Neuroblastoma

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Note: Neuroblastoma is a rare cancer but is the most common malignancy of infancy.
Last updated on 2024-12-02:17 regimens on this page
21 variants on this page
=Guidelines=
==NCCN==
*NCCN Guidelines - Neuroblastoma
=High-risk, upfront therapy=
==COG ANBL0931 post-consolidation==
===Regimen variant #1, weight more than 12 kg===
Study 	Dates of enrollment 	Evidence
Ozkaynak et al. 2018 (COG ANBL0931)	2009 to not reported	Non-randomized
Note: Patients were only eligible if they had previously completed therapy including intensive induction chemotherapy followed by ASCT and radiotherapy. Figure 1 is highly confusing, with the figure implying differing lengths of cycles, and the legend implying 28-day cycles for all cycles.
====Immunotherapy====
*Sargramostim (Leukine) as follows:
**Cycles 1, 3, 5: 250 mcg/m2 SC (strongly recommended) or IV over 2 hours once per day on days 0 to 13
*Aldesleukin (Proleukin) as follows:
**Cycles 2 & 4: 3,000,000 IU/m2 IV continuous infusion over 96 hours, started on day 0, then 4,500,000 IU/m2 IV continuous infusion over 96 hours, started on day 7 (total dose per cycle: 7,500,000 IU/m2)
====Targeted therapy====
*Dinutuximab (Unituxin) as follows:
**Cycles 1, 3, 5: 25 mg/m2 IV over 10 to 20 hours once per day on days 3 to 6, given 1 hour after completion of sargramostim infusion
**Cycles 2 & 4: 25 mg/m2 IV over 10 to 20 hours once per day on days 7 to 10
***Max Infusion Time = 20 hours even if the total dose has not been administered
====Chemotherapy====
*Isotretinoin (Accutane) as follows:
**Cycle 1: 80 mg/m2 PO twice per day on days 11 to 24
**Cycles 2, 4, 6: 80 mg/m2 PO twice per day on days 14 to 27
**Cycles 3 & 5: 80 mg/m2 PO twice per day on days 10 to 23
***Dose is rounded up to nearest 10 mg
25-day cycle, then 28-day cycle, then 24-day cycle, then 28-day cycle, then 24-day cycle, then 28-day cycle
====Dose and schedule modifications====
*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
===Regimen variant #2, weight 12 kg or less===
Study 	Dates of enrollment 	Evidence
Ozkaynak et al. 2018 (COG ANBL0931)	2009 to not reported	Non-randomized
Note: Patients were only eligible if they had previously completed therapy including intensive induction chemotherapy followed by ASCT and radiotherapy. Figure 1 is highly confusing, with the figure implying differing lengths of cycles, and the legend implying 28-day cycles for all cycles.
====Immunotherapy====
*Sargramostim (Leukine) as follows:
**Cycles 1, 3, 5: 250 mcg/m2 SC (strongly recommended) or IV over 2 hours once per day on days 0 to 13
*Aldesleukin (Proleukin) as follows:
**Cycles 2 & 4: 3,000,000 IU/m2 IV continuous infusion over 96 hours, started on day 0, then 4,500,000 IU/m2 IV continuous infusion over 96 hours, started on day 7 (total dose per cycle: 7,500,000 IU/m2)
====Targeted therapy====
*Dinutuximab (Unituxin) as follows:
**Cycles 1, 3, 5: 25 mg/m2 IV over 10 to 20 hours once per day on days 3 to 6, given 1 hour after completion of sargramostim infusion
**Cycles 2 & 4: 25 mg/m2 IV over 10 to 20 hours once per day on days 7 to 10
***Max Infusion Time = 20 hours even if the total dose has not been administered
====Chemotherapy====
*Isotretinoin (Accutane) as follows:
**Cycle 1: 2.67 mg/kg PO twice per day on days 11 to 24
**Cycles 2, 4, 6: 2.67 mg/kg PO twice per day on days 14 to 27
**Cycles 3 & 5: 2.67 mg/kg PO twice per day on days 10 to 23
***Dose is rounded up to nearest 10 mg
25-day cycle, then 28-day cycle, then 24-day cycle, then 28-day cycle, then 24-day cycle, then 28-day cycle
====Dose and schedule modifications====
*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
===References===
# 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 PMC article EuroPMC NCT01041638
==COG ANBL0532 Regimen B==
Study 	Dates of enrollment	Evidence
Seif et al. 2013 (COG ANBL00P1)	Not reported 	Pilot, >20 pts
Note: this is the experimental arm of COG ANBL0532; details are from the pilot study, COG ANBL00P1.
===Induction===
====Chemotherapy, Cycle 1 (CPM + TOPO)====
*Cyclophosphamide (Cytoxan) by the following weight-based criteria:
**12 kg or less: 13.3 mg/kg IV over 30 to 60 minutes once per day on days 1 to 5
**More than 12 kg: 400 mg/m2 IV over 30 to 60 minutes once per day on days 1 to 5
*Topotecan (Hycamtin) 1.2 mg/m2 IV over 30 minutes once per day on days 1 to 5
====Chemotherapy, Cycle 2 (CPM + TOPO)====
*Cyclophosphamide (Cytoxan) by the following weight-based criteria:
**12 kg or less: 13.3 mg/kg IV over 30 to 60 minutes once per day on days 1 to 5
**More than 12 kg: 400 mg/m2 IV over 30 to 60 minutes once per day on days 1 to 5
*Topotecan (Hycamtin) 1.2 mg/m2 IV over 30 minutes once per day on days 1 to 5
====Supportive therapy, Cycle 2====
*Filgrastim (Neupogen) 5 mcg/kg SC or IV once per day beginning 24 hours after completion of chemotherapy and continuing until ANC greater than 1000/μL
*Filgrastim (Neupogen) 10 mcg/kg SC or IV once per day beginning once ANC greater than 1000/μL and continuing until PBSC harvest is complete
*PBSC harvest on day 14
====Chemotherapy, Cycle 3 (CDDP + ETOP)====
*Cisplatin (Platinol) by the following weight-based criteria:
**12 kg or less: 1.66 mg/kg IV over 1 hour once per day on days 1 to 4
**More than 12 kg: 50 mg/m2 IV over 1 hour once per day on days 1 to 4
*Etoposide (Vepesid) by the following weight-based criteria:
**12 kg or less: 6.67 mg/kg IV over 1 hour once per day on days 1 to 3
**More than 12 kg: 200 mg/m2 IV over 1 hour once per day on days 1 to 3
====Chemotherapy, Cycle 4 (CPM + DOXO + VCR)====
*Cyclophosphamide (Cytoxan) by the following weight-based criteria:
**12 kg or less: 70 mg/kg IV over 6 hours once per day on days 1 to 2
**More than 12 kg: 2100 mg/m2 IV over 6 hours once per day on days 1 to 2
*Vincristine (Oncovin) by the following age- and weight-based criteria:
**Younger than 12 months old: 0.017 mg/kg (maximum dose of 2 mg in 72 hours) IV over 1 minute or infusion (per institutional policy) once per day on days 1 to 3, given prior to doxorubicin
**12 months old or older AND 12 kg or less: 0.022 mg/kg (maximum dose of 2 mg in 72 hours) IV over 1 minute or infusion (per institutional policy) once per day on days 1 to 3, given prior to doxorubicin
**12 months old or older AND more than 12 kg: 0.097 mg/m2 or 0.022 mg/kg (choose lower dose) (maximum dose of 2 mg in 72 hours) IV over 1 minute or infusion (per institutional policy) once per day on days 1 to 3, given prior to doxorubicin
*Doxorubicin (Adriamycin) by the following weight-based criteria:
**12 kg or less: 0.83 mg/kg IV over 24 hours once per day on days 1 to 3
**More than 12 kg: 25 mg/m2 IV over 24 hours once per day on days 1 to 3
====Supportive therapy, Cycle 4 (CPM + DOXO + VCR)====
*Mesna (Mesnex) by the following weight-based criteria:
**12 kg or less: 14 mg/kg IV over 15 minutes immediately prior to each cyclophosphamide dose and again at 4 and 8 hours after each cyclophosphamide infusion 
**More than 12 kg: 420 mg/m2 IV over 15 minutes immediately prior to each cyclophosphamide dose and again at 4 and 8 hours after each cyclophosphamide infusion
====Chemotherapy, Cycle 5 (CDDP + ETOP)====
*Cisplatin (Platinol) by the following weight-based criteria:
**12 kg or less: 1.66 mg/kg IV over 1 hour once per day on days 1 to 4
**More than 12 kg: 50 mg/m2 IV over 1 hour once per day on days 1 to 4
*Etoposide (Vepesid) by the following weight-based criteria:
**12 kg or less: 6.67 mg/kg IV over 1 hour once per day on days 1 to 3
**More than 12 kg: 200 mg/m2 IV over 1 hour once per day on days 1 to 3
====Chemotherapy, Cycle 6 (CPM + DOXO + VCR)====
*Cyclophosphamide (Cytoxan) by the following weight-based criteria:
**12 kg or less: 70 mg/kg IV over 6 hours once per day on days 1 to 2
**More than 12 kg: 2100 mg/m2 IV over 6 hours once per day on days 1 to 2
*Vincristine (Oncovin) by the following age- and weight-based criteria:
**Younger than 12 months old: 0.017 mg/kg (maximum dose of 2 mg in 72 hours) IV over 1 minute or infusion (per institutional policy) once per day on days 1 to 3, given prior to doxorubicin
**12 months old or older AND 12 kg or less: 0.022 mg/kg (maximum dose of 2 mg in 72 hours) IV over 1 minute or infusion (per institutional policy) once per day on days 1 to 3, given prior to doxorubicin
**12 months old or older AND more than 12 kg: 0.097 mg/m2 or 0.022 mg/kg (choose lower dose) (maximum dose of 2 mg in 72 hours) IV over 1 minute or infusion (per institutional policy) once per day on days 1 to 3, given prior to doxorubicin
*Doxorubicin (Adriamycin) by the following weight-based criteria:
**12 kg or less: 0.83 mg/kg IV over 24 hours once per day on days 1 to 3
**More than 12 kg: 25 mg/m2 IV over 24 hours once per day on days 1 to 3
====Supportive therapy, Cycle 6 (CPM + DOXO + VCR)====
*Mesna (Mesnex) by the following weight-based criteria:
**12 kg or less: 14 mg/kg IV over 15 minutes immediately prior to each cyclophosphamide dose and again at 4 and 8 hours after each cyclophosphamide infusion 
**More than 12 kg: 420 mg/m2 IV over 15 minutes immediately prior to each cyclophosphamide dose and again at 4 and 8 hours after each cyclophosphamide infusion
21-day cycle for 6 cycles
===Consolidation===
====Chemotherapy, Tandem HSCT #1 (Thiotepa and Cyclophosphamide)====
*Thiotepa (Thioplex) by the following weight-based criteria:
**12 kg or less: 10 mg/kg IV over 2 hours once per day on days -7, -6, -5
**More than 12 kg: 300 mg/m2 IV over 2 hours once per day on days -7, -6, -5 
*Cyclophosphamide (Cytoxan) by the following weight-based criteria:
**12 kg or less: 50mg/kg IV over 1 hour once per day on days -5, -4, -3, -2
**More than 12 kg: 1500 mg/m2 IV over 1 hour once per day on days -5, -4, -3, -2
*PBSC on day 0
====Supportive therapy, Tandem HSCT #1 (Thiotepa and Cyclophosphamide)====
*Mesna (Mesnex) by the following weight-based criteria:
**12 kg or less: 10 mg/kg IV over 15 minutes immediately prior to each cyclophosphamide dose and again at 4 and 8 hours after each cyclophosphamide infusion 
**More than 12 kg: 300 mg/m2 IV over 15 minutes immediately prior to each cyclophosphamide dose and again at 4 and 8 hours after each cyclophosphamide infusion
*Filgrastim (Neupogen) 5 mcg/kg SC or IV once per day starting on day 0 and continuing until post-nadir ANC greater than 2000/μL for 3 consecutive days
====Chemotherapy, Tandem HSCT #2 (CEM)====
*Melphalan (Alkeran) by the following renal function- and weight-based criteria:
**12 kg or less AND GFR 100 mL/min or more: 2 mg/kg IV over 15 to 30 minutes once per day on days -7, -6, -5 
**More than 12 kg AND GFR 100 mL/min or more: 60 mg/m2 IV over 15 to 30 minutes once per day on days -7, -6, -5
**12 kg or less AND GFR 60 to 100 mL/min: 2 mg/kg IV over 15 to 30 minutes once per day on days -7, -6, -5
**More than 12 kg AND GFR 60 to 100 mL/min: 60 mg/m2 IV over 15 to 30 minutes once per day on days -7, -6, -5
*Etoposide (Vepesid) by the following renal function- and weight-based criteria:
**12 kg or less AND GFR 100 mL/min or more: 12 mg/kg IV over 24 hours once per day on days -7, -6, -5, -4
**More than 12 kg AND GFR 100 mL/min or more: 300 mg/m2 IV over 24 hours once per day on days -7, -6, -5, -4
**12 kg or less AND GFR 60 to 100 mL/min: 6.7 mg/kg IV over 24 hours once per day on days -7, -6, -5, -4
**More than 12 kg AND GFR 60 to 100 mL/min: 200 mg/m2 IV over 24 hours once per day on days -7, -6, -5, -4
*Carboplatin (Paraplatin) by the following renal function- and weight-based criteria:
**12 kg or less AND GFR 100 mL/min or more: 12 mg/kg IV over 24 hours once per day on days -7, -6, -5, -4
**More than 12 kg AND GFR 100 mL/min or more: 375 mg/m2 IV over 24 hours once per day on days -7, -6, -5, -4
**12 kg or less AND GFR 60 to 100 mL/min: 4.1 AUC using Calvert Formula (Max Dose = 300 mg/m2) IV over 24 hours once per day on days -7, -6, -5, -4
**More than 12 kg AND GFR 60 to 100 mL/min: Use the lowest of either 4.1 AUC using Calvert Formula or 10 mg/kg IV over 24 hours once per day on days -7, -6, -5, -4
*PBSC on day 0
====Supportive therapy, Tandem HSCT #2 (CEM)====
*Filgrastim (Neupogen) 5 mcg/kg SC or IV once per day starting on day 0 and continuing until post-nadir ANC greater than 2000/μL for 3 consecutive days
50-day course, then 36-day course
===Maintenance===
====Chemotherapy====
*Isotretinoin (Accutane) by the following weight-based criteria:
**12 kg or less: 5.33 mg/kg (Round dose to nearest 10 mg) PO twice per day on days 1 to 14
**More than 12 kg: 160 mg/m2 (Round dose to nearest 10 mg) PO twice per day on days 1 to 14
28-day cycle for 6 cycles
===References===
#COG ANBL00P1: 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. Epub 2013 Jan 21. link to original article link to PMC article EuroPMC
#COG ANBL0532: Park JR, Kreissman SG, London WB, Naranjo A, Cohn SL, Hogarty MD, Tenney SC, Haas-Kogan D, Shaw PJ, Kraveka JM, Roberts SS, Geiger JD, Doski JJ, Voss SD, Maris JM, Grupp SA, Diller L. Effect of Tandem Autologous Stem Cell Transplant vs Single Transplant on Event-Free Survival in Patients With High-Risk Neuroblastoma: A Randomized Clinical Trial. JAMA. 2019 Aug 27;322(8):746-755. link to original article link to PMC article EuroPMC NCT00567567
==COG ANBL17P1 protocol==
Study 	Dates of enrollment 	Evidence
Furman et al. 2019 (COG ANBL17P1)	2013 to not reported	Phase 2
===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 per day on days 1 to 5
**0.30 to 0.34 m2: 100 mg IV over 15 to 30 minutes once per day on days 1 to 5
**0.35 to 0.39 m2: 124 mg IV over 15 to 30 minutes once per day on days 1 to 5
**0.40 to 0.44 m2: 148 mg IV over 15 to 30 minutes once per day on days 1 to 5
**0.45 to 0.49 m2: 180 mg IV over 15 to 30 minutes once per day on days 1 to 5
**0.50 to 0.54 m2: 200 mg IV over 15 to 30 minutes once per day on days 1 to 5
**0.55 to 0.59 m2: 220 mg IV over 15 to 30 minutes once per day on days 1 to 5
**0.60 m2 or more: 400 mg/m2 IV over 15 to 30 minutes once per day on days 1 to 5
*Topotecan (Hycamtin) by the following BSA-based criteria:
**0.25 to 0.29 m2: 0.32 mg IV over 30 minutes once per day on days 1 to 5
**0.30 to 0.34 m2: 0.38 mg IV over 30 minutes once per day on days 1 to 5
**0.35 to 0.39 m2: 0.44 mg IV over 30 minutes once per day on days 1 to 5
**0.40 to 0.44 m2: 0.5 mg IV over 30 minutes once per day on days 1 to 5
**0.45 to 0.49 m2: 0.56 mg IV over 30 minutes once per day on days 1 to 5
**0.50 to 0.54 m2: 0.62 mg IV over 30 minutes once per day on days 1 to 5
**0.55 to 0.59 m2: 0.68 mg IV over 30 minutes once per day on days 1 to 5
**0.60 m2 or more: 1.2 mg/m2 IV over 30 minutes once per day on days 1 to 5
====Supportive therapy, Cycle 1 (TOPO/CPM)====
*Filgrastim (Neupogen) 5 mcg/kg SC or IV once per day beginning 24 to 48 hours after completion of chemotherapy and continuing until ANC greater than 2000/μL
====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 per day on days 1 to 5
**0.30 to 0.34 m2: 100 mg IV over 15 to 30 minutes once per day on days 1 to 5
**0.35 to 0.39 m2: 124 mg IV over 15 to 30 minutes once per day on days 1 to 5
**0.40 to 0.44 m2: 148 mg IV over 15 to 30 minutes once per day on days 1 to 5
**0.45 to 0.49 m2: 180 mg IV over 15 to 30 minutes once per day on days 1 to 5
**0.50 to 0.54 m2: 200 mg IV over 15 to 30 minutes once per day on days 1 to 5
**0.55 to 0.59 m2: 220 mg IV over 15 to 30 minutes once per day on days 1 to 5
**0.60 m2 or more: 400 mg/m2 IV over 15 to 30 minutes once per day on days 1 to 5
*Topotecan (Hycamtin) by the following BSA-based criteria:
**0.25 to 0.29 m2: 0.32 mg IV over 30 minutes once per day on days 1 to 5
**0.30 to 0.34 m2: 0.38 mg IV over 30 minutes once per day on days 1 to 5
**0.35 to 0.39 m2: 0.44 mg IV over 30 minutes once per day on days 1 to 5
**0.40 to 0.44 m2: 0.5 mg IV over 30 minutes once per day on days 1 to 5
**0.45 to 0.49 m2: 0.56 mg IV over 30 minutes once per day on days 1 to 5
**0.50 to 0.54 m2: 0.62 mg IV over 30 minutes once per day on days 1 to 5
**0.55 to 0.59 m2: 0.68 mg IV over 30 minutes once per day on days 1 to 5
**0.60 m2 or more: 1.2 mg/m2 IV over 30 minutes once per day on days 1 to 5
*PBSC Harvest on Day 15 of Cycle 2
====Supportive therapy, Cycle 2 (TOPO/CPM)====
*Filgrastim (Neupogen) 5 mcg/kg SC or IV once per day beginning 24 to 48 hours after completion of chemotherapy and continuing until ANC greater than 2000/μL
====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 per day on days 1 to 3
**0.30 to 0.34 m2: 14 mg IV over 1 hour once per day on days 1 to 3
**0.35 to 0.39 m2: 18 mg IV over 1 hour once per day on days 1 to 3
**0.40 to 0.44 m2: 22 mg IV over 1 hour once per day on days 1 to 3
**0.45 to 0.49 m2: 26 mg IV over 1 hour once per day on days 1 to 3
**0.50 to 0.54 m2: 30 mg IV over 1 hour once per day on days 1 to 3
**0.55 to 0.59 m2: 34 mg IV over 1 hour once per day on days 1 to 3
**0.60 m2 or more: 60 mg/m2 IV over 1 hour once per day on days 1 to 3
*Etoposide (Vepesid) by the following BSA-based criteria:
**0.25 to 0.29 m2: 34 mg IV over 2 hours once per day on days 1 to 3
**0.30 to 0.34 m2: 48 mg IV over 2 hours once per day on days 1 to 3
**0.35 to 0.39 m2: 60 mg IV over 2 hours once per day on days 1 to 3
**0.40 to 0.44 m2: 72 mg IV over 2 hours once per day on days 1 to 3
**0.45 to 0.49 m2: 88 mg IV over 2 hours once per day on days 1 to 3
**0.50 to 0.54 m2: 100 mg IV over 2 hours once per day on days 1 to 3
**0.55 to 0.59 m2: 112 mg IV over 2 hours once per day on days 1 to 3
**0.60 m2 or more: 200 mg/m2 IV over 2 hours once per day on days 1 to 3
====Targeted therapy, Cycle 3====
*Dinutuximab (Unituxin) 17.5 mg/m2 IV over 10 hours (may be extended up to 20 hours) on days 2 to 5
====Immunotherapy, Cycle 3 (GM-CSF)====
*Sargramostim (Leukine) 250 mcg/m2 SC once on day 6 or 7, given 24 to 48 hours after completion of dinutuximab
====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
**0.30 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
**0.40 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
**0.50 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
**0.60 m2 or more: 2 mg/m2 (Max dose = 2 mg) IV push over 1 minute or IV infusion per institutional policy once on day 1
***Administer prior to dexrazoxane
*Doxorubicin (Adriamycin) by the following BSA-based criteria:
**0.25 to 0.29 m2: 6.6 mg IV over 5 to 15 minutes once per day on days 1 & 2
**0.30 to 0.34 m2: 9.2 mg IV over 5 to 15 minutes once per day on days 1 & 2
**0.35 to 0.39 m2: 12 mg IV over 5 to 15 minutes once per day on days 1 & 2
**0.40 to 0.44 m2: 14 mg IV over 5 to 15 minutes once per day on days 1 & 2
**0.45 to 0.49 m2: 16 mg IV over 5 to 15 minutes once per day on days 1 & 2
**0.50 to 0.54 m2: 18 mg IV over 5 to 15 minutes once per day on days 1 & 2
**0.55 to 0.59 m2: 20 mg IV over 5 to 15 minutes once per day on days 1 & 2
**0.60 m2 or more: 37.5 mg/m2 IV over 5 to 15 minutes once per day on days 1 & 2
***given immediately after dexrazoxane
*Cyclophosphamide (Cytoxan) by the following BSA-based criteria:
**0.25 to 0.29 m2: 360 mg IV over 60 minutes once per day on days 1 & 2
**0.30 to 0.34 m2: 480 mg IV over 60 minutes once per day on days 1 & 2
**0.35 to 0.39 m2: 600 mg IV over 60 minutes once per day on days 1 & 2
**0.40 to 0.44 m2: 720 mg IV over 60 minutes once per day on days 1 & 2
**0.45 to 0.49 m2: 880 mg IV over 60 minutes once per day on days 1 & 2
**0.50 to 0.54 m2: 1000 mg IV over 60 minutes once per day on days 1 & 2
**0.55 to 0.59 m2: 1100 mg IV over 60 minutes once per day on days 1 & 2
**0.60 m2 or more: 2000 mg/m2 IV over 60 minutes once per day on days 1 & 2
====Targeted therapy, Cycle 4 (VCR/DOXO/CPM/DIN)====
*Dinutuximab (Unituxin) 17.5 mg/m2 IV over 10 hours (may be extended up to 20 hours) on days 2 to 5
====Immunotherapy, Cycle 4 (GM-CSF)====
*Sargramostim (Leukine) 250 mcg/m2 SC once on day 6 or 7, given 24 to 48 hours after completion of dinutuximab
====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 once per day on days 1 & 2
**0.30 to 0.34 m2: 92 mg IV over 5 to 15 minutes once per day on days 1 & 2
**0.35 to 0.39 m2: 120 mg IV over 5 to 15 minutes once per day on days 1 & 2
**0.40 to 0.44 m2: 140 mg IV over 5 to 15 minutes once per day on days 1 & 2
**0.45 to 0.49 m2: 160 mg IV over 5 to 15 minutes once per day on days 1 & 2
**0.50 to 0.54 m2: 180 mg IV over 5 to 15 minutes once per day on days 1 & 2
**0.55 to 0.59 m2: 200 mg IV over 5 to 15 minutes once per day on days 1 & 2
**0.60 m2 or more: 375 mg/m2 IV over 5 to 15 minutes once per day on days 1 & 2
***Given immediately prior to doxorubicin
*Mesna (Mesnex) by the following BSA-based criteria:
**0.25 to 0.29 m2: 72 mg IV over 15 minutes immediately prior to each cyclophosphamide dose and again at 3, 6, 9, & 12 hours from the start of cyclophosphamide infusion
**0.30 to 0.34 m2: 96 mg IV over 15 minutes immediately prior to each cyclophosphamide dose and again at 3, 6, 9, & 12 hours from the start of cyclophosphamide infusion
**0.35 to 0.39 m2: 120 mg IV over 15 minutes immediately prior to each cyclophosphamide dose and again at 3, 6, 9, & 12 hours from the start of cyclophosphamide infusion
**0.40 to 0.44 m2: 144 mg IV over 15 minutes immediately prior to each cyclophosphamide dose and again at 3, 6, 9, & 12 hours from the start of cyclophosphamide infusion
**0.45 to 0.49 m2: 176 mg IV over 15 minutes immediately prior to each cyclophosphamide dose and again at 3, 6, 9, & 12 hours from the start of cyclophosphamide infusion
**0.50 to 0.54 m2: 200 mg IV over 15 minutes immediately prior to each cyclophosphamide dose and again at 3, 6, 9, & 12 hours from the start of cyclophosphamide infusion
**0.55 to 0.59 m2: 220 mg IV over 15 minutes immediately prior to each cyclophosphamide dose and again at 3, 6, 9, & 12 hours from the start of cyclophosphamide infusion
**0.60 m2 or more: 400 mg/m2 IV over 15 minutes immediately prior to each cyclophosphamide dose and again at 3, 6, 9, & 12 hours from the start of cyclophosphamide infusion
====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 per day on days 1 to 3
**0.30 to 0.34 m2: 14 mg IV over 1 hour once per day on days 1 to 3
**0.35 to 0.39 m2: 18 mg IV over 1 hour once per day on days 1 to 3
**0.40 to 0.44 m2: 22 mg IV over 1 hour once per day on days 1 to 3
**0.45 to 0.49 m2: 26 mg IV over 1 hour once per day on days 1 to 3
**0.50 to 0.54 m2: 30 mg IV over 1 hour once per day on days 1 to 3
**0.55 to 0.59 m2: 34 mg IV over 1 hour once per day on days 1 to 3
**0.60 m2 or more: 60 mg/m2 IV over 1 hour once per day on days 1 to 3
*Etoposide (Vepesid) by the following BSA-based criteria:
**0.25 to 0.29 m2: 34 mg IV over 2 hours once per day on days 1 to 3
**0.30 to 0.34 m2: 48 mg IV over 2 hours once per day on days 1 to 3
**0.35 to 0.39 m2: 60 mg IV over 2 hours once per day on days 1 to 3
**0.40 to 0.44 m2: 72 mg IV over 2 hours once per day on days 1 to 3
**0.45 to 0.49 m2: 88 mg IV over 2 hours once per day on days 1 to 3
**0.50 to 0.54 m2: 100 mg IV over 2 hours once per day on days 1 to 3
**0.55 to 0.59 m2: 112 mg IV over 2 hours once per day on days 1 to 3
**0.60 m2 or more: 200 mg/m2 IV over 2 hours once per day on days 1 to 3
====Targeted therapy, Cycle 5 (CDDP/ETOP/DIN)====
*Dinutuximab (Unituxin) 17.5 mg/m2 IV over 10 hours (may be extended up to 20 hours) on days 2 to 5
====Immunotherapy, Cycle 5 (GM-CSF)====
*Sargramostim (Leukine) 250 mcg/m2 SC once on day 6 or 7, given 24 to 48 hours after completion of dinutuximab
21-day cycle for 5 cycles
====Dose and schedule modifications====
**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
**Hold Sargramostim (Leukine) if Dinutuximab (Unituxin) is not given
===Consolidation===
====Chemotherapy, Tandem HSCT #1 (Thiotepa and Cyclophosphamide)====
*Thiotepa (Thioplex) by the following weight-based criteria:
**12 kg or less: 10 mg/kg IV over 2 hours once per day on days -7, -6, -5
**More than 12 kg: 300 mg/m2 IV over 2 hours once per day on days -7, -6, -5 
*Cyclophosphamide (Cytoxan) by the following weight-based criteria:
**12 kg or less: 50 mg/kg IV over 1 hour once per day on days -5, -4, -3, -2
**More than 12 kg: 1500 mg/m2 IV over 1 hour once per day on days -5, -4, -3, -2
*PBSC on day 0
====Supportive therapy, Tandem HSCT #1 (Thiotepa and Cyclophosphamide)====
*Mesna (Mesnex) by the following weight-based criteria:
**12 kg or less: 10 mg/kg IV over 15 minutes immediately prior to each cyclophosphamide dose and again at 4 and 8 hours after each cyclophosphamide infusion 
**More than 12 kg: 300 mg/m2 IV over 15 minutes immediately prior to each cyclophosphamide dose and again at 4 and 8 hours after each cyclophosphamide infusion
*Filgrastim (Neupogen) 5 mcg/kg SC or IV once per day starting on day 0 and continuing until post-nadir ANC greater than 2000/μL for 3 consecutive days
====Chemotherapy, Tandem HSCT #2 (CEM)====
*Melphalan (Alkeran) by the following weight-based criteria:
**12 kg or less: 2 mg/kg IV over 30 minutes once per day on days -7, -6, -5 
**More than 12 kg: 60 mg/m2 IV over 30 minutes once per day on days -7, -6, -5
*Etoposide (Vepesid) by the following renal function- and weight-based criteria:
**12 kg or less AND GFR 100 mL/min or more: 10 mg/kg IV continuous infusion on days -7, -6, -5, -4
**More than 12 kg AND GFR 100 mL/min or more: 300 mg/m2 IV continuous infusion on days -7, -6, -5, -4
**12 kg or less AND GFR 60 up to 100 mL/min: 6.7 mg/kg IV continuous infusion on days -7, -6, -5, -4
**More than 12 kg AND GFR 60 up to 100 mL/min: 200 mg/m2 IV continuous infusion on days -7, -6, -5, -4
*Carboplatin (Paraplatin) by the following BSA- and renal function-based criteria:
BSA (m2) 	GFR at least 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
At least 0.6	375 mg/m2 	300 mg/m2 	260 mg/m2 	230 mg/m2
*PBSC on day 0
====Supportive therapy, Tandem HSCT #2 (CEM)====
*Filgrastim (Neupogen) 5 mcg/kg SC or IV once per day starting on day 0 and continuing until post-nadir ANC greater than 2000/μL for 3 consecutive days
50-day cycle for 2 cycles
====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): 2160 cGy in 12 daily fractions
**Metastatic disease present after Induction (mCTVx/mPTVx): 2160 cGy in 12 daily fractions
**Hepatomegaly leading to respiratory distress: 450 cGy delivered in 3 daily fractions
===Post-consolidation===
====Targeted therapy, A portion (cycles 1 to 5)====
*Dinutuximab (Unituxin) 17.5 mg/m2 IV over 10 hours (may be extended up to 20 hours) once per day on days 4 to 7
*Isotretinoin (Accutane) by the following BSA-based criteria:
**0.25 to 0.29 m2: 10 mg PO twice per day on days 11 to 24
**0.30 to 0.39 m2: 20 mg PO twice per day on days 11 to 24
**0.40 to 0.49 m2: 30 mg PO twice per day on days 11 to 24
**0.50 to 0.59 m2: 40 mg PO twice per day on days 11 to 24
**0.60 m2 or more: 80 mg/m2 (round to nearest 10 mg) PO twice per day on days 11 to 24
====Immunotherapy, A portion (cycles 1 to 5)====
*Sargramostim (Leukine) 250 mcg/m2 SC once per day on days 1 to 14, given prior to dinutuximab
====Chemotherapy, B portion (cycle 6)====
*Isotretinoin (Accutane) by the following BSA-based criteria:
**0.25 to 0.29 m2: 10 mg PO twice per day on days 15 to 28
**0.30 to 0.39 m2: 20 mg PO twice per day on days 15 to 28
**0.40 to 0.49 m2: 30 mg PO twice per day on days 15 to 28
**0.50 to 0.59 m2: 40 mg PO twice per day on days 15 to 28
**0.60 m2 or more: 80 mg/m2 (round to nearest 10 mg) PO twice per day on days 15 to 28
28-day cycle for 6 cycles
====Dose and schedule modifications====
*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
===References===
#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. Epub 2019 Oct 10. link to original article link to PMC article EuroPMC NCT01857934
##Update: 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 EuroPMC
=Low-risk, adjuvant therapy=
==COG P9641 protocol==
===Regimen===
Study 	Dates of enrollment 	Evidence
Strother et al. 2012 (COG P9641)	1998-04-06 to 2004-11-16	Non-randomized phase 3
Note: "chemotherapy was offered to the following patients: patients with protocol-defined symptoms of disease that compromised organ function or were life threatening and could not be relieved by surgery; patients with less than partial resection of tumor; and, at the investigator's discretion, patients with, or at risk for developing, symptomatic spinal cord compression either before or after surgery." Certain patients received 2 identical courses, see paper for details.
====Preceding treatment====
*Surgical resection
====Chemotherapy, first portion (cycle 1)====
*Carboplatin (Paraplatin) by the following age- and weight-based criteria:
**Younger than 1 year old OR 12 kg or less: 18 mg/kg IV over 60 minutes once on day 1
**1 year old or older AND more than 12 kg: 560 mg/m2 IV over 60 minutes once on day 1
*Etoposide (Vepesid) by the following age- and weight-based criteria:
**Younger than 1 year old OR 12 kg or less: 4 mg/kg over 2 hours IV once per day on days 1 to 3, given 60 minutes after carboplatin
**1 year old or older AND more than 12 kg: 120 mg/m2 over 2 hours IV once per day on days 1 to 3, given 60 minutes after carboplatin
====Chemotherapy, second portion (cycle 2)====
*Carboplatin (Paraplatin) by the following age- and weight-based criteria:
**Younger than 1 year old OR 12 kg or less: 18 mg/kg IV over 60 minutes once on day 1
**1 year old or older AND more than 12 kg: 560 mg/m2 IV over 60 minutes once on day 1
*Cyclophosphamide (Cytoxan) by the following age- and weight-based criteria:
**Younger than 1 year old OR 12 kg or less: 33 mg/kg IV over 60 minutes once on day 1, given 60 minutes after carboplatin
**1 year old or older AND more than 12 kg: 1000 mg/m2 IV over 60 minutes once on day 1, given 60 minutes after carboplatin
*Doxorubicin (Adriamycin) by the following age- and weight-based criteria:
**Younger than 1 year old OR 12 kg or less: 1 mg/kg IV over 15 to 60 minutes once on day 1, given 60 minutes after cyclophosphamide
**1 year old or older AND more than 12 kg: 30 mg/m2 IV over 15 to 60 minutes once on day 1, given 60 minutes after cyclophosphamide
====Chemotherapy, third portion (cycle 3)====
*Cyclophosphamide (Cytoxan) by the following age- and weight-based criteria:
**Younger than 1 year old OR 12 kg or less: 33 mg/kg IV over 60 minutes once on day 1
**1 year old or older AND more than 12 kg: 1000 mg/m2 IV over 60 minutes once on day 1
*Etoposide (Vepesid) by the following age- and weight-based criteria:
**Younger than 1 year old OR 12 kg or less: 4 mg/kg over 2 hours IV once per day on days 1 to 3, given 60 minutes after cyclophosphamide
**1 year old or older AND more than 12 kg: 120 mg/m2 over 2 hours IV once per day on days 1 to 3, given 60 minutes after cyclophosphamide
====Chemotherapy, fourth portion (cycle 4)====
*Carboplatin (Paraplatin) by the following age- and weight-based criteria:
**Younger than 1 year old OR 12 kg or less: 18 mg/kg IV over 60 minutes once on day 1
**1 year old or older AND more than 12 kg: 560 mg/m2 IV over 60 minutes once on day 1
*Etoposide (Vepesid) by the following age- and weight-based criteria:
**Younger than 1 year old OR 12 kg or less: 4 mg/kg over 2 hours IV once per day on days 1 to 3, given 60 minutes after carboplatin
**1 year old or older AND more than 12 kg: 120 mg/m2 over 2 hours IV once per day on days 1 to 3, given 60 minutes after carboplatin
*Doxorubicin (Adriamycin) by the following age- and weight-based criteria:
**Younger than 1 year old OR 12 kg or less: 1 mg/kg IV over 15 to 60 minutes once on day 1, given 60 minutes after etoposide
**1 year old or older AND more than 12 kg: 30 mg/m2 IV over 15 to 60 minutes once on day 1, given 60 minutes after etoposide
====Supportive therapy, all portions (cycles 1 to 4)====
*G-CSF or GM-CSF by the following age-based criteria:
**Younger than 60 days old: given after chemotherapy (dose not specified)
21-day cycle for 4 cycles
===References===
#COG P9641: Strother DR, London WB, Schmidt ML, Brodeur GM, Shimada H, Thorner P, Collins MH, Tagge E, Adkins S, Reynolds CP, Murray K, Lavey RS, Matthay KK, Castleberry R, Maris JM, Cohn SL. Outcome after surgery alone or with restricted use of chemotherapy for patients with low-risk neuroblastoma: results of Children's Oncology Group study P9641. J Clin Oncol. 2012 May 20;30(15):1842-8. Epub 2012 Apr 23. link to original article link to PMC article EuroPMC NCT00003119
=Intermediate-risk, all lines of therapy=
==COG A3961 protocol==
===Regimen variant #1, BSA-based dosing===
Study 	Dates of enrollment	Evidence
Baker et al. 2010 (COG A3961)	1997-2005 	Non-randomized
Note: see paper for details about risk stratification and surgery
====Chemotherapy====
*Carboplatin (Paraplatin) as follows:
**Cycles 1, 2, 4, 6, 7: 560 mg/m2 IV once on day 1
*Etoposide (Vepesid) as follows: 
**Cycles 1, 3, 4, 5, 7: 120 mg/m2 IV once per day on days 1 to 3
*Cyclophosphamide (Cytoxan) as follows:
**Cycles 2, 3, 5, 6, 8: 1000 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) as follows:
**Cycles 2, 4, 6, 8: 30 mg/m2 IV once on day 1
21-day cycle for 8 cycles
===Regimen variant #2, weight-based dosing for children less than 12 kg===
Study 	Dates of enrollment	Evidence
Baker et al. 2010 (COG A3961)	1997-2005 	Non-randomized
Note: see paper for details about risk stratification and surgery
====Chemotherapy====
*Carboplatin (Paraplatin) as follows:
**Cycles 1, 2, 4, 6, 7: 18 mg/kg IV once on day 1
*Etoposide (Vepesid) as follows: 
**Cycles 1, 3, 4, 5, 7: 4 mg/kg IV once per day on days 1 to 3
*Cyclophosphamide (Cytoxan) as follows:
**Cycles 2, 3, 5, 6, 8: 33 mg/kg IV once on day 1
*Doxorubicin (Adriamycin) as follows:
**Cycles 2, 4, 6, 8: 1 mg/kg IV once on day 1
21-day cycle for 8 cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00003093
==COG ANBL0531 group 2==
===Regimen===
Study 	Dates of enrollment	Evidence
Twist et al. 2019 (COG ANBL0531)	2007-2011 	Phase 2
Note: see paper for details about risk stratification and surgery
====Chemotherapy, first portion (cycle 1)====
*Carboplatin (Paraplatin) by the following weight-based criteria:
**12 kg or less: 18.6 mg/kg IV over 1 hour once on day 1
**More than 12 kg: 560 mg/m2 IV over 1 hour once on day 1
*Etoposide (Vepesid) by the following weight-based criteria:
**12 kg or less: 4 mg/kg IV over 2 hours once per day on days 1 to 3, beginning 1 hour after carboplatin
**More than 12 kg: 120 mg/m2 IV over 2 hours once per day on days 1 to 3, beginning 1 hour after carboplatin
====Supportive therapy, first portion (cycle 1)====
*Filgrastim (Neupogen) 5 mcg/kg SC or IV once per day beginning on day 4 (24 hours after completion of chemotherapy) and continuing until ANC greater than 1500/μL
====Chemotherapy, second portion (cycle 2)====
*Carboplatin (Paraplatin) by the following weight-based criteria:
**12 kg or less: 18.6 mg/kg IV over 1 hour once on day 1
**More than 12 kg: 560 mg/m2 IV over 1 hour once on day 1
*Cyclophosphamide (Cytoxan) by the following weight-based criteria:
**12 kg or less: 33.3 mg/kg IV over 1 hour once on day 1, beginning 1 hour after Carboplatin
**More than 12 kg: 1000 mg/m2 IV over 1 hour once on day 1, beginning 1 hour after Carboplatin
*Doxorubicin (Adriamycin) by the following weight-based criteria:
**12 kg or less: 1 mg/kg IV over 15 to 60 minutes once on day 1, beginning 1 hour after Cyclophosphamide
**More than 12 kg: 30 mg/m2 IV over 15 to 60 minutes once on day 1, beginning 1 hour after Cyclophosphamide
====Supportive therapy, second portion (cycle 2)====
*Filgrastim (Neupogen) 5 mcg/kg SC or IV once per day beginning on day 2 (24 hours after completion of chemotherapy) and continuing until ANC greater than 1500/μL
21-day cycle for 2 cycles
===References===
#COG ANBL0531: Twist CJ, Schmidt ML, Naranjo A, London WB, Tenney SC, Marachelian A, Shimada H, Collins MH, Esiashvili N, Adkins ES, Mattei P, Handler M, Katzenstein H, Attiyeh E, Hogarty MD, Gastier-Foster J, Wagner E, Matthay KK, Park JR, Maris JM, Cohn SL. Maintaining Outstanding OUtcomes Using Response- and Biology-Based Therapy for Intermediate-Risk Neuroblastoma: A Report from the Children's Oncology Group Study ANBL0531. J Clin Oncol. 2019 Dec 1;37(34):3243-55. Epub 2019 Aug 6. link to original article link to PMC article EuroPMC NCT00499616
==COG ANBL0531 group 3==
===Regimen variant #1, BSA-based dosing===
Study 	Dates of enrollment	Evidence
Twist et al. 2019 (COG ANBL0531)	2007-2011 	Phase 2
Note: see paper for details about risk stratification and surgery.
====Chemotherapy====
*Carboplatin (Paraplatin) as follows:
**Cycles 1, 2, 4: 560 mg/m2 IV once on day 1
*Etoposide (Vepesid) as follows: 
**Cycles 1, 3, 4: 120 mg/m2 IV once per day on days 1 to 3
*Cyclophosphamide (Cytoxan) as follows:
**Cycles 2 & 3: 1000 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) as follows:
**Cycles 2 & 4: 30 mg/m2 IV once on day 1
====Supportive therapy====
*Filgrastim (Neupogen) as follows:
**Cycles 1, 3, 4: 5 mcg/kg SC or IV once per day beginning on day 4 (24 hours after completion of chemotherapy) and continuing until ANC greater than 1500/μL
**Cycle 2: 5 mcg/kg SC or IV once per day beginning on day 2 (24 hours after completion of chemotherapy) and continuing until ANC greater than 1500/μL
21-day cycle for 4 cycles
===Regimen variant #2, weight-based dosing for children less than 12 kg===
Study 	Dates of enrollment	Evidence
Twist et al. 2019 (COG ANBL0531)	2007-2011 	Phase 2
Note: see paper for details about risk stratification and surgery.
====Chemotherapy====
*Carboplatin (Paraplatin) as follows:
**Cycles 1, 2, 4: 18 mg/kg IV once on day 1
*Etoposide (Vepesid) as follows: 
**Cycles 1, 3, 4: 4 mg/kg IV once per day on days 1 to 3
*Cyclophosphamide (Cytoxan) as follows:
**Cycles 2 & 3: 33 mg/kg IV once on day 1
*Doxorubicin (Adriamycin) as follows:
**Cycles 2 & 4: 1 mg/kg IV once on day 1
====Supportive therapy====
*Filgrastim (Neupogen) as follows:
**Cycles 1, 3, 4: 5 mcg/kg SC or IV once per day beginning on day 4 (24 hours after completion of chemotherapy) and continuing until ANC greater than 1500/μL
**Cycle 2: 5 mcg/kg SC or IV once per day beginning on day 2 (24 hours after completion of chemotherapy) and continuing until ANC greater than 1500/μL
21-day cycle for 8 cycles
===References===
#COG ANBL0531: Twist CJ, Schmidt ML, Naranjo A, London WB, Tenney SC, Marachelian A, Shimada H, Collins MH, Esiashvili N, Adkins ES, Mattei P, Handler M, Katzenstein H, Attiyeh E, Hogarty MD, Gastier-Foster J, Wagner E, Matthay KK, Park JR, Maris JM, Cohn SL. Maintaining Outstanding OUtcomes Using Response- and Biology-Based Therapy for Intermediate-Risk Neuroblastoma: A Report from the Children's Oncology Group Study ANBL0531. J Clin Oncol. 2019 Dec 1;37(34):3243-55. Epub 2019 Aug 6. link to original article link to PMC article EuroPMC NCT00499616
==COG ANBL0531 group 4==
===Regimen variant #1, BSA-based dosing===
Study 	Dates of enrollment	Evidence
Twist et al. 2019 (COG ANBL0531)	2007-2011 	Phase 2
Note: see paper for details about risk stratification and surgery. Except for filgrastrim, this protocol is identical to that used in COG A3961.
====Chemotherapy====
*Carboplatin (Paraplatin) as follows:
**Cycles 1, 2, 4, 6, 7: 560 mg/m2 IV once on day 1
*Etoposide (Vepesid) as follows: 
**Cycles 1, 3, 4, 5, 7: 120 mg/m2 IV once per day on days 1 to 3
*Cyclophosphamide (Cytoxan) as follows:
**Cycles 2, 3, 5, 6, 8: 1000 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) as follows:
**Cycles 2, 4, 6, 8: 30 mg/m2 IV once on day 1
====Supportive therapy====
*Filgrastim (Neupogen) as follows:
**Cycles 1, 3, 4, 5, 7: 5 mcg/kg SC or IV once per day beginning on day 4 (24 hours after completion of chemotherapy) and continuing until ANC greater than 1500/μL
**Cycles 2, 6, 8: 5 mcg/kg SC or IV once per day beginning on day 2 (24 hours after completion of chemotherapy) and continuing until ANC greater than 1500/μL
21-day cycle for 8 cycles
===Regimen variant #2, weight-based dosing for children less than 12 kg===
Study 	Dates of enrollment	Evidence
Twist et al. 2019 (COG ANBL0531)	2007-2011 	Phase 2
Note: see paper for details about risk stratification and surgery. Except for filgrastrim, this protocol is identical to that used in COG A3961.
====Chemotherapy====
*Carboplatin (Paraplatin) as follows:
**Cycles 1, 2, 4, 6, 7: 18 mg/kg IV once on day 1
*Etoposide (Vepesid) as follows: 
**Cycles 1, 3, 4, 5, 7: 4 mg/kg IV once per day on days 1 to 3
*Cyclophosphamide (Cytoxan) as follows:
**Cycles 2, 3, 5, 6, 8: 33 mg/kg IV once on day 1
*Doxorubicin (Adriamycin) as follows:
**Cycles 2, 4, 6, 8: 1 mg/kg IV once on day 1
====Supportive therapy====
*Filgrastim (Neupogen) as follows:
**Cycles 1, 3, 4, 5, 7: 5 mcg/kg SC or IV once per day beginning on day 4 (24 hours after completion of chemotherapy) and continuing until ANC greater than 1500/μL
**Cycles 2, 6, 8: 5 mcg/kg SC or IV once per day beginning on day 2 (24 hours after completion of chemotherapy) and continuing until ANC greater than 1500/μL
21-day cycle for 8 cycles
===References===
#COG ANBL0531: Twist CJ, Schmidt ML, Naranjo A, London WB, Tenney SC, Marachelian A, Shimada H, Collins MH, Esiashvili N, Adkins ES, Mattei P, Handler M, Katzenstein H, Attiyeh E, Hogarty MD, Gastier-Foster J, Wagner E, Matthay KK, Park JR, Maris JM, Cohn SL. Maintaining Outstanding OUtcomes Using Response- and Biology-Based Therapy for Intermediate-Risk Neuroblastoma: A Report from the Children's Oncology Group Study ANBL0531. J Clin Oncol. 2019 Dec 1;37(34):3243-55. Epub 2019 Aug 6. link to original article link to PMC article EuroPMC NCT00499616
=High-risk, induction=
==COJEC==
COJEC: Cisplatin, Oncovin (Vicristine), JM8 (Carboplatin), Etoposide, Cyclophosphamide
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Pearson et al. 2008 (ENSG5)	1990-1999 	Phase 3 (E-esc)	OPEC/OJEC 	Seems to have higher EFS36 (co-primary endpoint)
====Chemotherapy====
*Cisplatin (Platinol) as follows:
**Cycles 2, 4, 6, 8: 80 mg/m2 IV continuous infusion over 24 hours, started on day 1
*Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once on day 1
*Carboplatin (Paraplatin) as follows:
**Cycles 1 & 5: 750 mg/m2 IV over 60 minutes once on day 1
*Etoposide (Vepesid) as follows:
**Cycles 1, 3, 5, 7: 175 mg/m2 IV over 4 hours once per day on days 1 & 2
*Cyclophosphamide (Cytoxan) as follows:
**Cycles 3 & 7: 1050 mg/m2 IV push once per day on days 1 & 2
10-day cycle for 8 cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00365755
##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 EuroPMC
==N5/N6==
===Regimen===
Study 	Dates 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===
#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 dosing details in supplement have been reviewed by our editors EuroPMC NCT03042429
=High-risk, consolidation after upfront induction=
==Busulfan & Melphalan, then auto HSCT==
===Regimen===
Study 	Dates 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	Higher EFS36 (primary endpoint)EFS36: 50% vs 38%
Note: the abstract does not specify exact days but this schedule is typical; IV dosing was used after a 2007 protocol amendment
====Chemotherapy====
*Busulfan (Myleran) 0.8 to 1.2 mg/kg IV every 6 hours on days -6 to -3 (16 total doses)
*Melphalan (Alkeran) 140 mg/m2 IV once on day -2
Stem cells re-infused on day 0
===References===
# 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 dosing details in abstract have been reviewed by our editors EuroPMC NCT01704716
==GM-CSF, IL-2, Isotretinoin, Dinutuximab [COG ANBL0032]==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Yu et al. 2010 (COG ANBL0032)	2001-2009 	Phase 3 (E-RT-esc)	Isotretinoin	Seems to have longer OS (secondary endpoint)Longer EFS (primary endpoint)
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, given 1 hour after completion of sargramostim infusion
**Cycles 2 & 4: 25 mg/m2 IV once per day on days 7 to 10
***Begin at a rate of 0.88 mg/m2/hr x 0.5 hrs, then increase to 1.75 mg/m2</hr for the remainder of the dose if tolerated
***Max Infusion Time = 20 hours even if the total dose has not been administered 
====Immunotherapy====
*[[Sargramostim (Leukine)]] as follows:
**Cycles 1, 3, 5: 250 mcg/m2 SC (strongly recommended) or IV 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====
*Isotretinoin (Accutane) by the following weight-based criteria:
**12 kg or less: 2.67 mg/kg (rounded to nearest 10 mg) PO twice per day on days 14 to 27
**More than 12 kg: 80 mg/m2 PO twice per day on days 14 to 27
28-day cycle for 6 cycles
====Dose and schedule modifications====
*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
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00026312
##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 EuroPMC
==Isotretinoin monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Matthay et al. 1999 	1991-1996 	Phase 3 (E-esc)	No further therapy 	Seems to have longer EFS (primary endpoint)
Yu et al. 2010 (COG ANBL0032)	2001-2009 	Phase 3 (C) 	GM-CSF, IL-2, Isotretinoin, Dinutuximab	Seems to have shorter OS
====Preceding treatment====
*Matthay et al. 1999: HDT with purged auto HSCT versus cisplatin, doxorubicin, etoposide consolidation
====Chemotherapy====
*Isotretinoin (Accutane) 80 mg/m2 PO twice per day on days 1 to 14
28-day cycle for 6 cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00026312
##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 EuroPMC
==Isotretinoin & Dinutuximab beta==
===Regimen===
Study 	Dates 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====
*Busulfan & Melphalan, then auto HSCT versus Carboplatin, Etoposide, Melphalan, then auto HSCT consolidation
====Chemotherapy, A portion (cycles 1, 3, 5, 7, 9, 11)====
*Isotretinoin (Accutane) 80 mg/m2 PO twice per day on days 1 to 14
====Targeted therapy, B portion (cycles 2, 4, 6, 8, 10)====
*Dinutuximab beta (Qarziba) by the following weight-based criteria:
**12 kg and more: 20 mg/m2 IV over 8 hours once per day on days 8 to 12
**5 kg up to 12 kg: 0.67 mg/kg IV over 8 hours once per day on days 8 to 12
**5 kg or less: 0.5 mg/kg IV over 8 hours once per day on days 8 to 12
14-day cycles alternating with 35-day cycles (A/B/A/B/A/B/A/B/A/B/A)
===References===
# 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 dosing details in supplement have been reviewed by our editors EuroPMC NCT01704716
=Maintenance=
==Eflornithine monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Sholler et al. 2018 (NMTRC003B)	2012-06 to 2016-02 	Phase 2 (RT)
Note: FDA approval was based on the propensity score analysis. Sholler et al. 2018 specified that a dosing table was provided for an exact dosing but gave a range of doses and the dosing table was not available in the manuscript.
====Targeted therapy====
*Eflornithine (Iwilfin) (dose not specified) PO twice per day on days 1 to 28
28-day cycle for 27 cycles (2 years)
===References===
#NMTRC003B: Sholler GLS, Ferguson W, Bergendahl G, Bond JP, Neville K, Eslin D, Brown V, Roberts W, Wada RK, Oesterheld J, Mitchell D, Foley J, Parikh NS, Eshun F, Zage P, Rawwas J, Sencer S, Pankiewicz D, Quinn M, Rich M, Junewick J, Kraveka JM. Maintenance DFMO Increases Survival in High Risk Neuroblastoma. Sci Rep. 2018 Sep 27;8(1):14445. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02395666
##Propensity score analysis: Oesterheld J, Ferguson W, Kraveka JM, Bergendahl G, Clinch T, Lorenzi E, Berry D, Wada RK, Isakoff MS, Eslin DE, Brown VI, Roberts W, Zage P, Harrod VL, Mitchell DS, Hanson D, Saulnier Sholler GL. Eflornithine as Postimmunotherapy Maintenance in High-Risk Neuroblastoma: Externally Controlled, Propensity Score-Matched Survival Outcome Comparisons. J Clin Oncol. 2024 Jan 1;42(1):90-102. Epub 2023 Oct 26. link to original article link to PMC article EuroPMC
=Relapsed or refractory=
==Irinotecan, Temozolomide, Dinutuximab==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Mody et al. 2017 (COG ANBL1221)	2013-2015 	Randomized Phase 2, fewer than 20 pts (E-switch-ooc)	Irinotecan, Temozolomide, Temsirolimus	Higher ORR (primary endpoint)
Note: this dinutuximab dose is based on a mid-protocol revision.
====Chemotherapy====
*Irinotecan (Camptosar) 50 mg/m2 IV over 90 minutes once per day on days 1 to 5
*Temozolomide (Temodar) 100 mg/m2 PO once per day on days 1 to 5
====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====
*Sargramostim (Leukine) 250 mcg/m2 SC once per day on days 6 to 12
21-day cycle for up to 17 cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01767194
==Naxitamab monotherapy==
===Regimen===
Study 	Dates 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====
*Naxitamab (Danyelza) 3 mg/kg (maximum of 150 mg) IV once per day on days 1, 3, 5
====Supportive therapy====
*GM-CSF 250 mcg/m2 SC once per day on days -4 to 0, then 500 mcg/m2 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===
# 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 PMC article EuroPMC NCT01757626
#Study 201: NCT03363373
Category:Neuroblastoma regimens
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