Neuroblastoma

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

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Neuroblastoma
11 regimens on this page
11 variants on this page
ICD-O-3 code: 123.456

Neuroblastoma is a rare cancer but is the most common malignancy of infancy.


High Risk

COG ANBL0931

Patients were only eligible if they had previously completed therapy including intensive induction chemotherapy followed by ASCT and radiotherapy

Post-Consolidation, Study Therapy

Immunotherapy, Course 1

  • Sargramostim (Leukine) 250 μg/m2 SubQ (strongly recommended) or IV over 2 hours once daily on days 0 through 13
    • Hold Sargramostim (Leukine) if the total white cell count is > 50,000/µL and resume once the total white cell count is < 20,000/µL and then resume at 50% dose for the remainder of that course

Chemotherapy, Course 1

  • Isotretinoin (Accutane) by the following weight-based criteria:
    • > 12 kg: 80 mg/m2 (rounded up to nearest 10 mg) PO BID on days 11 through 24
    • ≤ 12 kg: 2.67 mg/kg (rounded up to nearest 10 mg) PO BID on days 11 through 24

25 Day Course

Immunotherapy, Course 2 and 4

Chemotherapy, Course 2 and 4

  • Dinutuximab (Unituxin) 25 mg/m2 IV over 10 to 20 hours once daily on days 7 through 10
    • Max Infusion Time = 20 hours even if the total dose has not been administered
  • Isotretinoin (Accutane) by the following weight-based criteria:
    • > 12 kg: 80 mg/m2 (rounded up to nearest 10 mg) PO BID on days 14 through 27
    • ≤ 12 kg: 2.67 mg/kg (rounded up to nearest 10 mg) PO BID on days 14 through 27

32 Day Course

Immunotherapy, Courses 3 and 5

  • Sargramostim (Leukine) 250 μg/m2 SubQ (strongly recommended) or IV over 2 hours once daily on days 0 through 13
    • Hold Sargramostim (Leukine) if the total white cell count is > 50,000/µL and resume once the total white cell count is < 20,000/µL and then resume at 50% dose for the remainder of that course

Chemotherapy, Courses 3 and 5

  • Isotretinoin (Accutane) by the following weight-based criteria:
    • > 12 kg: 80 mg/m2 (rounded up to nearest 10 mg) PO BID on days 10 through 23
    • ≤ 12 kg: 2.67 mg/kg (rounded up to nearest 10 mg) PO BID on days 10 through 23

24 Day Cycle

Chemotherapy, Course 6

  • Isotretinoin (Accutane) by the following weight-based criteria:
    • > 12 kg: 80 mg/m2 (rounded up to nearest 10 mg) PO BID on days 14 through 27
    • ≤ 12 kg: 2.67 mg/kg (rounded up to nearest 10 mg) PO BID on days 14 through 27

28 Day Cycle

References

  1. COG ANBL0931: Ozkaynak MF, Gilman AL, London WB, Naranjo A, Diccianni MB, Tenney SC, Smith M, Messer KS, Seeger R, Reynolds CP, Smith LM, Shulkin BL, Parisi M, Maris JM, Park JR, Sondel PM, Yu AL; A Comprehensive Safety Trial of Chimeric Antibody 14.18 With GM-CSF, IL-2, and Isotretinoin in High-Risk Neuroblastoma Patients Following Myeloablative Therapy: Children's Oncology Group Study ANBL0931. Front Immunol. 2018 Jun 18;9:1355 link to original article link to PubMed link to PMC article NCT01041638

COG ANBL0532 Regimen B

Induction,

Chemotherapy, Cycle 1 (CPM + TOPO)

  • Cyclophosphamide (Cytoxan) by the following weight-based criteria:
    • ≤ 12 kg: 13.3 mg/kg iV over 30 to 60 minutes once daily on days 1 through 5
    • > 12 kg: 400 mg/m2 IV over 30 to 60 minutes once daily on days 1 through 5

21 Day Cycle

Chemotherapy, Cycle 2 (CPM + TOPO)

  • Cyclophosphamide (Cytoxan) by the following weight-based criteria:
    • ≤ 12 kg: 13.3 mg/kg iV over 30 to 60 minutes once daily on days 1 through 5
    • > 12 kg: 400 mg/m2 IV over 30 to 60 minutes once daily on days 1 through 5

21 Day Cycle

Supportive Therapy, Cycle 2

  • Filgrastim (Neupogen) 5 μg/kg SubQ or IV once daily on Day 6 beginning 24 hours after completion of chemotherapy and continuing until ANC > 1000/μL
  • Filgrastim (Neupogen) 10 μg/kg SubQ or IV once daily beginning once ANC > 1000/μL and continuing until PBSC harvest is complete
  • PBSC harvest on day 14

21 Day Cycle

Chemotherapy, Cycle 3 (CDDP + ETOP)

  • Cisplatin (Platinol) by the following weight-based criteria:
    • ≤ 12 kg: 1.66 mg/kg IV over 1 hour once daily on days 1 through 4
    • > 12 kg: 50 mg/m2 IV over 1 hour once daily on days 1 through 4
  • Etoposide (Vepesid) by the following weight-based criteria:
    • ≤ 12 kg: 6.67 mg/kg IV over 1 hour once daily on days 1 through 3
    • > 12 kg: 200 mg/m2 IV over 1 hour once daily on days 1 through 3

Chemotherapy, Cycle 4 (CPM + DOXO + VCR)

  • Cyclophosphamide (Cytoxan) by the following weight-based criteria:
    • ≤ 12 kg: 70 mg/kg iV over 6 hours once daily on days 1 through 2
    • > 12 kg: 2100 mg/m2 IV over 6 hours once daily on days 1 through 2
  • Vincristine (Oncovin) by the following criteria:
    • < 12 months: 0.017 mg/kg (Max Dose of 2 mg in 72 hours) IV over 1 minute or infusion (per institutional policy) once daily before Doxorubicin (Adriamycin) on days 1 through 3
    • ≥ 12 months and > 12 kg: 0.097 mg/m2 or 0.022 mg/kg (choose lower dose) (Max Dose of 2 mg in 72 hours) IV over 1 minute or infusion (per institutional policy) once daily before Doxorubicin (Adriamycin) on days 1 through 3
    • ≥ 12 months and ≤ 12 kg: 0.022 mg/kg (Max Dose of 2 mg in 72 hours) IV over 1 minute or infusion (per institutional policy) once daily before Doxorubicin (Adriamycin) on days 1 through 3
  • Doxorubicin (Adriamycin) by the following weight-based criteria:
    • ≤ 12 kg: 0.83 mg/kg iV over 24 hours once daily on days 1 through 3
    • > 12 kg: 25 mg/m2 IV over 24 hours once daily on days 1 through 3

21 Day Cycle

Supportive Therapy, Cycle 4 (CPM + DOXO + VCR)

21 Day Cycle

Chemotherapy, Cycle 5 (CDDP + ETOP)

  • Cisplatin (Platinol) by the following weight-based criteria:
    • ≤ 12 kg: 1.66 mg/kg IV over 1 hour once daily on days 1 through 4
    • > 12 kg: 50 mg/m2 IV over 1 hour once daily on days 1 through 4
  • Etoposide (Vepesid) by the following weight-based criteria:
    • ≤ 12 kg: 6.67 mg/kg IV over 1 hour once daily on days 1 through 3
    • > 12 kg: 200 mg/m2 IV over 1 hour once daily on days 1 through 3

21 Day Cycle

Chemotherapy, Cycle 6 (CPM + DOXO + VCR)

  • Cyclophosphamide (Cytoxan) by the following weight-based criteria:
    • ≤ 12 kg: 70 mg/kg iV over 6 hours once daily on days 1 through 2
    • > 12 kg: 2100 mg/m2 IV over 6 hours once daily on days 1 through 2
  • Vincristine (Oncovin) by the following criteria:
    • < 12 months: 0.017 mg/kg (Max Dose of 2 mg in 72 hours) IV over 1 minute or infusion (per institutional policy) once daily before Doxorubicin (Adriamycin) on days 1 through 3
    • ≥ 12 months and > 12 kg: 0.097 mg/m2 or 0.022 mg/kg (choose lower dose) (Max Dose of 2 mg in 72 hours) IV over 1 minute or infusion (per institutional policy) once daily before Doxorubicin (Adriamycin) on days 1 through 3
    • ≥ 12 months and ≤ 12 kg: 0.022 mg/kg (Max Dose of 2 mg in 72 hours) IV over 1 minute or infusion (per institutional policy) once daily before Doxorubicin (Adriamycin) on days 1 through 3
  • Doxorubicin (Adriamycin) by the following weight-based criteria:
    • ≤ 12 kg: 0.83 mg/kg iV over 24 hours once daily on days 1 through 3
    • > 12 kg: 25 mg/m2 IV over 24 hours once daily on days 1 through 3

21 Day Cycle

Supportive Therapy, Cycle 6 (CPM + DOXO + VCR)

21 Day Cycle

Consolidation,

Chemotherapy, Tandem HSCT #1 (Thiotepa and Cyclophosphamide)

  • Thiotepa (Thioplex) by the following weight-based criteria:
    • ≤ 12 kg: 10 mg/kg IV over 2 hours once daily on days -7, -6, -5
    • > 12 kg: 300 mg/m2 IV over 2 hours once daily on days -7, -6, -5
  • Cyclophosphamide (Cytoxan) by the following weight-based criteria:
    • ≤ 12 kg: 50mg/kg IV over 1 hour once daily on days -5, -4, -3, -2
    • > 12 kg: 1500 mg/m2 IV over 1 hour once daily on days -5, -4, -3, -2
  • PBSC on day 0

50 Day Cycle

Supportive therapy, Tandem HSCT #1 (Thiotepa and Cyclophosphamide)

  • Filgrastim (Neupogen) 5 μg/kg SubQ or IV once daily starting on day 0 and continuing until post-nadir ANC > 2000/μL for 3 consecutive days

50 Day Cycle

Chemotherapy, Tandem HSCT #2 (CEM)

  • Melphalan (Alkeran) by the following criteria:
    • ≤ 12 kg and GFR ≥ 100 mL/min: 2 mg/kg IV over 15 to 30 minutes once daily on days -7, -6, -5
    • > 12 kg and GFR ≥ 100 mL/min: 60 mg/m2 IV over 15 to 30 minutes once daily on days -7, -6, -5
    • ≤ 12 kg and GFR between 100 mL/min and 60 mL/min: 2 mg/kg IV over 15 to 30 minutes once daily on days -7, -6, -5
    • > 12 kg and GFR between 100 mL/min and 60 mL/min: 60 mg/m2 IV over 15 to 30 minutes once daily on days -7, -6, -5
  • Etoposide (Vepesid) by the following criteria:
    • ≤ 12 kg and GFR ≥ 100 mL/min: 12 mg/kg IV over 24 hours once daily on days -7, -6, -5, -4
    • > 12 kg and GFR ≥ 100 mL/min: 300 mg/m2 IV over 24 hours once daily on days -7, -6, -5, -4
    • ≤ 12 kg and GFR between 100 mL/min and 60 mL/min: 6.7 mg/kg IV over 24 hours once daily on days -7, -6, -5, -4
    • > 12 kg and GFR between 100 mL/min and 60 mL/min: 200 mg/m2 IV over 24 hours once daily on days -7, -6, -5, -4
  • Carboplatin (Paraplatin) by the following criteria:
    • ≤ 12 kg and GFR ≥ 100 mL/min: 12 mg/kg IV over 24 hours once daily on days -7, -6, -5, -4
    • > 12 kg and GFR ≥ 100 mL/min: 375 mg/m2 IV over 24 hours once daily on days -7, -6, -5, -4
    • ≤ 12 kg and GFR between 100 mL/min and 60 mL/min: 4.1 AUC using Calvert Formula (Max Dose = 300 mg/m2) IV over 24 hours once daily on days -7, -6, -5, -4
    • > 12 kg and GFR between 100 mL/min and 60 mL/min: Use the lowest of either 4.1 AUC using Calvert Formula or 10 mg/kg IV over 24 hours once daily on days -7, -6, -5, -4
  • PBSC on day 0

36 Day Cycle

Supportive Therapy, Tandem HSCT #2 (CEM)

  • Filgrastim (Neupogen) 5 μg/kg SubQ or IV once daily starting on day 0 and continuing until post-nadir ANC > 2000/μL for 3 consecutive days

36 Day Cycle

Maintenance, 6 Cycles

Chemotherapy,

  • Isotretinoin (Accutane) by the following weight-based criteria:
    • ≤ 12 kg: 5.33 mg/kg (Round dose to nearest 10 mg) PO twice daily on days 1 through 14
    • > 12 kg: 160 mg/m2 (Round dose to nearest 10 mg) PO twice daily on days 1 through 14

28 Day Cycle

References

  1. COG ANBL0532:Seif AE, Naranjo A, Baker DL, Bunin NJ, Kletzel M, Kretschmar CS, Maris JM, McGrady PW, von Allmen D, Cohn SL, London WB, Park JR, Diller LR, Grupp SA. A pilot study of tandem high-dose chemotherapy with stem cell rescue as consolidation for high-risk neuroblastoma: Children's Oncology Group study ANBL00P1. Bone Marrow Transplant. 2013 Jul;48(7):947-52. link to original article link to PMC article PubMed

COG ANBL 0032 Regimen B

Post Consolidation, Study Phase

Immunotherapy, Course 1

  • Sargramostim (Leukine) 250 μg/m2 SubQ (strongly recommended) or IV over 2 hours once daily on days 0 through 13
    • Hold Sargramostim (Leukine) if the total white cell count is > 50,000/µL and resume once the total white cell count is < 20,000/µL and then resume at 50% dose for the remainder of that course

Chemotherapy, Course 1

  • Dinutuximab (Unituxin) 25 mg/m2 IV over 10 to 20 hours on days 3 through 6
    • Begin Dinutuximab (Unituxin) at a rate of 0.88 mg/m2/hr x 0.5 hrs, then increase to 1.75 mg/m2 12 kg: 80 mg/m2 (Round to nearest 10 mg) PO BID on days 11 through 24
    • ≤ 12 kg: 2.67 mg/kg (Round to nearest 10 mg) PO BID on days 11 through 24

25-Day Cycle

Immunotherapy, Course 2 and 4

Chemotherapy, Course 2 and 4

  • Dinutuximab (Unituxin) 25 mg/m2 IV over 10 to 20 hours on days 3 through 6
    • Begin Dinutuximab (Unituxin) at a rate of 0.88 mg/m2/hr x 0.5 hrs, then increase to 1.75 mg/m2 12 kg: 80 mg/m2 (Round to nearest 10 mg) PO BID on days 11 through 24
    • ≤ 12 kg: 2.67 mg/kg (Round to nearest 10 mg) PO BID on days 11 through 24

32 Day Cycle

Immunotherapy, Courses 3 and 5

  • Sargramostim (Leukine) 250 μg/m2 SubQ (strongly recommended) or IV over 2 hours once daily on days 0 through 13
    • Hold Sargramostim (Leukine) if the total white cell count is > 50,000/µL and resume once the total white cell count is < 20,000/µL and then resume at 50% dose for the remainder of that course

Chemotherapy, Courses 3 and 5

  • Isotretinoin (Accutane) by the following weight based criteria:
    • > 12 kg: 80 mg/m2 (Round to nearest 10 mg) PO BID on days 11 through 24
    • ≤ 12 kg: 2.67 mg/kg (Round to nearest 10 mg) PO BID on days 11 through 24

24 Day Cycle

Chemotherapy, Course 6

  • Isotretinoin (Accutane) by the following weight based criteria:
    • > 12 kg: 80 mg/m2 (Round to nearest 10 mg) PO BID on days 11 through 24
    • ≤ 12 kg: 2.67 mg/kg (Round to nearest 10 mg) PO BID on days 11 through 24

28 Day Cycle

References

  1. COG ANBL0032:Yu AL, Gilman AL, Ozkaynak MF, London WB, Kreissman SG, Chen HX, SMith M, Anderson B, Villablanca JG, Matthay KK, Shimada H, Grupp SA, Seeger R, Reynolds CP, Buxton A, Reisfeld R, Gillies SD, Cohn SL, Maris JM, Sondel PM. Anti-GD2 Antibody with GM-CSF, IL2, and Isotretinoin for Neuroblastoma. N Engl J Med. 2010 Sep;363(14):1324-34. link to original article link to PMC article PubMed

COG ANBL17P1

Induction

Chemotherapy, Cycle 1 (TOPO/CPM)

  • Cyclophosphamide (Cytoxan) by the following BSA-based criteria:
    • 0.25 to 0.29 m2: 68 mg IV over 15 to 30 minutes once daily on days 1 through 5
    • 0.3 to 0.34 m2: 100 mg IV over 15 to 30 minutes once daily on days 1 through 5
    • 0.35 to 0.39 m2: 124 mg IV over 15 to 30 minutes once daily on days 1 through 5
    • 0.4 to 0.44 m2: 148 mg IV over 15 to 30 minutes once daily on days 1 through 5
    • 0.45 to 0.49 m2: 180 mg IV over 15 to 30 minutes once daily on days 1 through 5
    • 0.5 to 0.54 m2: 200 mg IV over 15 to 30 minutes once daily on days 1 through 5
    • 0.55 to 0.59 m2: 220 mg IV over 15 to 30 minutes once daily on days 1 through 5
    • ≥ 0.6 m2: 400 mg/m2 IV over 15 to 30 minutes once daily on days 1 through 5
  • Topotecan (Hycamtin) by the following BSA-based criteria:
    • 0.25 to 0.29 m2: 0.32 mg IV over 30 minutes once daily on days 1 through 5
    • 0.3 to 0.34 m2: 0.38 mg IV over 30 minutes once daily on days 1 through 5
    • 0.35 to 0.39 m2: 0.44 mg IV over 30 minutes once daily on days 1 through 5
    • 0.4 to 0.44 m2: 0.5 mg IV over 30 minutes once daily on days 1 through 5
    • 0.45 to 0.49 m2: 0.56 mg IV over 30 minutes once daily on days 1 through 5
    • 0.5 to 0.54 m2: 0.62 mg IV over 30 minutes once daily on days 1 through 5
    • 0.55 to 0.59 m2: 0.68 mg IV over 30 minutes once daily on days 1 through 5
    • ≥ 0.6 m2: 1.2 mg/m2 IV over 30 minutes once daily on days 1 through 5

21-Day Cycle

Supportive Therapy, Cycle 1 (TOPO/CPM)

  • Filgrastim (Neupogen) 5 μg/kg SubQ or IV once daily on Day 6 beginning 24 to 48 hours after completion of chemotherapy and continuing until ANC > 2000/μL

21-Day Cycle

Chemotherapy, Cycle 2 (TOPO/CPM)

  • Cyclophosphamide (Cytoxan) by the following BSA-based criteria:
    • 0.25 to 0.29 m2: 68 mg IV over 15 to 30 minutes once daily on days 1 through 5
    • 0.3 to 0.34 m2: 100 mg IV over 15 to 30 minutes once daily on days 1 through 5
    • 0.35 to 0.39 m2: 124 mg IV over 15 to 30 minutes once daily on days 1 through 5
    • 0.4 to 0.44 m2: 148 mg IV over 15 to 30 minutes once daily on days 1 through 5
    • 0.45 to 0.49 m2: 180 mg IV over 15 to 30 minutes once daily on days 1 through 5
    • 0.5 to 0.54 m2: 200 mg IV over 15 to 30 minutes once daily on days 1 through 5
    • 0.55 to 0.59 m2: 220 mg IV over 15 to 30 minutes once daily on days 1 through 5
    • ≥ 0.6 m2: 400 mg/m2 IV over 15 to 30 minutes once daily on days 1 through 5
  • Topotecan (Hycamtin) by the following BSA-based criteria:
    • 0.25 to 0.29 m2: 0.32 mg IV over 30 minutes once daily on days 1 through 5
    • 0.3 to 0.34 m2: 0.38 mg IV over 30 minutes once daily on days 1 through 5
    • 0.35 to 0.39 m2: 0.44 mg IV over 30 minutes once daily on days 1 through 5
    • 0.4 to 0.44 m2: 0.5 mg IV over 30 minutes once daily on days 1 through 5
    • 0.45 to 0.49 m2: 0.56 mg IV over 30 minutes once daily on days 1 through 5
    • 0.5 to 0.54 m2: 0.62 mg IV over 30 minutes once daily on days 1 through 5
    • 0.55 to 0.59 m2: 0.68 mg IV over 30 minutes once daily on days 1 through 5
    • ≥ 0.6 m2: 1.2 mg/m2 IV over 30 minutes once daily on days 1 through 5
  • PBSC Harvest on Day 15 of Cycle 2

21-Day Cycle

Supportive Therapy, Cycle 2 (TOPO/CPM)

  • Filgrastim (Neupogen) 5 μg/kg SubQ or IV once daily on Day 6 beginning 24 to 48 hours after completion of chemotherapy and continuing until ANC > 2000/μL

21-Day Cycle

Chemotherapy, Cycle 3 (CDDP/ETOP/DIN)

  • Cisplatin (Platinol) by the following BSA-based criteria:
    • 0.25 to 0.29 m2: 10 mg IV over 1 hour once daily on days 1 through 3
    • 0.3 to 0.34 m2: 14 mg IV over 1 hour once daily on days 1 through 3
    • 0.35 to 0.39 m2: 18 mg IV over 1 hour once daily on days 1 through 3
    • 0.4 to 0.44 m2: 22 mg IV over 1 hour once daily on days 1 through 3
    • 0.45 to 0.49 m2: 26 mg IV over 1 hour once daily on days 1 through 3
    • 0.5 to 0.54 m2: 30 mg IV over 1 hour once daily on days 1 through 3
    • 0.55 to 0.59 m2: 34 mg IV over 1 hour once daily on days 1 through 3
    • ≥ 0.6 m2: 60 mg/m2 IV over 1 hour once daily on days 1 through 3
  • Etoposide (Vepesid) by the following BSA-based criteria:
    • 0.25 to 0.29 m2: 34 mg IV over 2 hours once daily on days 1 through 3
    • 0.3 to 0.34 m2: 48 mg IV over 2 hours once daily on days 1 through 3
    • 0.35 to 0.39 m2: 60 mg IV over 2 hours once daily on days 1 through 3
    • 0.4 to 0.44 m2: 72 mg IV over 2 hours once daily on days 1 through 3
    • 0.45 to 0.49 m2: 88 mg IV over 2 hours once daily on days 1 through 3
    • 0.5 to 0.54 m2: 100 mg IV over 2 hours once daily on days 1 through 3
    • 0.55 to 0.59 m2: 112 mg IV over 2 hours once daily on days 1 through 3
    • ≥ 0.6 m2: 200 mg/m2 IV over 2 hours once daily on days 1 through 3

21-Day Cycle

Immunotherapy, Cycle 3 (GM-CSF)

21-Day Cycle

Chemotherapy, Cycle 4 (VCR/DOXO/CPM/DIN)

  • Vincristine (Oncovin) by the following BSA-based criteria:
    • 0.25 to 0.29 m2: 0.32 mg IV push over 1 minute or IV infusion per institutional policy once on day 1
    • 0.3 to 0.34 m2: 0.46 mg IV push over 1 minute or IV infusion per institutional policy once on day 1
    • 0.35 to 0.39 m2: 0.6 mg IV push over 1 minute or IV infusion per institutional policy once on day 1
    • 0.4 to 0.44 m2: 0.72 mg IV push over 1 minute or IV infusion per institutional policy once on day 1
    • 0.45 to 0.49 m2: 0.88 mg IV push over 1 minute or IV infusion per institutional policy once on day 1
    • 0.5 to 0.54 m2: 1 mg IV push over 1 minute or IV infusion per institutional policy once on day 1
    • 0.55 to 0.59 m2: 1.1 mg IV push over 1 minute or IV infusion per institutional policy once on day 1
    • ≥ 0.6 m2: 2 mg/m2 (Max dose = 2 mg) IV push over 1 minute or IV infusion per institutional policy once on day 1
  • Doxorubicin (Adriamycin) by the following BSA-based criteria:
    • 0.25 to 0.29 m2: 6.6 mg IV over 5 to 15 minutes on days 1, 2
    • 0.3 to 0.34 m2: 9.2 mg IV over 5 to 15 minutes on days 1, 2
    • 0.35 to 0.39 m2: 12 mg IV over 5 to 15 minutes on days 1, 2
    • 0.4 to 0.44 m2: 14 mg IV over 5 to 15 minutes on days 1, 2
    • 0.45 to 0.49 m2: 16 mg IV over 5 to 15 minutes on days 1, 2
    • 0.5 to 0.54 m2: 18 mg IV over 5 to 15 minutes on days 1, 2
    • 0.55 to 0.59 m2: 20 mg IV over 5 to 15 minutes on days 1, 2
    • ≥ 0.6 m2: 37.5 mg/m2 IV over 5 to 15 minutes on days 1, 2
  • Cyclophosphamide (Cytoxan) by the following BSA-based criteria:
    • 0.25 to 0.29 m2: 360 mg IV over 1 hour on days 1, 2
    • 0.3 to 0.34 m2: 480 mg IV over 1 hour on days 1, 2
    • 0.35 to 0.39 m2: 600 mg IV over 1 hour on days 1, 2
    • 0.4 to 0.44 m2: 720 mg IV over 1 hour on days 1, 2
    • 0.45 to 0.49 m2: 880 mg IV over 1 hour on days 1, 2
    • 0.5 to 0.54 m2: 1000 mg IV over 1 hour on days 1, 2
    • 0.55 to 0.59 m2: 1100 mg IV over 1 hour on days 1, 2
    • ≥ 0.6 m2: 2000 mg/m2 IV over 1 hour on days 1, 2

21-Day Cycle

Immunotherapy, Cycle 4 (GM-CSF)

21-Day Cycle

Supportive Therapy, Cycle 4

  • Dexrazoxane (Zinecard) by the following BSA-based criteria:
    • 0.25 to 0.29 m2: 66 mg IV over 5 to 15 minutes on days 1, 2
    • 0.3 to 0.34 m2: 92 mg IV over 5 to 15 minutes on days 1, 2
    • 0.35 to 0.39 m2: 120 mg IV over 5 to 15 minutes on days 1, 2
    • 0.4 to 0.44 m2: 140 mg IV over 5 to 15 minutes on days 1, 2
    • 0.45 to 0.49 m2: 160 mg IV over 5 to 15 minutes on days 1, 2
    • 0.5 to 0.54 m2: 180 mg IV over 5 to 15 minutes on days 1, 2
    • 0.55 to 0.59 m2: 200 mg IV over 5 to 15 minutes on days 1, 2
    • ≥ 0.6 m2: 375 mg/m2 IV over 5 to 15 minutes on days 1, 2

21-Day Cycle

Chemotherapy, Cycle 5 (CDDP/ETOP/DIN)

  • Cisplatin (Platinol) by the following BSA-based criteria:
    • 0.25 to 0.29 m2: 10 mg IV over 1 hour once daily on days 1 through 3
    • 0.3 to 0.34 m2: 14 mg IV over 1 hour once daily on days 1 through 3
    • 0.35 to 0.39 m2: 18 mg IV over 1 hour once daily on days 1 through 3
    • 0.4 to 0.44 m2: 22 mg IV over 1 hour once daily on days 1 through 3
    • 0.45 to 0.49 m2: 26 mg IV over 1 hour once daily on days 1 through 3
    • 0.5 to 0.54 m2: 30 mg IV over 1 hour once daily on days 1 through 3
    • 0.55 to 0.59 m2: 34 mg IV over 1 hour once daily on days 1 through 3
    • ≥ 0.6 m2: 60 mg/m2 IV over 1 hour once daily on days 1 through 3
  • Etoposide (Vepesid) by the following BSA-based criteria:
    • 0.25 to 0.29 m2: 34 mg IV over 2 hours once daily on days 1 through 3
    • 0.3 to 0.34 m2: 48 mg IV over 2 hours once daily on days 1 through 3
    • 0.35 to 0.39 m2: 60 mg IV over 2 hours once daily on days 1 through 3
    • 0.4 to 0.44 m2: 72 mg IV over 2 hours once daily on days 1 through 3
    • 0.45 to 0.49 m2: 88 mg IV over 2 hours once daily on days 1 through 3
    • 0.5 to 0.54 m2: 100 mg IV over 2 hours once daily on days 1 through 3
    • 0.55 to 0.59 m2: 112 mg IV over 2 hours once daily on days 1 through 3
    • ≥ 0.6 m2: 200 mg/m2 IV over 2 hours once daily on days 1 through 3

21-Day Cycle

Immunotherapy, Cycle 5 (GM-CSF)

21-Day Cycle

Consolidation

Chemotherapy, Tandem HSCT #1 (Thiotepa and Cyclophosphamide)

  • Thiotepa (Thioplex) by the following weight-based criteria:
    • ≤ 12 kg: 10 mg/kg IV over 2 hours once daily on days -7, -6, -5
    • > 12 kg: 300 mg/m2 IV over 2 hours once daily on days -7, -6, -5
  • Cyclophosphamide (Cytoxan) by the following weight-based criteria:
    • ≤ 12 kg: 50 mg/kg IV over 1 hour once daily on days -5, -4, -3, -2
    • > 12 kg: 1500 mg/m2 IV over 1 hour once daily on days -5, -4, -3, -2
  • PBSC on day 0

50 Day Cycle

Supportive Therapy, Tandem HSCT #1 (Thiotepa and Cyclophosphamide)

  • Filgrastim (Neupogen) 5 μg/kg SubQ or IV once daily starting on day 0 and continuing until post-nadir ANC > 2000/μL for 3 consecutive days

50 Day Cycle

Chemotherapy, Tandem HSCT #2 (CEM)

  • Melphalan (Alkeran) by the following criteria:
    • ≤ 12 kg: 2 mg/kg IV over 30 minutes once daily on days -7, -6, -5
    • > 12 kg: 60 mg/m2 IV over 30 minutes once daily on days -7, -6, -5
  • Etoposide (Vepesid) by the following criteria:
    • ≤ 12 kg and GFR ≥ 100 mL/min: 10 mg/kg IV continuous infusion on days -7, -6, -5, -4
    • > 12 kg and GFR ≥ 100 mL/min: 300 mg/m2 IV continuous infusion on days -7, -6, -5, -4
    • ≤ 12 kg and GFR between 100 mL/min and 60 mL/min: 6.7 mg/kg IV continuous infusion on days -7, -6, -5, -4
    • > 12 kg and GFR between 100 mL/min and 60 mL/min: 200 mg/m2 IV continuous infusion on days -7, -6, -5, -4
BSA (m2) GFR ≤ 100 mL/min/1.73 m2 GFR 91-99 mL/min/1.73 m2 GFR 76-90 mL/min/1.73 m2 GFR 60-75 mL/min/1.73 m2
0.25 - 0.29 68 mg 54 mg 48 mg 40 mg
0.3 - 0.34 80 mg 64 mg 56 mg 48 mg
0.35 - 0.39 90 mg 72 mg 64 mg 54 mg
0.4 - 0.44 110 mg 90 mg 74 mg 66 mg
0.45 - 0.49 130 mg 100 mg 90 mg 80 mg
0.5 - 0.54 160 mg 130 mg 110 mg 100 mg
0.55 - 0.59 190 mg 150 mg 130 mg 120 mg
≥ 0.6 375 mg/m2 300 mg/m2 260 mg/m2 230 mg/m2
  • PBSC on day 0

50-Day Cycle

Supportive Therapy, Tandem HSCT #2 (CEM)

  • Filgrastim (Neupogen) 5 μg/kg SubQ or IV once daily starting on day 0 and continuing until post-nadir ANC > 2000/μL for 3 consecutive days

50-Day Cycle

Radiotherapy,

  • External beam radiotherapy by the following criteria no sooner than 42 days post-transplant:
    • Primary tumor site and initially involved lymph nodes (CTV/PTV): 21.6 Gy in 12 daily fractions
    • Metastatic disease present after Induction (mCTVx/mPTVx): 21.6 Gy in 12 daily fractions
    • Hepatomegaly leading to respiratory distress: 4.5 Gy delivered in 3 daily fractions

Post-Consolidation

Cycles 1 through 5 Cycle 6

Chemotherapy, Cycle 1 through 5

  • Isotretinoin (Accutane) by the following BSA-based criteria:
    • 0.25 - 0.29 m2: 10 mg PO BID on days 11 through 24
    • 0.3 - 0.39 m2: 20 mg PO BID on days 11 through 24
    • 0.4 - 0.49 m2: 30 mg PO BID on days 11 through 24
    • 0.5 - 0.59 m2: 40 mg PO BID on days 11 through 24
    • ≥ 0.6 m2: 80 mg/m2 (round to nearest 10 mg) PO BID on days 11 through 24

28-Day Cycle

Immunotherapy, Cycle 1 through 5

28-Day Cycles

Chemotherapy, Cycle 6

  • Isotretinoin (Accutane) by the following BSA-based criteria:
    • 0.25 - 0.29 m2: 10 mg PO BID on days 15 through 28
    • 0.3 - 0.39 m2: 20 mg PO BID on days 15 through 28
    • 0.4 - 0.49 m2: 30 mg PO BID on days 15 through 28
    • 0.5 - 0.59 m2: 40 mg PO BID on days 15 through 28
    • ≥ 0.6 m2: 80 mg/m2 (round to nearest 10 mg) PO BID on days 15 through 28

28-Day Cycle

References

  1. COG ANBL17P1:Furman WL, Federico SM, McCarville MB, Shulkin BL, Davidoff AM, Krasin MJ, Sahr N, Sykes A, Wu J, Brennan RC, Bishop MW, Helmig S, Stewart E, Navid F, Triplett B, Santana VM, Bahrami A, Anthony G, Yu AL, Hank J, Gillies SD, Sondel PM, Leung WH, Pappo AS. A Phase II Trial of Hu14.18K322A in Combination with Induction Chemotherapy in Children with Newly Diagnosed High-Risk Neuroblastoma. Clin Cancer Res. 2019 Nov 1;28(21):6320-28. link to original article link to PMC article PubMed
  2. COG ANBL17P1:Furman WL, McCarville B, Shulkin BL, Davidoff A, Krasin M, Hsu CW, Pan H, Wu J, Brennan R, Bishop MW, Helmig S, Stewart E, Navid F, Triplett B, Santana V, Santiago T, Hank JA, Gillies SD, Yu A, Sondel PM, Leung WH, Pappo A, Federico SM. Improved OUtcome in Children with Newly Diagnosed High-Risk Neuroblastoma Treated with Chemoimmunotherapy: Updated Results of a Phase II Study Using hu14.18K322A. J Clin Oncol. 2022 Feb 1;40(4):335-344. link to original article link to PMC article PubMed

Low-risk

Intermediate-risk, all lines of therapy

COG A3961 regimen

Regimen

Study Evidence
Baker et al. 2010 (COG A3961) Non-randomized

To be completed.

Chemotherapy

  • See paper for details

References

  1. COG A3961: Baker DL, Schmidt ML, Cohn SL, Maris JM, London WB, Buxton A, Stram D, Castleberry RP, Shimada H, Sandler A, Shamberger RC, Look AT, Reynolds CP, Seeger RC, Matthay KK; Children’s Oncology Group. Outcome after reduced chemotherapy for intermediate-risk neuroblastoma. N Engl J Med. 2010 Sep 30;363(14):1313-23. link to original article link to PMC article PubMed

High-risk, induction

COJEC

COJEC: Cisplatin, Oncovin (Vicristine), JM8 (Carboplatin), Etoposide, Cyclophosphamide

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Pearson et al. 2008 (ENSG5) 1990-1999 Phase 3 (E-esc) OPEC/OJEC Seems to have superior EFS36

Chemotherapy

References

  1. ENSG5: Pearson AD, Pinkerton CR, Lewis IJ, Imeson J, Ellershaw C, Machin D; European Neuroblastoma Study Group; Children's Cancer and Leukaemia Group (CCLG formerly United Kingdom Children's Cancer Study Group). High-dose rapid and standard induction chemotherapy for patients aged over 1 year with stage 4 neuroblastoma: a randomised trial. Lancet Oncol. 2008 Mar;9(3):247-56. link to original article PubMed NCT00365755
    1. Update: Moreno L, Vaidya SJ, Pinkerton CR, Lewis IJ, Imeson J, Machin D, Pearson AD; European Neuroblastoma Study Group; Children's Cancer and Leukaemia Group (CCLG) (formerly UKCCSG). Long-term follow-up of children with high-risk neuroblastoma: the ENSG5 trial experience. Pediatr Blood Cancer. 2013 Jul;60(7):1135-40. Epub 2012 Dec 31. link to original article PubMed

N5/N6

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Berthold et al. 2020 (NB2004-HR) 2004-2016 Phase 3 (C) N8, then N5/N6 Did not meet primary endpoint of EFS

Chemotherapy, N5 cycles

  • Vindesine (Eldisine) as follows:
    • Cycles 1, 3, 5: 3 mg/m2 IV over 60 minutes once on day 1
  • Cisplatin (Platinol) as follows:
    • Cycles 1, 3, 5: 40 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 160 mg/m2)
  • Etoposide (Vepesid) as follows:
    • Cycles 1, 3, 5: 100 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 400 mg/m2)

Chemotherapy, N6 cycles

  • Vincristine (Oncovin) as follows:
    • Cycles 2, 4, 6: 1.5 mg/m2 IV over 60 minutes once per day on days 1 & 8
  • Dacarbazine (DTIC) as follows:
    • Cycles 2, 4, 6: 200 mg/m2 IV over 60 minutes once per day on days 1 to 5
  • Ifosfamide (Ifex) as follows:
    • Cycles 2, 4, 6: 1500 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 7500 mg/m2)
  • Doxorubicin (Adriamycin) as follows:
    • Cycles 2, 4, 6: 30 mg/m2 IV over 4 hours once per day on days 6 & 7

21-day cycle for 6 cycles

References

  1. NB2004-HR: Berthold F, Faldum A, Ernst A, Boos J, Dilloo D, Eggert A, Fischer M, Frühwald M, Henze G, Klingebiel T, Kratz C, Kremens B, Krug B, Leuschner I, Schmidt M, Schmidt R, Schumacher-Kuckelkorn R, von Schweinitz D, Schilling FH, Theissen J, Volland R, Hero B, Simon T. Extended induction chemotherapy does not improve the outcome for high-risk neuroblastoma patients: results of the randomized open-label GPOH trial NB2004-HR. Ann Oncol. 2020 Mar;31(3):422-429. Epub 2020 Jan 24. link to original article contains dosing details in supplement PubMed NCT03042429

High-risk, consolidation

Busulfan & Melphalan, then auto HSCT

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Ladenstein et al. 2017 (HR-NBL1 part 1) 2002-2010 Phase 3 (E-esc) Carboplatin, Etoposide, Melphalan, then auto HSCT Superior EFS36

Note: the abstract does not specify exact days but this schedule is typical; IV dosing was used after a 2007 protocol amendment

Chemotherapy

Stem cells re-infused on day 0

References

  1. HR-NBL1 part 1: Ladenstein R, Pötschger U, Pearson ADJ, Brock P, Luksch R, Castel V, Yaniv I, Papadakis V, Laureys G, Malis J, Balwierz W, Ruud E, Kogner P, Schroeder H, de Lacerda AF, Beck-Popovic M, Bician P, Garami M, Trahair T, Canete A, Ambros PF, Holmes K, Gaze M, Schreier G, Garaventa A, Vassal G, Michon J, Valteau-Couanet D; SIOP Europe Neuroblastoma Group (SIOPEN). Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): an international, randomised, multi-arm, open-label, phase 3 trial. Lancet Oncol. 2017 Apr;18(4):500-514. Epub 2017 Mar 2. link to original article contains dosing details in abstract PubMed NCT01704716

GM-CSF, IL-2, Isotretinoin, Dinutuximab

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Yu et al. 2010 (COG ANBL0032) 2001-2009 Phase 3 (E-RT-esc) Isotretinoin Seems to have superior OS

Note: in distinction from most chemotherapy regimens, the first day of a cycle is day 0 and the last day of a 28-day cycle is day 27.

Targeted therapy

  • Dinutuximab (Unituxin) as follows:
    • Cycles 1, 3, 5: 25 mg/m2 IV once per day on days 3 to 6
    • Cycles 2 & 4: 25 mg/m2 IV once per day on days 7 to 10

Immunotherapy

  • Sargramostim (Leukine) as follows:
    • Cycles 1, 3, 5: 250 mcg/m2 SC once per day on days 0 to 13
  • Aldesleukin (Proleukin) as follows:
    • Cycles 2 & 4: 3,000,000 IU/m2/day IV continuous infusion over 96 hours, started on day 0, then 4,500,000 IU/m2/day IV continuous infusion over 96 hours, started on day 7 (total dose per cycle: 30,000,000 IU/m2)

Chemotherapy

28-day cycle for 6 cycles

References

  1. COG ANBL0032: Yu AL, Gilman AL, Ozkaynak MF, London WB, Kreissman SG, Chen HX, Smith M, Anderson B, Villablanca JG, Matthay KK, Shimada H, Grupp SA, Seeger R, Reynolds CP, Buxton A, Reisfeld RA, Gillies SD, Cohn SL, Maris JM, Sondel PM; Children's Oncology Group. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010 Sep 30;363(14):1324-34. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00026312
    1. Update: Yu AL, Gilman AL, Ozkaynak MF, Naranjo A, Diccianni MB, Gan J, Hank JA, Batova A, London WB, Tenney SC, Smith M, Shulkin BL, Parisi M, Matthay KK, Cohn SL, Maris JM, Bagatell R, Park JR, Sondel PM. Long-Term Follow-up of a Phase III Study of ch14.18 (Dinutuximab) + Cytokine Immunotherapy in Children with High-Risk Neuroblastoma: COG Study ANBL0032. Clin Cancer Res. 2021 Apr 15;27(8):2179-2189. Epub 2021 Jan 27. link to original article link to PMC article PubMed

Isotretinoin monotherapy

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Matthay et al. 1999 1991-1996 Phase 3 (E-esc) No further therapy Seems to have superior EFS
Yu et al. 2010 (COG ANBL0032) 2001-2009 Phase 3 (C) GM-CSF, IL-2, Isotretinoin, Dinutuximab Seems to have inferior OS

Preceding treatment

Chemotherapy

28-day cycle for 6 cycles

References

  1. Matthay KK, Villablanca JG, Seeger RC, Stram DO, Harris RE, Ramsay NK, Swift P, Shimada H, Black CT, Brodeur GM, Gerbing RB, Reynolds CP; Children's Cancer Group. Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. N Engl J Med. 1999 Oct 14;341(16):1165-73. link to original article contains dosing details in manuscript PubMed
  2. COG ANBL0032: Yu AL, Gilman AL, Ozkaynak MF, London WB, Kreissman SG, Chen HX, Smith M, Anderson B, Villablanca JG, Matthay KK, Shimada H, Grupp SA, Seeger R, Reynolds CP, Buxton A, Reisfeld RA, Gillies SD, Cohn SL, Maris JM, Sondel PM; Children's Oncology Group. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010 Sep 30;363(14):1324-34. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00026312
    1. Update: Yu AL, Gilman AL, Ozkaynak MF, Naranjo A, Diccianni MB, Gan J, Hank JA, Batova A, London WB, Tenney SC, Smith M, Shulkin BL, Parisi M, Matthay KK, Cohn SL, Maris JM, Bagatell R, Park JR, Sondel PM. Long-Term Follow-up of a Phase III Study of ch14.18 (Dinutuximab) + Cytokine Immunotherapy in Children with High-Risk Neuroblastoma: COG Study ANBL0032. Clin Cancer Res. 2021 Apr 15;27(8):2179-2189. Epub 2021 Jan 27. link to original article link to PMC article PubMed

Isotretinoin & Dinutuximab

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Ladenstein et al. 2018 (HR-NBL1 part 2) 2009-2013 Phase 3 (C) IL-2, Isotretinoin, Dinutuximab Did not meet primary endpoint of EFS36

Note: this was a second randomization and second cohort of patients enrolled in HR-NBL1.

Preceding treatment

Chemotherapy

Targeted therapy

References

  1. HR-NBL1 part 2: Ladenstein R, Pötschger U, Valteau-Couanet D, Luksch R, Castel V, Yaniv I, Laureys G, Brock P, Michon JM, Owens C, Trahair T, Chan GCF, Ruud E, Schroeder H, Beck Popovic M, Schreier G, Loibner H, Ambros P, Holmes K, Castellani MR, Gaze MN, Garaventa A, Pearson ADJ, Lode HN. Interleukin 2 with anti-GD2 antibody ch14 18/CHO (dinutuximab beta) in patients with high-risk neuroblastoma (HR-NBL1/SIOPEN): a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Dec;19(12):1617-1629. Epub 2018 Nov 12. link to original article PubMed NCT01704716

Relapsed or refractory

Cyclophosphamide monotherapy

Regimen

Study Evidence
Thurman et al. 1964 Non-randomized

Of historic interest.

Chemotherapy

References

  1. Thurman WG, Fernbach DJ, Sullivan MP. Cyclophosphamide therapy in childhood neuroblastoma. N Engl J Med. 1964 Jun 18;270:1336-40. link to original article PubMed

Cyclophosphamide & Vincristine

Regimen

Study Evidence
Evans et al. 1969 Non-randomized

Of historic interest.

Chemotherapy

References

  1. Evans AE, Heyn RM, Newton WA Jr, Leikin SL. Vincristine sulfate and cyclophosphamide for children with metastatic neuroblastoma. JAMA. 1969 Feb 17;207(7):1325-7. link to original article PubMed

Irinotecan, Temozolomide, Dinutuximab

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Mody et al. 2017 (COG ANBL1221) 2013-2015 Randomized Phase 2, <20 pts (E-switch-ooc) Irinotecan, Temozolomide, Temsirolimus Superior ORR

Note: this dinutuximab dose is based on a mid-protocol revision.

Chemotherapy

Targeted therapy

  • Dinutuximab (Unituxin) 17.5 mg/m2 IV over 10 hours once per day on days 2 to 5
    • Infusion time could be extended to 20 hours "if patients experienced pain, fever, tachycardia, tachypnea, or hypotension unresponsive to supportive measures."

Supportive therapy

21-day cycle for up to 17 cycles

References

  1. COG ANBL1221: Mody R, Naranjo A, Van Ryn C, Yu AL, London WB, Shulkin BL, Parisi MT, Servaes SE, Diccianni MB, Sondel PM, Bender JG, Maris JM, Park JR, Bagatell R. Irinotecan-temozolomide with temsirolimus or dinutuximab in children with refractory or relapsed neuroblastoma (COG ANBL1221): an open-label, randomised, phase 2 trial. Lancet Oncol. 2017 Jul;18(7):946-957. Epub 2017 May 23. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01767194

Naxitamab monotherapy

Regimen

Study Years of enrollment Evidence
Kushner et al. 2018 (Study 12-230) 2012-2016 Phase 1 (RT)
Awaiting publication (Study 201) 2018-ongoing Phase 2 (RT)

Targeted therapy

Supportive therapy

  • GM-CSF 250 mcg/m2/day SC once per day on days -4 to 0, then 500 mcg/m2/day SC once per day on days 1 to 5

28-day cycle for 4 cycles until complete response or partial response, followed by 5 additional cycles Subsequent cycles may be repeated every 8 weeks.

References

  1. Study 12-230: Kushner BH, Cheung IY, Modak S, Basu EM, Roberts SS, Cheung NK. Humanized 3F8 Anti-GD2 Monoclonal Antibody Dosing With Granulocyte-Macrophage Colony-Stimulating Factor in Patients With Resistant Neuroblastoma: A Phase 1 Clinical Trial. JAMA Oncol. 2018 Dec 1;4(12):1729-1735. link to original article link to original article PubMed NCT01757626
  2. Study 201: NCT03363373