Medulloblastoma

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Nikki M. Wood, DO
University of Missouri
Kansas City, MO

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Guidelines

EANO/EURACAN

Upfront Therapy Older Children

COG ACNS0331 Protocol for Standard Dose CSRT with Reduced Volume Boost to Tumor Bed

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

Protocol

Note: this protocol is given in two parts, induction and maintenance. The induction portion lasts 7 weeks, and the maintenance portion lasts for 54 weeks, consisting of alternating A cycles and B cycles (AAB-AAB-AAB).

Radiotherapy, induction portion

Chemotherapy, induction portion

  • 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, followed by:

Chemotherapy, maintenance part A

  • Cisplatin (Platinol) as follows:
    • Cycles 1, 2, 4, 5, 7, 8: 75 mg/m2 IV once on day 1
  • Lomustine (CCNU) as follows:
    • Cycles 1, 2, 4, 5, 7, 8: 75 mg/m2 PO once on day 1 on an empty stomach (at least 2 hours after food) preferably at bedtime (reduce N/V)
  • Vincristine (Oncovin) as follows:
    • Cycles 1, 2, 4, 5, 7, 8: 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, maintenance part B

  • Cyclophosphamide (Cytoxan) as follows:
    • Cycles 3, 6, 9: 1000 mg/m2 IV given over 1 hour on Days 1, 2
  • Vincristine (Oncovin) as follows:
    • Cycles 3, 6, 9: 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, maintenance part B

42-day cycle for 9 cycles; this is given in an AAB-AAB-AAB sequence

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 Protocol for Standard Dose CSRT with Standard Volume Boost

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

Protocol

Radiotherapy, induction portion

Chemotherapy, induction portion

  • 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, followed by:

Chemotherapy, maintenance part A (Cycles 1, 2, 4, 5, 7, 8)

  • 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)
  • 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

Chemotherapy, maintenance part B (Cycles 3, 6, 9)

  • Cyclophosphamide (Cytoxan) 1000 mg/m2 IV given over 1 hour 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, maintenance part B (Cycles 3, 6, 9)

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 Protocol A

Protocol

Radiotherapy, induction

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, induction

  • 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, followed by:

Chemotherapy, maintenance

  • 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 per day on days 1, 8
    • Round vincristine down to the nearest 0.1 mg
  • Cyclophosphamide (Cytoxan) 1000 mg/m2 IV over 60 minutes once on days 2, 3, given at least 24 hours after cisplatin on day 2

28-day cycle for 6 cycles; 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

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 Protocol B

Protocol

Radiotherapy, induction

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, induction

  • 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, given 1 to 4 hours prior to radiation therapy (Total of 30 doses)
    • First dose administered on the first day of radiation therapy
    • Should be HELD if radiation treatment is not given
    • Since there are 31 fractions of radiation, No carboplatin should be given prior to the final radiation fraction

6-week course, followed by:

Chemotherapy, maintenance

  • 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 per day on days 1 & 8
    • Round vincristine down to the nearest 0.1 mg
  • Cyclophosphamide (Cytoxan) 1000 mg/m2 IV over 60 minutes once per day on days 2 & 3, given at least 24 hours after cisplatin on day 2

28-day cycle for 6 cycles; 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

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

Upfront Therapy Younger Children

COG ACNS0334 Protocol A

Induction, 21-Day Cycle for 3 Cycles

Chemotherapy,

Supportive therapy,

  • 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
  • Filgrastim (Neupogen) 5 μg/kg SubQ or IV (per institutional policy) once daily starting 24-36 hours after Cisplatin infusion and continue until ANC > 1000/μL then increase to 10 μg/kg and plan for harvest 2 days later. If PBSC harvest after the first cycle is insufficient, then harvests may occur after the second (and third if required) cycle. If PBSC harvest is not planned, continue until ANC > 2000/μL.

21-day cycle for 3 cycles

Consolidation, 28-day cycle for 3 cycles

Chemotherapy, Autologous Transplant

Supportive therapy, Autologous Transplant

  • Filgrastim (Neupogen) 5 μg/kg SC or IV (per institutional policy) once per day, 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 for 3 cycles

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 Protocol B

Induction

Chemotherapy, induction

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
  • 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
  • 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

Supportive therapy, induction

  • Folinic acid (Leucovorin) 10 mg/m2 PO or IV every 6 hours until serum Methotrexate (MTX) levels are less than 0.1 micromolar
  • Mesna (Mesnex) 12 mg/kg IV on days A, B as described below:
  • Filgrastim (Neupogen) 5 μg/kg SubQ or IV (per institutional policy) once daily starting on day D (24-36 hours after Cisplatin infusion) and continue until ANC > 1000/μL then increase to 10 μg/kg and plan for harvest 2 days later. If PBSC harvest after the first cycle is insufficient, then harvests may occur after the second (and third if required) cycle. If PBSC harvest is not planned, continue until ANC > 2000/μL.

21-day course, followed by:

Consolidation

Chemotherapy, Autologous Transplan

3 Cycles

Supportive therapy, Autologous Transplant

  • 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

Head Start III Protocol D2

Protocol

Chemotherapy, induction cycles 1 & 3

Supportive therapy, induction cycles 1 & 3

15-day cycle

Chemotherapy, induction cycles 2 & 4

15-day cycles

Chemotherapy, induction cycle 5

Supportive therapy, induction cycle 5

15-day course; patients with no evidence of disease (NED) after induction or second look surgery proceed to:

Chemotherapy, myeloablative with autologous stem cell rescue

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-Oncology 2020 Apr 18: 22(12);1862-1872 link to original article link to PubMed link to PMC article NCT00392327

SJMB 96 Protocol High Risk

Protocol

Chemotherapy

2 Cycles

Supportive therapy

14-day Cycle

Radiotherapy

  • Craniospinal axis External beam radiotherapy by the following staging:
    • M0 - M1: 36 Gy in 18 daily fractions
    • M2 - M3: 36 to 39.6 Gy in 18 to 22 daily fractions
      • See protocol for additional details on dose

~ 6 week duration

Chemotherapy, High Dose with PBSC support

4 Cycles

Supportive therapy

  • Mesna (Mesnex) 500 mg/m2 IV push 15 minutes prior to Cyclophosphamide (Cytoxan) infusion on days -3, -2
  • Mesna (Mesnex) 1500 mg/m2 IV continuous infusion on days -3, -2
  • PBSC Infusion on day 0
  • Filgrastim (Neupogen) 5 μg/kg SubQ or IV (per institutional policy) once daily beginning on day 1 (24-36 hours after PBSC reinfusion) and continue for at least 7 days or continue until ANC > 2000/μL for 2 consecutive days.

28-day cycles

References

  1. SJMB96: Gajjar A, Chintagumpala M, Ashley D, Kellie S, Kun LE, Merchant TE, Woo S, Wheeler G, Ahern V, Krasin MJ, Fouladi M, Broniscer A, Krance R, Hale GA, Stewart CF, Dauser R, Sanford RA, Fuller C, Lau C, Boyett JM, Wallace D, Gilbertson RJ. Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial. Lancet Oncol. 2006 Oct;7(10):813-820 link to original article PubMed NCT00003211
    1. Update: Laughton SJ, Merchant TE, Sklar CA, Kun LE, Fouladi M, Broniscer A, Morris EB, Sanders RP, Krasin MJ, Shelso J, Xiong Z, Wallace D, Gajjar A. Endocrine outcomes for children with embryonal brain tumors after risk-adapted craniospinal and conformal primary-site irradiation and high-dose chemotherapy with stem-cell rescue on the SJMB-96 trial. J Clin Oncol. 2008 Mar;26(7):1112-1118 link to original article PubMed NCT00003211

SJMB 96 Protocol Average Risk

Protocol

Growth factor therapy

Radiotherapy

~ 6 week duration

Chemotherapy, High Dose with PBSC support

4 Cycles

Supportive medications

  • Mesna (Mesnex) 500 mg/m2 IV push 15 minutes prior to Cyclophosphamide (Cytoxan) infusion on days -3, -2
  • Mesna (Mesnex) 1500 mg/m2 IV continuous infusion on days -3, -2
  • PBSC Infusion on day 0
  • Filgrastim (Neupogen) 5 μg/kg SubQ or IV (per institutional policy) once daily beginning on day 1 (24-36 hours after PBSC reinfusion) and continue for at least 7 days or continue until ANC > 2000/μL for 2 consecutive days.

28-day cycles

References

  1. SJMB96: Gajjar A, Chintagumpala M, Ashley D, Kellie S, Kun LE, Merchant TE, Woo S, Wheeler G, Ahern V, Krasin MJ, Fouladi M, Broniscer A, Krance R, Hale GA, Stewart CF, Dauser R, Sanford RA, Fuller C, Lau C, Boyett JM, Wallace D, Gilbertson RJ. Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial. Lancet Oncol. 2006 Oct;7(10):813-820 link to original article PubMed NCT00003211
    1. Update: Laughton SJ, Merchant TE, Sklar CA, Kun LE, Fouladi M, Broniscer A, Morris EB, Sanders RP, Krasin MJ, Shelso J, Xiong Z, Wallace D, Gajjar A. Endocrine outcomes for children with embryonal brain tumors after risk-adapted craniospinal and conformal primary-site irradiation and high-dose chemotherapy with stem-cell rescue on the SJMB-96 trial. J Clin Oncol. 2008 Mar;26(7):1112-1118 link to original article PubMed NCT00003211