Medulloblastoma

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Upfront Therapy

COG ACNS0331 Standard Dose CSRT/Reduced Volume Boost to Tumor Bed

• Ages 3+
• All patients must begin therapy within 31 days of surgery.

Chemoradiotherapy

XRT

• Craniospinal External beam radiotherapy 23.4 Gy in 13 daily fractions
• Tumor Bed Boost External beam radiotherapy 30.6 Gy in 17 daily fractions

Chemotherapy

• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV push over 1 minute or IV infusion (per institution) once on day 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 Regimen A

Cycles 1, 2, 4, 5, 7, 8

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Lomustine (CCNU) 75 mg/m² PO once on day 1 on an empty stomach (at least 2 hours after food) preferably at bedtime (reduce N/V)
  • Pediatric Lomustine Dosing Chart
  • Give Lomustine (CCNU) with at least 8 oz of fluids for children > 3 years old and at least 4 oz of fluids for children < 3 years of age
• 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

6-week cycle

Maintenance Regimen B

Cycles 3, 6, and 9

Chemotherapy

• Cyclophosphamide (Cytoxan) 1000 mg/m² IV given over 1 hour on Days 1, 2
• Mesna (Mesnex) 360 mg/m² IV over 15 to 30 minutes on Days 1, 2
  • Dose is given at least 15 minutes prior to or at the same time as Cyclophosphamide (Cytoxan) and repeated at 4 and 8 hours post Cyclophosphamide (Cytoxan)
  • Can be given via continuous infusion starting 15 to 30 minutes before or at the same time as Cyclophosphamide (Cytoxan) and finished no sooner than 8 hours after the end of the Cyclophosphamide (Cytoxan) infusion
• 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

6-week course

References

1. COG ACNS0331: Michalski JM, Janss AJ, Vezina LG, Smith KS, Billups CA, Burger PC, Embry LM, Cullen PL, Hardy PC, Pomeroy SL, Bass JK, Perkins SM, Merchant TE, Colte PD, Fitzgerald TJ, JBooth 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. Journal of Clinical Oncology 39, no. 24 (August 20, 2021) 2685-2697. link to original article NCT00085735

COG ACNS0331 Standard Dose CSRT/Standard Volume Boost

• Ages 3+
• All patients must begin therapy within 31 days of surgery.

Chemoradiotherapy

XRT

• Craniospinal External beam radiotherapy 23.4 Gy in 13 daily fractions
• Posterior Fossa Boost External beam radiotherapy 30.6 Gy in 17 daily fractions

Chemotherapy

• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV push over 1 minute or IV infusion (per institution) once on day 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 Regimen A

Cycles 1, 2, 4, 5, 7, 8

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Lomustine (CCNU) 75 mg/m² PO once on day 1 on an empty stomach (at least 2 hours after food) preferably at bedtime (reduce N/V)
  • Pediatric Lomustine Dosing Chart
  • Give Lomustine (CCNU) with at least 8 oz of fluids for children > 3 years old and at least 4 oz of fluids for children < 3 years of age
• 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

6-week cycle

Maintenance Regimen B

Cycles 3, 6, and 9

Chemotherapy

• Cyclophosphamide (Cytoxan) 1000 mg/m² IV given over 1 hour on Days 1, 2
• Mesna (Mesnex) 360 mg/m² IV over 15 to 30 minutes on Days 1, 2
  • Dose given at least 15 minutes prior to or at the same time as Cyclophosphamide (Cytoxan) and repeated at 4 and 8 hours post Cyclophosphamide (Cytoxan)
  • Can be given via continuous infusion starting 15 to 30 minutes before or at the same time as Cyclophosphamide (Cytoxan) and finished no sooner than 8 hours after the end of the Cyclophosphamide (Cytoxan) infusion
• 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

6-week course

References

1. COG ACNS0331: Michalski JM, Janss AJ, Vezina LG, Smith KS, Billups CA, Burger PC, Embry LM, Cullen PL, Hardy PC, Pomeroy SL, Bass JK, Perkins SM, Merchant TE, Colte PD, Fitzgerald TJ, JBooth 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. Journal of Clinical Oncology 39, no. 24 (August 20, 2021) 2685-2697. link to original article NCT00085735

COG ACNS0332 Regimen A

Chemoradiotherapy

XRT

• Craniospinal External beam radiotherapy 36 Gy in 20 daily fractions (Monday - Friday)
• Posterior Fossa Boost External beam radiotherapy 19.8 Gy in 11 daily fractions (Cumulative dose of 55.8 Gy)

For additional boost details, such as technique and location, please see the full protocol as this depends on the 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 on day 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

Maintenance Cycle

Begin each cycle on Day 29 and when ANC ≥ 750/μL, platelets ≥ 75,000/μL, and the patient has been off of myeloid growth factor for at least 24 hours for a total of 6 cycles.

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV over 60 minutes once on day 1
• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV push over 1 minute or IV infusion (per institution) once on days 1, 8
  • Round vincristine down to the nearest 0.1 mg
• Cyclophosphamide (Cytoxan) 1000 mg/m² IV over 1 hour once on days 2, 3
  • Cyclophosphamide (Cytoxan) should be given at least 24 hours after Cisplatin on day 2

28-Day Course

References

1. COG ACNS0332: Hwang EI, Kool M, Capper D, Chavez L, Brabetz S, Williams-Hughes C, Billups C, Heier L, Jaju A, Michalski J, Li Y, Leary S, Zhou T, von Deimling A, Jones DTW, Fouladi M, Pollack IF, Gajjar A, Packer RJ, Pfister SM, Olson JM. Extensive Molecular and Clinical Heterogeneity in Patients with Histologically Diagnosed CNS-PNET Treated as a Single Entity: A Report From the Children's Oncology Group Randomized ACNS0332 Trial. Journal of Clinical Oncology 2018 Oct 17:JCO2017764720. link to original article NCT00392327
2. COG ACNS0332: Leary SES, Packer RJ, LiY, 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 Oncology 2021 Sep 1; 7(9): 1313-1321. link to original article NCT00392327

COG ACNS0332 Regimen B

Chemoradiotherapy

XRT

• Craniospinal External beam radiotherapy 36 Gy in 20 daily fractions (Monday - Friday)
• Posterior Fossa Boost External beam radiotherapy 19.8 Gy in 11 daily fractions (Cumulative dose of 55.8 Gy)

For additional boost details, such as technique and location, please see the full protocol as this depends on the 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 on day 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 given daily 1 to 4 hours prior to radiation therapy (Total of 30 doses)
  • Carboplatin (Paraplatin) first dose administered on the first day of radiation therapy
  • Carboplatin (Paraplatin) should be HELD if radiation treatment is not given
  • Since there are 31 fractions of radiation, No Carboplatin (Paraplatin) should be given prior to the final radiation fraction

6-Week Course

Maintenance Cycle

Begin each cycle on Day 29 and when ANC ≥ 750/μL, platelets ≥ 75,000/μL, and the patient has been off of myeloid growth factor for at least 24 hours for a total of 6 cycles.

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV over 60 minutes once on day 1
• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV push over 1 minute or IV infusion (per institution) once on days 1, 8
  • Round vincristine down to the nearest 0.1 mg
• Cyclophosphamide (Cytoxan) 1000 mg/m² IV over 1 hour once on days 2, 3
  • Cyclophosphamide (Cytoxan) should be given at least 24 hours after Cisplatin on day 2

28-Day Course

References

1. COG ACNS0332: Hwang EI, Kool M, Capper D, Chavez L, Brabetz S, Williams-Hughes C, Billups C, Heier L, Jaju A, Michalski J, Li Y, Leary S, Zhou T, von Deimling A, Jones DTW, Fouladi M, Pollack IF, Gajjar A, Packer RJ, Pfister SM, Olson JM. Extensive Molecular and Clinical Heterogeneity in Patients with Histologically Diagnosed CNS-PNET Treated as a Single Entity: A Report From the Children's Oncology Group Randomized ACNS0332 Trial. Journal of Clinical Oncology 2018 Oct 17:JCO2017764720. link to original article NCT00392327
2. COG ACNS0332: Leary SES, Packer RJ, LiY, 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 Oncology 2021 Sep 1; 7(9): 1313-1321. link to original article NCT00392327

COG ACNS0334 Regimen A

Induction

Chemotherapy

3 Cycles

• Vincristine (Oncovin) 0.05 mg/kg (maximum single dose of 2 mg) IV push over 1 minute or IV infusion (per institution) once on Day 1, 8, 15

• Etoposide (Vepesid) 2.5 mg/kg (maximum concentration of Etoposide (Vepesid) is 0.4 mg/ml) IV over 1 hour once daily on Day 1, 2, 3
  • Begin Etoposide (Vepesid) infusion 1 hour before the Cyclophosphamide (Cytoxan) or Cisplatin (Platinol) infusions

• Cyclophosphamide (Cytoxan) 60 mg/kg IV over 1 hour (Hour 1-2) on Days 1, 2 with hyperhydration and Mesna (Mesnex)
  • Must reduce urine specific gravity to ≤ 1.010 prior to administration and maintain urine output at greater than 3 mL/kg/hour

• Mesna (Mesnex) 60 mg/kg IV on Days 1, 2, of which the total daily Mesna (Mesnex) dose is administered in 5 equally divided doses of 12 mg/kg:
  • Dose 1: Initial bolus dose of mesna may be administered before or at the same time as the Cyclophosphamide (Cytoxan)
  • Dose 2: A 3-hour infusion of Mesna (Mesnex) immediately following the Cyclophosphamide (Cytoxan) infusion (Hours 2 - 5)
  • Dose 3-5: 3 subsequent Mesna (Mesnex) bolus doses are given at hours 6, 9, 12, or by institutional protocol
  • Mesna (Mesnex) may also be given as a 24-hour continuous infusion starting 30 minutes before cyclophosphamide and finishing no sooner than 12 hours after the end of the cyclophosphamide infusion, or by institutional protocol

• Cisplatin (Platinol) 3.5 mg/kg IV infusion over 6 hours on Day 3
  • Cisplatin (Platinol) doses may require the use of mannitol to augment hydration and diuresis
  • Must reduce urine specific gravity to ≤1.010 prior to starting of [[Cisplatin (Platinol)]

21 Day Course

Consolidation

Chemotherapy

3 Cycles

• Carboplatin (Paraplatin) 17 mg/kg IV over 2 hours given daily on Days 1 & 2
  • If corrected GFR is < 100 ml/min/1.73m², the Carboplatin (Paraplatin) dose should be calculated using the modified Calvert formula

• Thiotepa (Thioplex) 10 mg/kg IV over 2 hours once daily on Days 1 & 2 immediately following Carboplatin (Paraplatin) administration
  • Skincare, frequent bathing, and linen changes during Thiotepa (Thioplex) administration are important and required to avoid chemical skin burns

• Filgrastim (Neupogen) 5 μg/kg SubQ or IV (per institutional policy) once daily starting on Day 5 (24 hours after infusion of PBSC) and continue until ANC > 2000/μL
  • If Filgrastim (Neupogen) is given IV, it should be administered by IV bolus over 15 to 30 minutes or by continuous infusion

28-Day Course

References

1. COG ACNS0334: P.D. Aridgides, G. Kang, C. Mazewski, T.E. Merchant. Outcomes after Radiation Therapy for Very Young Children with High-Risk Medulloblastoma or Supratentorial Primitive Neuroectodermal Tumor Treated on COG ACNS0334. Radiation Oncology 105, no. 1 (September 1, 2019)link to original article NCT00336024

COG ACNS0334 Regimen B

Induction

Chemotherapy

3 Cycles

• Vincristine (Oncovin) 0.05 mg/kg (maximum single dose of 2 mg) IV push over 1 minute or IV infusion (per institution) once on day 1, 8, 15
• High Dose Methotrexate (MTX) 400 mg/kg (20 gram maximum) IV over 4 hours on day 1
• Folinic acid (Leucovorin) 10 mg/m² PO or IV every 6 hours until serum Methotrexate (MTX) levels are less than 0.1 micromolar
  • Folinic acid (Leucovorin) must be started 24 hours from the beginning of the Methotrexate (MTX) infusion
• Etoposide (Vepesid) 2.5 mg/kg (maximum concentration of Etoposide (Vepesid) is 0.4 mg/ml) IV over 1 hour once daily on days A, B, C
  • Day A of chemotherapy begins when the serum Methotrexate (MTX) level is less than 0.1 micromolar
  • Begin Etoposide (Vepesid) infusion 1 hour before the Cyclophosphamide or CIS platin infusions
• Cyclophosphamide (Cytoxan) 60 mg/kg IV once per day over 1 hour on days A, B
  • Day A of chemotherapy begins when the serum Methotrexate (MTX) level is less than 0.1 micromolar
  • Must reduce urine specific gravity to ≤ 1.010 prior to administration and maintain urine output at greater than 3 mL/kg/hour
• Mesna (Mesnex) 12 mg/kg IV on days A, B as described below:
  • Dose 1:Initial bolus dose of Mesna (Mesnex) may be administered before or at the same time as the Cyclophosphamide (Cytoxan)
  • Dose 2:A 3 hour infusion of Mesna (Mesnex) immediately following the Cyclophosphamide (Cytoxan) infusion
  • Dose 3 to 5: 3 Subsequent Mesna (Mesnex) bolus doses given at hours 6, 9, 12 or by institutional protocol
  • Mesna (Mesnex) 60 mg/kg/day may also be given as a 24 hour continuous infusion by institutional protocol
  • Day A of chemotherapy begins when the serum Methotrexate (MTX) level is less than 0.1 micromolar
• Cisplatin (Platinol) 3.5 mg/kg IV infusion over 6 hours on day C
  • Day A of chemotherapy begins when the serum Methotrexate (MTX) level is less than 0.1 micromolar
  • Cisplatin (Platinol) doses may require use of mannitol to augment hydration and diuresis
  • Must reduce urine specific gravity to ≤ 1.010 prior to administration and maintain urine output at greater than 3 mL/kg/hour

21 Day Course

Consolidation

Chemotherapy

3 Cycles

• Carboplatin (Paraplatin) 17 mg/kg IV over 2 hours given daily on Days 1 & 2
  • If corrected GFR is < 100 ml/min/1.73m², the Carboplatin (Paraplatin) dose should be calculated using the modified Calvert formula

• Thiotepa (Thioplex) 10 mg/kg IV over 2 hours once daily on Days 1 & 2 immediately following Carboplatin (Paraplatin) administration
  • Skincare, frequent bathing, and linen changes during Thiotepa (Thioplex) administration are important and required to avoid chemical skin burns

• Filgrastim (Neupogen) 5 μg/kg SubQ or IV (per institutional policy) once daily starting on Day 5 (24 hours after infusion of PBSC) and continue until ANC > 2000/μL
  • If Filgrastim (Neupogen) is given IV, it should be administered by IV bolus over 15 to 30 minutes or by continuous infusion

28-Day Cycle

References

1. COG ACNS0334: P.D. Aridgides, G. Kang, C. Mazewski, T.E. Merchant. Outcomes after Radiation Therapy for Very Young Children with High-Risk Medulloblastoma or Supratentorial Primitive Neuroectodermal Tumor Treated on COG ACNS0334. Radiation Oncology 105, no. 1 (September 1, 2019)link to original article NCT00336024