Neuroblastoma - historical

Section editor
	Nicole M. Wood, DO University of Missouri Kansas City, MO, USA LinkedIn

The purpose of this page is to provide references to regimens that are obsolete, outdated, or of historical interest only.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

2 regimens on this page 2 variants on this page

High-risk, upfront therapy

COG ANBL0532 Regimen A

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Park et al. 2019 (COG ANBL0532)		Phase 3 (C)	COG ANBL0532 Regimen B	Inferior EFS

Induction

Chemotherapy, CPM + TOPO portion (cycles 1 & 2)

• 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, CPM + TOPO portion (cycles 1 & 2)

• Filgrastim (Neupogen) as follows:
  • Cycle 1: 5 mcg/kg SC or IV once per day, beginning 24 hours after completion of chemotherapy and continuing until ANC greater than 1000/μL
  • Cycle 2: 5 mcg/kg SC or IV once per day, beginning 24 hours after completion of chemotherapy and continuing until ANC greater than 1000/μL, then 10 mcg/kg SC or IV once per day until PBSC harvest is complete
    • PBSC harvest on day 14

Chemotherapy, EP portion (cycles 3 & 5)

• 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, CAV portion (cycles 4 & 6)

• 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 prior to doxorubicin on days 1 to 3
  • 12 months old or older AND more than 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 per day prior to doxorubicin on days 1 to 3
  • 12 months old or older AND 12 kg or less: 0.022 mg/kg (Max Dose of 2 mg in 72 hours) IV over 1 minute or infusion (per institutional policy) once per day prior to doxorubicin on days 1 to 3
• 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, CAV portion (cycles 4 & 6)

• 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, single autologous HSCT

Chemotherapy

• Melphalan (Alkeran) by the following laboratory- and weight-based criteria:
  • 12 kg or less AND GFR 100 mL/min or more: 2.3 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: 70 mg/m² IV over 15 to 30 minutes once per day on days -7, -6, -5
  • 12 kg or less and GFR 60 up 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 up 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 laboratory- and weight-based criteria:
  • 12 kg or less AND GFR 100 mL/min or more: 11.3 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: 338 mg/m² IV over 24 hours once per day on days -7, -6, -5, -4
  • 12 kg or less and GFR 60 up 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 up 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 laboratory- and weight-based criteria:
  • 12 kg or less AND GFR 100 mL/min or more: 14.2 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: 425 mg/m² IV over 24 hours once per day on days -7, -6, -5, -4
  • 12 kg or less and GFR 60 up 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 up 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,

• 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

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

1. 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 PubMed NCT00567567

COG ANBL 0032 Regimen A

Post-consolidation, Study Phase

Study	Dates of enrollment	Evidence
Yu et al. 2010 (COG ANBL0032)	2001-2009	Non-randomized part of phase 3 RCT

Chemotherapy

• Isotretinoin (Accutane) by the following weight-based criteria:
  • More than 12 kg: 80 mg/m² (round to nearest 10 mg) PO twice per day on days 11 to 24
  • 12 kg or less: 2.67 mg/kg (round to nearest 10 mg) PO twice per day on days 11 to 24

25-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 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

COG A3973 with Myeloablative Therapy

Study	Dates of enrollment	Evidence
Kreissman et al. 2013 (COG A3973)	2001-2006	Non-randomized part of phase 3 RCT

Note: PBSC Harvest occurs on Week 6 of treatment (cycle 2).

Induction

Chemotherapy, CAV portion (cycles 1, 2, 4, 6)

• Vincristine (Oncovin) by the following age- and weight-based criteria:
  • Younger than 12 months old: 0.017 mg/kg (Max Dose of 2 mg in 72 hours) IV over 1 minute or infusion (per institutional policy) once per day prior to doxorubicin on days 0 to 2
  • 12 months old or older AND more than 12 kg: 0.67 mg/m² or 0.022 mg/kg (choose lower dose) (Max Dose of 2 mg/m² in 72 hours) IV over 1 minute or infusion (per institutional policy) once per day prior to doxorubicin on days 0 to 2
  • 12 months old or older AND 12 kg or less: 0.022 mg/kg (Max Dose of 2 mg in 72 hours) IV over 1 minute or infusion (per institutional policy) once per day prior to doxorubicin on days 0 to 2
• Cyclophosphamide (Cytoxan) by the following weight-based criteria:
  • 12 kg or less: 70 mg/kg IV over 6 hours once per day on days 0, 1
  • More than 12 kg: 2100 mg/m² IV over 6 hours once per day on days 0, 1
• 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 0 to 2
  • More than 12 kg: 25 mg/m² IV over 24 hours once per day on days 0 to 2

Supportive therapy, CAV portion (cycles 1, 2, 4, 6)

• 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 on days 0, 1
  • More than 12 kg: 420 mg/m² IV over 15 minutes immediately prior to each cyclophosphamide dose and again at 3, 6, and 9 hours after each cyclophosphamide infusion on days 0, 1
• Filgrastim (Neupogen) 5 mcg/kg SC or IV once per day starting on day 3 and continuing until post-nadir ANC greater than 1500/μL

Chemotherapy, EP portion (cycles 3 & 5)

• 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 0 to 3
  • More than 12 kg: 50 mg/m² IV over 1 hour once per day on days 0 to 3
• Etoposide (Vepesid) by the following weight-based criteria:
  • 12 kg or less: 6.67 mg/kg IV over 2 hours once per day on days 0 to 2
  • More than 12 kg: 200 mg/m² IV over 2 hours once per day on days 0 to 2

Supportive therapy, EP portion (cycles 3 & 5)

• Filgrastim (Neupogen) 5 mcg/kg SC or IV once per day starting on day 4 and continuing until post-nadir ANC greater than 1500/μL

21-day cycle for 6 cycles

Consolidation

CEM: Carboplatin, Etoposide, Melphalan

Chemotherapy

• Carboplatin (Paraplatin) by the following laboratory- and weight-based criteria:
  • 12 kg or less AND GFR 100 mL/min or more: 14.2 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: 425 mg/m² IV over 24 hours once per day on days -7, -6, -5, -4
  • 12 kg or less and GFR 60 up 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
  • More than 12 kg and GFR 60 up 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
• Etoposide (Vepesid) by the following laboratory- and weight-based criteria:
  • 12 kg or less AND GFR 100 mL/min or more: 11.3 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: 338 mg/m² IV over 24 hours once per day on days -7, -6, -5, -4
  • 12 kg or less and GFR 60 up 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 up to 100 mL/min: 200 mg/m² IV over 24 hours once per day on days -7, -6, -5, -4
• Melphalan (Alkeran) by the following laboratory- and weight-based criteria:
  • 12 kg or less AND GFR 100 mL/min or more: 2.3 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: 70 mg/m² IV over 15 to 30 minutes once per day on days -7, -6, -5
  • 12 kg or less and GFR 60 up 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 up to 100 mL/min: 60 mg/m² IV over 15 to 30 minutes once per day on days -7, -6, -5

Stem cells re-infused on day 0

Maintenance, "Post Consolidation" Isotretinoin

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

1. COG A3973: Kreissman SG, Seeger RC, Matthay KK, London WB, Sposto R, Grupp SA, Haas-Kogan DA, Laquaglia MP, Yu AL, Diller L, Buxton A, Park JR, Cohn SL, Maris JM, Reynolds CP, Villablanca JG. Purged versus non-purged peripheral blood stem-cell transplantation for high-risk neuroblastoma (COG A3973): a randomised phase 3 trial. Lancet Oncol. 2013 Sep;14(10):999-1008. Epub 2013 Jul 25. link to original article link to PMC article PubMed NCT00004188
   1. Subgroup analysis: von Allmen D, Davidoff AM, London WB, Van Ryn C, Haas-Kogan DA, Kreissman SG, Khanna G, Rosen N, Park JR, La Quaglia MP. Impact of Extent of Resection on Local Control and Survival in Patients from the COG A3973 Study with High-Risk Neuroblastoma. J Clin Oncol. 2017 Jan 35;2:208-216. Epub 2016 Nov 21. link to original article link to PMC article link to PubMed

COG A3973 without Myeloablative Therapy

Study	Dates of enrollment	Evidence
Kreissman et al. 2013 (COG A3973)	2001-2006	Non-randomized part of phase 3 RCT

Induction

Chemotherapy, Cycles 1, 2, 4, and 6

• 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 prior to doxorubicin on days 0 to 2
  • 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 prior to doxorubicin on days 0 to 2
  • 12 months old or older AND more than 12 kg: 0.67 mg/m² or 0.022 mg/kg (choose lower dose) (maximum dose of 2 mg/m² in 72 hours) IV over 1 minute or infusion (per institutional policy) once per day prior to doxorubicin on days 0 to 2
• Cyclophosphamide (Cytoxan) by the following weight-based criteria:
  • 12 kg or less: 70 mg/kg IV over 6 hours once per day on days 0, 1
  • More than 12 kg: 2100 mg/m² IV over 6 hours once per day on days 0, 1
• 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 0 to 2
  • More than 12 kg: 25 mg/m² IV over 24 hours once per day on days 0 to 2

21-day cycles PBSC Harvest occurs on Week 6 of treatment (cycle 2)

Supportive therapy, Cycle 1, 2, 4, and 6

• 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 on days 0, 1
  • More than 12 kg: 420 mg/m² IV over 15 minutes immediately prior to each cyclophosphamide dose and again at 3, 6, and 9 hours after each cyclophosphamide infusion on days 0, 1
• Filgrastim (Neupogen) 5 mcg/kg SC or IV once per day starting on day 3 and continuing until post-nadir ANC greater than 1500/μL

21-day cycles

Chemotherapy, Cycles 3 and 5

• 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 0 to 3
  • More than 12 kg: 50 mg/m² IV over 1 hour once per day on days 0 to 3
• Etoposide (Vepesid) by the following weight-based criteria:
  • 12 kg or less: 6.67 mg/kg IV over 2 hours once per day on days 0 to 2
  • More than 12 kg: 200 mg/m² IV over 2 hours once per day on days 0 to 2

21-day cycles

Supportive therapy, Cycles 3 and 5

• Filgrastim (Neupogen) 5 mcg/kg SC or IV once per day starting on day 4 and continuing until post-nadir ANC greater than 1500/μL

21-day cycles

Maintenance, Cyclophosphamide and Topotecan

Chemotherapy, 3 cycles

• Cyclophosphamide (Cytoxan) by the following weight-based criteria:
  • 12 kg or less: 8.33 mg/kg IV over 30 minutes once per day on days 0 to 4
  • More than 12 kg: 250 mg/m² IV over 30 minutes once per day on days 0 to 4
• Topotecan (Hycamtin) by the following weight-based criteria:
  • 12 kg or less: 0.025 mg/kg IV over 30 minutes once per day on days 0 to 4
  • More than 12 kg: 0.75 mg/m² IV over 30 minutes once per day on days 0 to 4

21-day cycle

Supportive therapy, 3 cycles

• Mesna (Mesnex) by the following weight-based criteria:
  • 12 kg or less: 1.7 mg/kg IV over 15 minutes immediately prior to each cyclophosphamide dose and again at 4 and 8 hours after each cyclophosphamide infusion on days 0, 1
  • More than 12 kg: 50 mg/m² IV over 15 minutes immediately prior to each cyclophosphamide dose and again 3 hours after each cyclophosphamide infusion on days 0, 1
• Filgrastim (Neupogen) 5 mcg/kg SC or IV once per day starting on day 5 and continuing until post-nadir ANC greater than 1500/μL

21-day cycles

Maintenance, "Post Maintenance" Isotretinoin

Chemotherapy, 6 cycles

• 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

References

1. COG A3973: Kreissman SG, Seeger RC, Matthay KK, London WB, Sposto R, Grupp SA, Haas-Kogan DA, Laquaglia MP, Yu AL, Diller L, Buxton A, Park JR, Cohn SL, Maris JM, Reynolds CP, Villablanca JG. Purged versus non-purged peripheral blood stem-cell transplantation for high-risk neuroblastoma (COG A3973): a randomised phase 3 trial. Lancet Oncol. 2013 Sep;14(10):999-1008. Epub 2013 Jul 25. link to original article link to PMC article PubMed NCT00004188
   1. Subgroup analysis: von Allmen D, Davidoff AM, London WB, Van Ryn C, Haas-Kogan DA, Kreissman SG, Khanna G, Rosen N, Park JR, La Quaglia MP. Impact of Extent of Resection on Local Control and Survival in Patients from the COG A3973 Study with High-Risk Neuroblastoma. J Clin Oncol. 2017 Jan 35;2:208-216. Epub 2016 Nov 21. link to original article link to PMC article link to PubMed

Relapsed or refractory

Cyclophosphamide monotherapy

Regimen

Study	Evidence
Thurman et al. 1964	Non-randomized

Chemotherapy

• Cyclophosphamide (Cytoxan) 5 mg/kg IV once per day on days 1 to 10

10-day course

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 contains dosing details in manuscript PubMed

Cyclophosphamide & Vincristine

Regimen

Study	Evidence
Evans et al. 1969	Non-randomized

Chemotherapy

• Cyclophosphamide (Cytoxan) 10 mg/kg IV once on day 8
• Vincristine (Oncovin) 0.05 mg/kg IV once on day 1

14-day cycle for at least 6 cycles

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 contains dosing details in manuscript PubMed