Gardner SL, Allen JC, Cornelius AS, Pradhan K, Garvin JH, Olshefski RS, Hukin J, Comito M, Goldman S, Atlas MP, Walter AW, Sands S, Sposto R, Finlay JL. Excellent outcome of young children with nodular desmoplastic medulloblastoma treated on "Head Start" III: a multi-institutional, prospective clinical trial. Neuro Oncol. 2020 Dec 18;22(12):1862-1872. link to original article link to PMC article PubMed NCT00392327

HIT-SKK'92 regimen

Regimen

Study Dates of enrollment Evidence
Rutkowski et al. 2005 1992-1997 Non-randomized

Preceding treatment

Chemotherapy

References

  1. Rutkowski S, Bode U, Deinlein F, Ottensmeier H, Warmuth-Metz M, Soerensen N, Graf N, Emser A, Pietsch T, Wolff JE, Kortmann RD, Kuehl J. Treatment of early childhood medulloblastoma by postoperative chemotherapy alone. N Engl J Med. 2005 Mar 10;352(10):978-86. link to original article PubMed

Baby POG I protocol

Regimen variant #1, 12 months

Study Dates of enrollment Evidence
Duffner et al. 1993 1986-1990 Non-randomized

Note: this length of treatment was intended for children 24 to 36 months of age at diagnosis.

Preceding treatment

Chemotherapy, A portion (cycles 1, 2, 4, 5, 7, 8, 10, 11, 13)

Chemotherapy, B portion (cycles 3, 6, 9, 12)

28-day cycle for 13 cycles (1 year)

Subsequent treatment

  • Adjuvant RT


Regimen variant #2, 24 months

Study Dates of enrollment Evidence
Duffner et al. 1993 1986-1990 Non-randomized

Note: this length of treatment was intended for children under 24 months of age at diagnosis.

Preceding treatment

Chemotherapy, A portion (cycles 1, 2, 4, 5, 7, 8, 10, 11, 13, 14, 16, 17, 19, 20, 22, 23, 25, 26)

Chemotherapy, B portion (cycles 3, 6, 9, 12, 15, 18, 21, 24)

28-day cycle for 26 cycles (2 years)

Subsequent treatment

  • Adjuvant RT

References

  1. Duffner PK, Horowitz ME, Krischer JP, Friedman HS, Burger PC, Cohen ME, Sanford RA, Mulhern RK, James HE, Freeman CR, Seidel FG, Kun LE. Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. N Engl J Med. 1993 Jun 17;328(24):1725-31. link to original article contains dosing details in manuscript PubMed

VCP [CCG-921]

VCP: Vincristine, CCNU (Lomustine), Prednisone

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Zeltzer et al. 1999 (CCG-921) 1986-1992 Phase 3 (C) 8-in-1 Superior PFS

Preceding treatment

Chemotherapy

Glucocorticoid therapy

42-day cycle for 8 cycles

References

  1. CCG-921: Zeltzer PM, Boyett JM, Finlay JL, Albright AL, Rorke LB, Milstein JM, Allen JC, Stevens KR, Stanley P, Li H, Wisoff JH, Geyer JR, McGuire-Cullen P, Stehbens JA, Shurin SB, Packer RJ. Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma in children: conclusions from the Children's Cancer Group 921 randomized phase III study. J Clin Oncol. 1999 Mar;17(3):832-45. link to original article contains dosing details in manuscript PubMed

COG A9961 regimen

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Packer et al. 2006 (COG A9961) 1996-2000 Phase 3 (C) Cisplatin, Cyclophosphamide, Vincristine Did not meet primary endpoint of EFS

Note: neither the cycle length nor the exact dosing instructions for vincristine are clear from the manuscript.

Preceding treatment

Chemotherapy

8 cycles (see note)

References

  1. COG A9961: Packer RJ, Gajjar A, Vezina G, Rorke-Adams L, Burger PC, Robertson PL, Bayer L, LaFond D, Donahue BR, Marymont MH, Muraszko K, Langston J, Sposto R. Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma. J Clin Oncol. 2006 Sep 1;24(25):4202-8. link to original article contains dosing details in manuscript PubMed NCT00002875
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