Difference between revisions of "Staging page"

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''Are you looking for a regimen, but can't find it here? It is possible that we've moved it to the [[Neuroblastoma_-_historical|historical regimens page]]. If you still can't find it, please let us know so we can add it!''
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Note: these are regimens tested in histology-specific populations, please see the '''[[Thyroid cancer|main thyroid cancer page]]''' for other regimens.
 
 
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|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div>
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|<b>Neuroblastoma</b>
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<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div>
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|-
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|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div>
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<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div>
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|-
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|ICD-O-3 code: 123.456
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|}
 +
''Neuroblastoma is a rare cancer but is the most common malignancy of infancy.''
 +
{{TOC limit|limit=4}}
 +
=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/m<sup>2</sup> 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/m<sup>2</sup> IV over 10 to 20 hours once daily on days 3 through 6
 +
**Begin [[Dinutuximab (Unituxin)]] infusion 1 hour after completion of [[Sargramostim (Leukine)]] infusion each day
 +
**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/m<sup>2</sup> (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====
 +
*[[Aldesleukin (Proleukin)]] 3,000,000 IU/m<sup>2</sup> IV continuous infusion over 96 hours (4 days) on day 0
 +
*[[Aldesleukin (Proleukin)]] 4,500,000 IU/m<sup>2</sup> IV continuous infusion over 96 hours (4 days) on day 7
 +
====Chemotherapy, Course 2 and 4====
 +
*[[Dinutuximab (Unituxin)]] 25 mg/m<sup>2</sup> 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/m<sup>2</sup> (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/m<sup>2</sup> 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====
 +
*[[Dinutuximab (Unituxin)]] 25 mg/m<sup>2</sup> IV over 10 to 20 hours once daily on days 3 through 6
 +
**Begin [[Dinutuximab (Unituxin)]] infusion 1 hour after completion of [[Sargramostim (Leukine)]] infusion each day
 +
**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/m<sup>2</sup> (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/m<sup>2</sup> (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'''
 +
</div></div>
 +
===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 [https://doi.org/10.3389/fimmu.2018.01355 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29967609/ link to PubMed] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6016521/ link to PMC article]  NCT01041638
 +
==COG ANBL0532 Regimen B==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===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/m<sup>2</sup> IV over 30 to 60 minutes once daily on days 1 through 5
 +
*[[Topotecan (Hycamtin)]] 1.2 mg/m<sup>2</sup> IV over 30 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/m<sup>2</sup> IV over 30 to 60 minutes once daily on days 1 through 5
 +
*[[Topotecan (Hycamtin)]] 1.2 mg/m<sup>2</sup> IV over 30 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/m<sup>2</sup> 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/m<sup>2</sup> 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/m<sup>2</sup> 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/m<sup>2</sup> 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/m<sup>2</sup> IV over 24 hours once daily on days 1 through 3
 +
'''21 Day Cycle'''
 +
====Supportive Therapy, Cycle 4 (CPM + DOXO + VCR)====
 +
*[[Mesna (Mesnex)]] by the following weight-based criteria:
 +
**≤ 12 kg: 14 mg/kg IV over 15 minutes immediately prior to each [[Cyclophosphamide (Cytoxan)]] dose and again at 4 and 8 hours after  each[[Cyclophosphamide (Cytoxan)]] infusion
 +
**> 12 kg: 420 mg/m<sup>2</sup> IV over 15 minutes immediately prior to each [[Cyclophosphamide (Cytoxan)]] dose and again at 4 and 8 hours after  each[[Cyclophosphamide (Cytoxan)]] infusion
 +
'''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/m<sup>2</sup> 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/m<sup>2</sup> 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/m<sup>2</sup> 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/m<sup>2</sup> 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/m<sup>2</sup> IV over 24 hours once daily on days 1 through 3
 +
'''21 Day Cycle'''
 +
====Supportive Therapy, Cycle 6 (CPM + DOXO + VCR)====
 +
*[[Mesna (Mesnex)]] by the following weight-based criteria:
 +
**≤ 12 kg: 14 mg/kg IV over 15 minutes immediately prior to each [[Cyclophosphamide (Cytoxan)]] dose and again at 4 and 8 hours after  each[[Cyclophosphamide (Cytoxan)]] infusion
 +
**> 12 kg: 420 mg/m<sup>2</sup> IV over 15 minutes immediately prior to each [[Cyclophosphamide (Cytoxan)]] dose and again at 4 and 8 hours after  each[[Cyclophosphamide (Cytoxan)]] infusion
 +
'''21 Day Cycle'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===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/m<sup>2</sup> 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/m<sup>2</sup> 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)====
 +
*[[Mesna (Mesnex)]] by the following weight-based criteria:
 +
**≤ 12 kg: 10 mg/kg IV over 15 minutes immediately prior to each [[Cyclophosphamide (Cytoxan)]] dose and again at 4 and 8 hours after  each[[Cyclophosphamide (Cytoxan)]] infusion
 +
**> 12 kg: 300 mg/m<sup>2</sup> IV over 15 minutes immediately prior to each [[Cyclophosphamide (Cytoxan)]] dose and again at 4 and 8 hours after  each[[Cyclophosphamide (Cytoxan)]] infusion
 +
*[[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/m<sup>2</sup> 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/m<sup>2</sup> 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/m<sup>2</sup> 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/m<sup>2</sup> 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/m<sup>2</sup> 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/m<sup>2</sup>) 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'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===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/m<sup>2</sup> (Round dose to nearest 10 mg) PO twice daily on days 1 through 14
 +
'''28 Day Cycle'''
 +
</div></div>
 +
===References===
 +
#'''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. [https://doi.org/10.1038/bmt.2012.276 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3638062/pdf/nihms426908.pdf link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23334272/ PubMed]
 +
==COG ANBL 0032 Regimen B==
 +
===Post Consolidation, Study Phase===
 +
====Immunotherapy, Course 1====
 +
*[[Sargramostim (Leukine)]] 250 μg/m<sup>2</sup> 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/m<sup>2</sup> IV over 10 to 20 hours on days 3 through 6
 +
**Begin [[Dinutuximab (Unituxin)]] at a rate of 0.88 mg/m<sup>2</sup>/hr x 0.5 hrs, then increase to 1.75 mg/m<sup>2</hr for the remainder of the dose if tolerated
 +
**Begin [[Dinutuximab (Unituxin)]] infusion 1 hour after completion of [[Sargramostim (Leukine)]] infusion each day
 +
**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/m<sup>2</sup> (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====
 +
*[[Aldesleukin (Proleukin)]] 3,000,000 IU/m<sup>2</sup> IV continuous infusion over 96 hours (4 days) on day 0
 +
*[[Aldesleukin (Proleukin)]] 4,500,000 IU/m<sup>2</sup> IV continuous infusion over 96 hours (4 days) on day 7
 +
====Chemotherapy, Course 2 and 4====
 +
*[[Dinutuximab (Unituxin)]] 25 mg/m<sup>2</sup> IV over 10 to 20 hours on days 3 through 6
 +
**Begin [[Dinutuximab (Unituxin)]] at a rate of 0.88 mg/m<sup>2</sup>/hr x 0.5 hrs, then increase to 1.75 mg/m<sup>2</hr for the remainder of the dose if tolerated
 +
**Begin [[Dinutuximab (Unituxin)]] infusion 1 hour after completion of [[Sargramostim (Leukine)]] infusion each day
 +
**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/m<sup>2</sup> (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/m<sup>2</sup> 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====
 +
*[[Dinutuximab (Unituxin)]] 25 mg/m<sup>2</sup> IV over 10 to 20 hours once daily on days 3 through 6
 +
**Begin [[Dinutuximab (Unituxin)]] infusion 1 hour after completion of [[Sargramostim (Leukine)]] infusion each day
 +
**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/m<sup>2</sup> (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/m<sup>2</sup> (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'''
 +
</div></div>
 +
===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 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. [https://doi.org/10.1056/nejmoa0911123 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3086629/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20879881/ PubMed]
 +
==COG ANBL17P1==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Induction===
 +
====Chemotherapy, Cycle 1 (TOPO/CPM)====
 +
*[[Cyclophosphamide (Cytoxan)]] by the following BSA-based criteria:
 +
**0.25 to 0.29 m<sup>2</sup>: 68 mg IV over 15 to 30 minutes once daily on days 1 through 5
 +
**0.3 to 0.34 m<sup>2</sup>: 100 mg IV over 15 to 30 minutes once daily on days 1 through 5
 +
**0.35 to 0.39 m<sup>2</sup>: 124 mg IV over 15 to 30 minutes once daily on days 1 through 5
 +
**0.4 to 0.44 m<sup>2</sup>: 148 mg IV over 15 to 30 minutes once daily on days 1 through 5
 +
**0.45 to 0.49 m<sup>2</sup>: 180 mg IV over 15 to 30 minutes once daily on days 1 through 5
 +
**0.5 to 0.54 m<sup>2</sup>: 200 mg IV over 15 to 30 minutes once daily on days 1 through 5
 +
**0.55 to 0.59 m<sup>2</sup>: 220 mg IV over 15 to 30 minutes once daily on days 1 through 5
 +
**≥ 0.6 m<sup>2</sup>: 400 mg/m<sup>2</sup> 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 m<sup>2</sup>: 0.32 mg IV over 30 minutes once daily on days 1 through 5
 +
**0.3 to 0.34 m<sup>2</sup>: 0.38 mg IV over 30 minutes once daily on days 1 through 5
 +
**0.35 to 0.39 m<sup>2</sup>: 0.44 mg IV over 30 minutes once daily on days 1 through 5
 +
**0.4 to 0.44 m<sup>2</sup>: 0.5 mg IV over 30 minutes once daily on days 1 through 5
 +
**0.45 to 0.49 m<sup>2</sup>: 0.56 mg IV over 30 minutes once daily on days 1 through 5
 +
**0.5 to 0.54 m<sup>2</sup>: 0.62 mg IV over 30 minutes once daily on days 1 through 5
 +
**0.55 to 0.59 m<sup>2</sup>: 0.68 mg IV over 30 minutes once daily on days 1 through 5
 +
**≥ 0.6 m<sup>2</sup>: 1.2 mg/m<sup>2</sup> 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 m<sup>2</sup>: 68 mg IV over 15 to 30 minutes once daily on days 1 through 5
 +
**0.3 to 0.34 m<sup>2</sup>: 100 mg IV over 15 to 30 minutes once daily on days 1 through 5
 +
**0.35 to 0.39 m<sup>2</sup>: 124 mg IV over 15 to 30 minutes once daily on days 1 through 5
 +
**0.4 to 0.44 m<sup>2</sup>: 148 mg IV over 15 to 30 minutes once daily on days 1 through 5
 +
**0.45 to 0.49 m<sup>2</sup>: 180 mg IV over 15 to 30 minutes once daily on days 1 through 5
 +
**0.5 to 0.54 m<sup>2</sup>: 200 mg IV over 15 to 30 minutes once daily on days 1 through 5
 +
**0.55 to 0.59 m<sup>2</sup>: 220 mg IV over 15 to 30 minutes once daily on days 1 through 5
 +
**≥ 0.6 m<sup>2</sup>: 400 mg/m<sup>2</sup> 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 m<sup>2</sup>: 0.32 mg IV over 30 minutes once daily on days 1 through 5
 +
**0.3 to 0.34 m<sup>2</sup>: 0.38 mg IV over 30 minutes once daily on days 1 through 5
 +
**0.35 to 0.39 m<sup>2</sup>: 0.44 mg IV over 30 minutes once daily on days 1 through 5
 +
**0.4 to 0.44 m<sup>2</sup>: 0.5 mg IV over 30 minutes once daily on days 1 through 5
 +
**0.45 to 0.49 m<sup>2</sup>: 0.56 mg IV over 30 minutes once daily on days 1 through 5
 +
**0.5 to 0.54 m<sup>2</sup>: 0.62 mg IV over 30 minutes once daily on days 1 through 5
 +
**0.55 to 0.59 m<sup>2</sup>: 0.68 mg IV over 30 minutes once daily on days 1 through 5
 +
**≥ 0.6 m<sup>2</sup>: 1.2 mg/m<sup>2</sup> 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 m<sup>2</sup>: 10 mg IV over 1 hour once daily on days 1 through 3
 +
**0.3 to 0.34 m<sup>2</sup>: 14 mg IV over 1 hour once daily on days 1 through 3
 +
**0.35 to 0.39 m<sup>2</sup>: 18 mg IV over 1 hour once daily on days 1 through 3
 +
**0.4 to 0.44 m<sup>2</sup>: 22 mg IV over 1 hour once daily on days 1 through 3
 +
**0.45 to 0.49 m<sup>2</sup>: 26 mg IV over 1 hour once daily on days 1 through 3
 +
**0.5 to 0.54 m<sup>2</sup>: 30 mg IV over 1 hour once daily on days 1 through 3
 +
**0.55 to 0.59 m<sup>2</sup>: 34 mg IV over 1 hour once daily on days 1 through 3
 +
**≥ 0.6 m<sup>2</sup>: 60 mg/m<sup>2</sup> IV over 1 hour once daily on days 1 through 3
 +
*[[Etoposide (Vepesid)]] by the following BSA-based criteria:
 +
**0.25 to 0.29 m<sup>2</sup>: 34 mg IV over 2 hours once daily on days 1 through 3
 +
**0.3 to 0.34 m<sup>2</sup>: 48 mg IV over 2 hours once daily on days 1 through 3
 +
**0.35 to 0.39 m<sup>2</sup>: 60 mg IV over 2 hours once daily on days 1 through 3
 +
**0.4 to 0.44 m<sup>2</sup>: 72 mg IV over 2 hours once daily on days 1 through 3
 +
**0.45 to 0.49 m<sup>2</sup>: 88 mg IV over 2 hours once daily on days 1 through 3
 +
**0.5 to 0.54 m<sup>2</sup>: 100 mg IV over 2 hours once daily on days 1 through 3
 +
**0.55 to 0.59 m<sup>2</sup>: 112 mg IV over 2 hours once daily on days 1 through 3
 +
**≥ 0.6 m<sup>2</sup>: 200 mg/m<sup>2</sup> IV over 2 hours once daily on days 1 through 3
 +
*[[Dinutuximab (Unituxin)]] 17.5 mg/m<sup>2</sup> IV over 10 hours (may be extended up to 20 hours) on days 2 through 5
 +
'''21-Day Cycle'''
 +
====Immunotherapy, Cycle 3 (GM-CSF)====
 +
*[[Sargramostim (Leukine)]] 250 μg/m<sup>2</sup> SubQ once on Day 6 (or Day 7) beginning 24 to 48 hours after completion of [[Dinutuximab (Unituxin)]] (Day 5)
 +
**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
 +
'''21-Day Cycle'''
 +
====Chemotherapy, Cycle 4 (VCR/DOXO/CPM/DIN)====
 +
*[[Vincristine (Oncovin)]] by the following BSA-based criteria:
 +
**0.25 to 0.29 m<sup>2</sup>: 0.32 mg IV push over 1 minute or IV infusion per institutional policy once on day 1
 +
**0.3 to 0.34 m<sup>2</sup>: 0.46 mg IV push over 1 minute or IV infusion per institutional policy once on day 1
 +
**0.35 to 0.39 m<sup>2</sup>: 0.6 mg IV push over 1 minute or IV infusion per institutional policy once on day 1
 +
**0.4 to 0.44 m<sup>2</sup>: 0.72 mg IV push over 1 minute or IV infusion per institutional policy once on day 1
 +
**0.45 to 0.49 m<sup>2</sup>: 0.88 mg IV push over 1 minute or IV infusion per institutional policy once on day 1
 +
**0.5 to 0.54 m<sup>2</sup>: 1 mg IV push over 1 minute or IV infusion per institutional policy once on day 1
 +
**0.55 to 0.59 m<sup>2</sup>: 1.1 mg IV push over 1 minute or IV infusion per institutional policy once on day 1
 +
**≥ 0.6 m<sup>2</sup>: 2 mg/m<sup>2</sup> (Max dose = 2 mg) IV push over 1 minute or IV infusion per institutional policy once on day 1
 +
***Administer prior to [[Dexrazoxane (Zinecard)]]
 +
*[[Doxorubicin (Adriamycin)]] by the following BSA-based criteria:
 +
**0.25 to 0.29 m<sup>2</sup>: 6.6 mg IV over 5 to 15 minutes on days 1, 2
 +
**0.3 to 0.34 m<sup>2</sup>: 9.2 mg IV over 5 to 15 minutes on days 1, 2
 +
**0.35 to 0.39 m<sup>2</sup>: 12 mg IV over 5 to 15 minutes on days 1, 2
 +
**0.4 to 0.44 m<sup>2</sup>: 14 mg IV over 5 to 15 minutes on days 1, 2
 +
**0.45 to 0.49 m<sup>2</sup>: 16 mg IV over 5 to 15 minutes on days 1, 2
 +
**0.5 to 0.54 m<sup>2</sup>: 18 mg IV over 5 to 15 minutes on days 1, 2
 +
**0.55 to 0.59 m<sup>2</sup>: 20 mg IV over 5 to 15 minutes on days 1, 2
 +
**≥ 0.6 m<sup>2</sup>: 37.5 mg/m<sup>2</sup> IV over 5 to 15 minutes on days 1, 2
 +
***given immediately after [[Dexrazoxane (Zinecard)]]
 +
*[[Cyclophosphamide (Cytoxan)]] by the following BSA-based criteria:
 +
**0.25 to 0.29 m<sup>2</sup>: 360 mg IV over 1 hour on days 1, 2
 +
**0.3 to 0.34 m<sup>2</sup>: 480 mg IV over 1 hour on days 1, 2
 +
**0.35 to 0.39 m<sup>2</sup>: 600 mg IV over 1 hour on days 1, 2
 +
**0.4 to 0.44 m<sup>2</sup>: 720 mg IV over 1 hour on days 1, 2
 +
**0.45 to 0.49 m<sup>2</sup>: 880 mg IV over 1 hour on days 1, 2
 +
**0.5 to 0.54 m<sup>2</sup>: 1000 mg IV over 1 hour on days 1, 2
 +
**0.55 to 0.59 m<sup>2</sup>: 1100 mg IV over 1 hour on days 1, 2
 +
**≥ 0.6 m<sup>2</sup>: 2000 mg/m<sup>2</sup> IV over 1 hour on days 1, 2
 +
*[[Dinutuximab (Unituxin)]] 17.5 mg/m<sup>2</sup> IV over 10 hours (may be extended up to 20 hours) on days 2 through 5
 +
'''21-Day Cycle'''
 +
====Immunotherapy, Cycle 4 (GM-CSF)====
 +
*[[Sargramostim (Leukine)]] 250 μg/m<sup>2</sup> SubQ once on Day 6 (or Day 7) beginning 24 to 48 hours after completion of [[Dinutuximab (Unituxin)]] (Day 5)
 +
**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
 +
'''21-Day Cycle'''
 +
====Supportive Therapy, Cycle 4====
 +
*[[Dexrazoxane (Zinecard)]] by the following BSA-based criteria:
 +
**0.25 to 0.29 m<sup>2</sup>: 66 mg IV over 5 to 15 minutes on days 1, 2
 +
**0.3 to 0.34 m<sup>2</sup>: 92 mg IV over 5 to 15 minutes on days 1, 2
 +
**0.35 to 0.39 m<sup>2</sup>: 120 mg IV over 5 to 15 minutes on days 1, 2
 +
**0.4 to 0.44 m<sup>2</sup>: 140 mg IV over 5 to 15 minutes on days 1, 2
 +
**0.45 to 0.49 m<sup>2</sup>: 160 mg IV over 5 to 15 minutes on days 1, 2
 +
**0.5 to 0.54 m<sup>2</sup>: 180 mg IV over 5 to 15 minutes on days 1, 2
 +
**0.55 to 0.59 m<sup>2</sup>: 200 mg IV over 5 to 15 minutes on days 1, 2
 +
**≥ 0.6 m<sup>2</sup>: 375 mg/m<sup>2</sup> IV over 5 to 15 minutes on days 1, 2
 +
***given immediately prior to [[Doxorubicin (Adriamycin)]]
 +
*[[Mesna (Mesnex)]] by the following weight-based criteria:
 +
**0.25 to 0.29 m<sup>2</sup>: 72 mg IV over 15 minutes immediately prior to each [[Cyclophosphamide (Cytoxan)]] dose and again at 3, 6, 9, & 12 hours from the start of [[Cyclophosphamide (Cytoxan)]] infusion
 +
**0.3 to 0.34 m<sup>2</sup>: 96 mg IV over 15 minutes immediately prior to each [[Cyclophosphamide (Cytoxan)]] dose and again at 3, 6, 9, & 12 hours from the start of [[Cyclophosphamide (Cytoxan)]] infusion
 +
**0.35 to 0.39 m<sup>2</sup>: 120 mg IV over 15 minutes immediately prior to each [[Cyclophosphamide (Cytoxan)]] dose and again at 3, 6, 9, & 12 hours from the start of [[Cyclophosphamide (Cytoxan)]] infusion
 +
**0.4 to 0.44 m<sup>2</sup>: 144 mg IV over 15 minutes immediately prior to each [[Cyclophosphamide (Cytoxan)]] dose and again at 3, 6, 9, & 12 hours from the start of [[Cyclophosphamide (Cytoxan)]] infusion
 +
**0.45 to 0.49 m<sup>2</sup>: 176 mg IV over 15 minutes immediately prior to each [[Cyclophosphamide (Cytoxan)]] dose and again at 3, 6, 9, & 12 hours from the start of [[Cyclophosphamide (Cytoxan)]] infusion
 +
**0.5 to 0.54 m<sup>2</sup>: 200 mg IV over 15 minutes immediately prior to each [[Cyclophosphamide (Cytoxan)]] dose and again at 3, 6, 9, & 12 hours from the start of [[Cyclophosphamide (Cytoxan)]] infusion
 +
**0.55 to 0.59 m<sup>2</sup>: 220 mg IV over 15 minutes immediately prior to each [[Cyclophosphamide (Cytoxan)]] dose and again at 3, 6, 9, & 12 hours from the start of [[Cyclophosphamide (Cytoxan)]] infusion
 +
**≥ 0.6 m<sup>2</sup>: 400 mg/m<sup>2</sup> IV over 15 minutes immediately prior to each [[Cyclophosphamide (Cytoxan)]] dose and again at 3, 6, 9, & 12 hours from the start of [[Cyclophosphamide (Cytoxan)]] infusion
 +
'''21-Day Cycle'''
 +
====Chemotherapy, Cycle 5 (CDDP/ETOP/DIN)====
 +
*[[Cisplatin (Platinol)]] by the following BSA-based criteria:
 +
**0.25 to 0.29 m<sup>2</sup>: 10 mg IV over 1 hour once daily on days 1 through 3
 +
**0.3 to 0.34 m<sup>2</sup>: 14 mg IV over 1 hour once daily on days 1 through 3
 +
**0.35 to 0.39 m<sup>2</sup>: 18 mg IV over 1 hour once daily on days 1 through 3
 +
**0.4 to 0.44 m<sup>2</sup>: 22 mg IV over 1 hour once daily on days 1 through 3
 +
**0.45 to 0.49 m<sup>2</sup>: 26 mg IV over 1 hour once daily on days 1 through 3
 +
**0.5 to 0.54 m<sup>2</sup>: 30 mg IV over 1 hour once daily on days 1 through 3
 +
**0.55 to 0.59 m<sup>2</sup>: 34 mg IV over 1 hour once daily on days 1 through 3
 +
**≥ 0.6 m<sup>2</sup>: 60 mg/m<sup>2</sup> IV over 1 hour once daily on days 1 through 3
 +
*[[Etoposide (Vepesid)]] by the following BSA-based criteria:
 +
**0.25 to 0.29 m<sup>2</sup>: 34 mg IV over 2 hours once daily on days 1 through 3
 +
**0.3 to 0.34 m<sup>2</sup>: 48 mg IV over 2 hours once daily on days 1 through 3
 +
**0.35 to 0.39 m<sup>2</sup>: 60 mg IV over 2 hours once daily on days 1 through 3
 +
**0.4 to 0.44 m<sup>2</sup>: 72 mg IV over 2 hours once daily on days 1 through 3
 +
**0.45 to 0.49 m<sup>2</sup>: 88 mg IV over 2 hours once daily on days 1 through 3
 +
**0.5 to 0.54 m<sup>2</sup>: 100 mg IV over 2 hours once daily on days 1 through 3
 +
**0.55 to 0.59 m<sup>2</sup>: 112 mg IV over 2 hours once daily on days 1 through 3
 +
**≥ 0.6 m<sup>2</sup>: 200 mg/m<sup>2</sup> IV over 2 hours once daily on days 1 through 3
 +
*[[Dinutuximab (Unituxin)]] 17.5 mg/m<sup>2</sup> IV over 10 hours (may be extended up to 20 hours) on days 2 through 5
 +
'''21-Day Cycle'''
 +
====Immunotherapy, Cycle 5 (GM-CSF)====
 +
*[[Sargramostim (Leukine)]] 250 μg/m<sup>2</sup> SubQ once on Day 6 (or Day 7) beginning 24 to 48 hours after completion of [[Dinutuximab (Unituxin)]] (Day 5)
 +
**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
 +
'''21-Day Cycle'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===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/m<sup>2</sup> 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/m<sup>2</sup> 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)====
 +
*[[Mesna (Mesnex)]] by the following weight-based criteria:
 +
**≤ 12 kg: 10 mg/kg IV over 15 minutes immediately prior to each [[Cyclophosphamide (Cytoxan)]] dose and again at 4 and 8 hours after  each[[Cyclophosphamide (Cytoxan)]] infusion
 +
**> 12 kg: 300 mg/m<sup>2</sup> IV over 15 minutes immediately prior to each [[Cyclophosphamide (Cytoxan)]] dose and again at 4 and 8 hours after  each[[Cyclophosphamide (Cytoxan)]] infusion
 +
*[[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/m<sup>2</sup> 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/m<sup>2</sup> 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/m<sup>2</sup> IV continuous infusion on days -7, -6, -5, -4
 +
*[[Carboplatin (Paraplatin)]] by the following criteria:
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 20%" |BSA (m<sup>2</sup>)
 +
! style="width: 20%" |GFR ≤ 100 mL/min/1.73 m<sup>2</sup>
 +
! style="width: 20%" |GFR 91-99 mL/min/1.73 m<sup>2</sup>
 +
! style="width: 20%" |GFR 76-90 mL/min/1.73 m<sup>2</sup>
 +
! style="width: 20%" |GFR 60-75 mL/min/1.73 m<sup>2</sup>
 +
|-
 +
|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/m<sup>2</sup>
 +
|300 mg/m<sup>2</sup>
 +
|260 mg/m<sup>2</sup>
 +
|230 mg/m<sup>2</sup>
 
|}
 
|}
−
{{TOC limit|limit=3}}
+
*PBSC on day 0
−
=Guidelines=
+
'''50-Day Cycle'''
−
==[https://www.thyroid.org/ ATA]==
+
====Supportive Therapy, Tandem HSCT #2 (CEM)====
−
*'''2015:''' Guidelines for the management of medullary thyroid carcinoma [https://pubmed.ncbi.nlm.nih.gov/27118126 PubMed]
+
*[[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
−
==[http://www.esmo.org/ ESMO]==
+
'''50-Day Cycle'''
−
*'''2019:''' Filetti et al. [https://doi.org/10.1093/annonc/mdz400 Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]
+
====Radiotherapy, ====
−
===Older===
+
*[[External beam radiotherapy]] by the following criteria no sooner than 42 days post-transplant:
−
*'''2012:''' Pacini et al. [http://annonc.oxfordjournals.org/content/23/suppl_7/vii110.full.pdf+html Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/22997443 PubMed]
+
**Primary tumor site and initially involved lymph nodes (CTV/PTV): 21.6  Gy in 12 daily fractions
−
==[https://www.nccn.org/ NCCN]==
+
**Metastatic disease present after Induction (mCTVx/mPTVx): 21.6 Gy in 12 daily fractions
−
*[https://www.nccn.org/professionals/physician_gls/pdf/thyroid.pdf NCCN Guidelines - Thyroid Carcinoma]
+
**Hepatomegaly leading to respiratory distress: 4.5 Gy delivered in 3 daily fractions
−
=All lines of therapy=
+
===Post-Consolidation===
−
==Cabozantinib monotherapy {{#subobject:1d67e4|Regimen=1}}==
+
'''Cycles 1 through 5'''
 +
'''Cycle 6'''
 +
====Chemotherapy, Cycle 1 through 5====
 +
*[[Dinutuximab (Unituxin)]] 17.5 mg/m<sup>2</sup> IV over 10 hours (may be extended up to 20 hours) on days 4 through 7
 +
*[[Isotretinoin (Accutane)]] by the following BSA-based criteria:
 +
**0.25 - 0.29 m<sup>2</sup>: 10 mg PO BID on days 11 through 24
 +
**0.3 - 0.39 m<sup>2</sup>: 20 mg PO BID on days 11 through 24
 +
**0.4 - 0.49 m<sup>2</sup>: 30 mg PO BID on days 11 through 24
 +
**0.5 - 0.59 m<sup>2</sup>: 40 mg PO BID on days 11 through 24
 +
**≥ 0.6 m<sup>2</sup>: 80 mg/m<sup>2</sup> (round to nearest 10 mg) PO BID on days 11 through 24
 +
'''28-Day Cycle'''
 +
====Immunotherapy, Cycle 1 through 5====
 +
*[[Sargramostim (Leukine)]] 250 μg/m<sup>2</sup> SubQ once on Day 1 through 14 prior to [[Dinutuximab (Unituxin)]]
 +
**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
 +
'''28-Day Cycles'''
 +
====Chemotherapy, Cycle 6====
 +
*[[Isotretinoin (Accutane)]] by the following BSA-based criteria:
 +
**0.25 - 0.29 m<sup>2</sup>: 10 mg PO BID on days 15 through 28
 +
**0.3 - 0.39 m<sup>2</sup>: 20 mg PO BID on days 15 through 28
 +
**0.4 - 0.49 m<sup>2</sup>: 30 mg PO BID on days 15 through 28
 +
**0.5 - 0.59 m<sup>2</sup>: 40 mg PO BID on days 15 through 28
 +
**≥ 0.6 m<sup>2</sup>: 80 mg/m<sup>2</sup> (round to nearest 10 mg) PO BID on days 15 through 28
 +
'''28-Day Cycle'''
 +
</div></div>
 +
===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. [https://doi.org/10.1158/1078-0432.ccr-19-1452 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825564/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31601569/ PubMed]
 +
#'''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. [https://doi.org/10.1200/JCO.21.01375 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825564/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34871104/ PubMed]
 +
=Low-risk=
 +
=Intermediate-risk, all lines of therapy=
 +
==COG A3961 regimen {{#subobject:fd2c99|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:d4c2dd|Variant=1}}===
+
===Regimen {{#subobject:c71517|Variant=1}}===
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
!style="width: 25%"|Study
 +
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2993160/ Baker et al. 2010 (COG A3961)]
 +
| style="background-color:#91cf61" |Non-randomized
 +
|-
 +
|}
 +
''To be completed.''
 +
====Chemotherapy====
 +
*See paper for details
 +
</div></div>
 +
===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. [https://doi.org/10.1056/NEJMoa1001527 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2993160/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20879880 PubMed]
 +
=High-risk, induction=
 +
==COJEC {{#subobject:4gjzb6|Regimen=1}}==
 +
COJEC: '''<u>C</u>'''isplatin, '''<u>O</u>'''ncovin (Vicristine), '''<u>J</u>'''M8 (Carboplatin), '''<u>E</u>'''toposide, '''<u>C</u>'''yclophosphamide
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:188h51|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
!style="width: 20%"|Study
 
!style="width: 20%"|Study
Line 34: Line 536:
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646303/ Kurzrock et al. 2011 (XL184-001)]
+
|[https://doi.org/10.1016/s1470-2045(08)70069-x Pearson et al. 2008 (ENSG5)]
−
|2005-2008
+
|1990-1999
−
| style="background-color:#91cf61" |Non-randomized
+
| style="background-color:#1a9851" |Phase 3 (E-esc)
−
| style="background-color:#d3d3d3" |
+
|[[#OPEC.2FOJEC_88|OPEC/OJEC]]
−
| style="background-color:#d3d3d3" |
+
| style="background-color:#91cf60" |Seems to have superior EFS36
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4164813/ Elisei et al. 2013 (EXAM)]
 
−
|2008-2011
 
−
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 
−
|[[#Placebo_2|Placebo]]
 
−
| style="background-color:#1a9850" |Superior PFS<br>Median PFS: 11.2 vs 4 mo<br>(HR 0.28, 95% CI 0.19-0.40)
 
 
|-
 
|-
 
|}
 
|}
−
''Note: To be taken at least 2 hours before or 1 hour after meals.''
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Targeted therapy====
+
====Chemotherapy====
−
*[[Cabozantinib (Cometriq)]] 140 mg PO once per day
+
*[[Cisplatin (Platinol)]]
−
'''Continued indefinitely'''
+
*[[Vincristine (Oncovin)]]
 +
*[[Carboplatin (Paraplatin)]]
 +
*[[Etoposide (Vepesid)]]
 +
*[[Cyclophosphamide (Cytoxan)]]
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''XL184-001:''' Kurzrock R, Sherman SI, Ball DW, Forastiere AA, Cohen RB, Mehra R, Pfister DG, Cohen EE, Janisch L, Nauling F, Hong DS, Ng CS, Ye L, Gagel RF, Frye J, Müller T, Ratain MJ, Salgia R. Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J Clin Oncol. 2011 Jul 1;29(19):2660-6. Epub 2011 May 23. [https://doi.org/10.1200/jco.2010.32.4145 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646303/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21606412 PubMed] NCT00215605
+
#'''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. [https://doi.org/10.1016/s1470-2045(08)70069-x link to original article] [https://pubmed.ncbi.nlm.nih.gov/18308250/ PubMed] NCT00365755
−
# '''EXAM:''' Elisei R, Schlumberger MJ, Müller SP, Schöffski P, Brose MS, Shah MH, Licitra L, Jarzab B, Medvedev V, Kreissl MC, Niederle B, Cohen EE, Wirth LJ, Ali H, Hessel C, Yaron Y, Ball D, Nelkin B, Sherman SI. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013 Oct 10;31(29):3639-46. Epub 2013 Sep 3. Erratum in: J Clin Oncol. 2014 Jun 10;32(17):1864. [https://doi.org/10.1200/jco.2012.48.4659 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4164813/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24002501 PubMed] NCT00704730
+
##'''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. [https://doi.org/10.1002/pbc.24452 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23281263/ PubMed]
−
## '''Update:''' Schlumberger M, Elisei R, Müller S, Schöffski P, Brose M, Shah M, Licitra L, Krajewska J, Kreissl MC, Niederle B, Cohen EEW, Wirth L, Ali H, Clary DO, Yaron Y, Mangeshkar M, Ball D, Nelkin B, Sherman S. Overall survival analysis of EXAM, a phase III trial of cabozantinib in patients with radiographically progressive medullary thyroid carcinoma. Ann Oncol. 2017 Nov 1;28(11):2813-2819. [https://doi.org/10.1093/annonc/mdx479 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834040/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29045520 PubMed]
+
==N5/N6 {{#subobject:4uyha6|Regimen=1}}==
−
==Placebo==
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen===
+
===Regimen {{#subobject:ayyh51|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
!style="width: 20%"|Study
 
!style="width: 20%"|Study
Line 67: Line 564:
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3675689/ Wells et al. 2011 (ZETA)]
+
|[https://doi.org/10.1016/j.annonc.2019.11.011 Berthold et al. 2020 (NB2004-HR)]
−
|2006-2007
+
|2004-2016
−
| style="background-color:#1a9851" |Phase 3 (C)
 
−
|[[#Vandetanib_monotherapy_2|Vandetanib]]
 
−
| style="background-color:#d73027" |Inferior PFS
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4164813/ Elisei et al. 2013 (EXAM)]
 
−
|2008-2011
 
 
| style="background-color:#1a9851" |Phase 3 (C)
 
| style="background-color:#1a9851" |Phase 3 (C)
−
|[[#Cabozantinib_monotherapy|Cabozantinib]]
+
|[[#N8_99|N8]], then [[#N5.2FN6|N5/N6]]
−
| style="background-color:#d73027" |Inferior PFS
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of EFS
 
|-
 
|-
 
|}
 
|}
−
''No active antineoplastic treatment. Included for reference purposes only.''
+
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, N5 cycles====
 +
*[[Vindesine (Eldisine)]] as follows:
 +
**Cycles 1, 3, 5: 3 mg/m<sup>2</sup> IV over 60 minutes once on day 1
 +
*[[Cisplatin (Platinol)]] as follows:
 +
**Cycles 1, 3, 5: 40 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 160 mg/m<sup>2</sup>)
 +
*[[Etoposide (Vepesid)]] as follows:
 +
**Cycles 1, 3, 5: 100 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 400 mg/m<sup>2</sup>)
 +
====Chemotherapy, N6 cycles====
 +
*[[Vincristine (Oncovin)]] as follows:
 +
**Cycles 2, 4, 6: 1.5 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 8
 +
*[[Dacarbazine (DTIC)]] as follows:
 +
**Cycles 2, 4, 6: 200 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5
 +
*[[Ifosfamide (Ifex)]] as follows:
 +
**Cycles 2, 4, 6: 1500 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 7500 mg/m<sup>2</sup>)
 +
*[[Doxorubicin (Adriamycin)]] as follows:
 +
**Cycles 2, 4, 6: 30 mg/m<sup>2</sup> IV over 4 hours once per day on days 6 & 7
 +
'''21-day cycle for 6 cycles'''
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''ZETA:''' Wells SA Jr, Robinson BG, Gagel RF, Dralle H, Fagin JA, Santoro M, Baudin E, Elisei R, Jarzab B, Vasselli JR, Read J, Langmuir P, Ryan AJ, Schlumberger MJ. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012 Jan 10;30(2):134-41. Epub 2011 Oct 24. [https://doi.org/10.1200/jco.2011.35.5040 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3675689/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22025146 PubMed] NCT00410761
+
#'''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. [https://doi.org/10.1016/j.annonc.2019.11.011 link to original article] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/32067684 PubMed] NCT03042429
−
# '''EXAM:''' Elisei R, Schlumberger MJ, Müller SP, Schöffski P, Brose MS, Shah MH, Licitra L, Jarzab B, Medvedev V, Kreissl MC, Niederle B, Cohen EE, Wirth LJ, Ali H, Hessel C, Yaron Y, Ball D, Nelkin B, Sherman SI. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013 Oct 10;31(29):3639-46. Epub 2013 Sep 3. Erratum in: J Clin Oncol. 2014 Jun 10;32(17):1864. [https://doi.org/10.1200/jco.2012.48.4659 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4164813/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24002501 PubMed] NCT00704730
+
=High-risk, consolidation=
−
==Sorafenib monotherapy {{#subobject:7e7480|Regimen=1}}==
+
==Busulfan & Melphalan, then auto HSCT {{#subobject:484436|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:1e2f21|Variant=1}}===
+
===Regimen {{#subobject:a61951|Variant=1}}===
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 33%"|Study
+
!style="width: 20%"|Study
−
!style="width: 33%"|Years of enrollment
+
!style="width: 20%"|Years of enrollment
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881718/ Lam et al. 2010 (OSU 06054)]
+
|[https://doi.org/10.1016/S1470-2045(17)30070-0 Ladenstein et al. 2017 (HR-NBL1 part 1)]
−
|2006-2008
+
|2002-2010
−
| style="background-color:#91cf61" |Phase 2
+
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[#Carboplatin.2C_Etoposide.2C_Melphalan.2C_then_auto_HSCT_88|Carboplatin, Etoposide, Melphalan, then auto HSCT]]
 +
| style="background-color:#1a9850" |Superior EFS36
 
|-
 
|-
 
|}
 
|}
 +
''Note: the abstract does not specify exact days but this schedule is typical; IV dosing was used after a 2007 protocol amendment''
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Targeted therapy====
+
====Chemotherapy====
−
*[[Sorafenib (Nexavar)]] 400 mg PO twice per day
+
*[[Busulfan (Myleran)]] 0.8 to 1.2 mg/kg IV every 6 hours on days -6 to -3 (16 total doses)
−
'''Continued indefinitely'''
+
*[[Melphalan (Alkeran)]] 140 mg/m<sup>2</sup> IV once on day -2
 +
'''Stem cells re-infused on day 0'''
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''OSU 06054:''' Lam ET, Ringel MD, Kloos RT, Prior TW, Knopp MV, Liang J, Sammet S, Hall NC, Wakely PE Jr, Vasko VV, Saji M, Snyder PJ, Wei L, Arbogast D, Collamore M, Wright JJ, Moley JF, Villalona-Calero MA, Shah MH. Phase II clinical trial of sorafenib in metastatic medullary thyroid cancer. J Clin Oncol. 2010 May 10;28(14):2323-30. Epub 2010 Apr 5. [https://doi.org/10.1200/jco.2009.25.0068 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881718/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20368568 PubMed] NCT00390325
+
# '''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. [https://doi.org/10.1016/S1470-2045(17)30070-0 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/28259608 PubMed] NCT01704716
−
==Sunitinib monotherapy {{#subobject:59fa83|Regimen=1}}==
+
==GM-CSF, IL-2, Isotretinoin, Dinutuximab {{#subobject:231faf|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:7e9b73|Variant=1}}===
+
===Regimen {{#subobject:abc626|Variant=1}}===
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 33%"|Study
+
!style="width: 20%"|Study
−
!style="width: 33%"|Years of enrollment
+
!style="width: 20%"|Years of enrollment
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3063514/ Carr et al. 2010]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3086629/ Yu et al. 2010 (COG ANBL0032)]
−
|2007-2009
+
|2001-2009
−
| style="background-color:#91cf61" |Phase 2
+
|style="background-color:#1a9851"|Phase 3 (E-RT-esc)
 +
|[[#Isotretinoin_monotherapy|Isotretinoin]]
 +
|style="background-color:#91cf60"|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.''
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Targeted therapy====
 
====Targeted therapy====
−
*[[Sunitinib (Sutent)]] 37.5 mg PO once per day
+
*[[Dinutuximab (Unituxin)]] as follows:
−
'''Continued indefinitely'''
+
**Cycles 1, 3, 5: 25 mg/m<sup>2</sup> IV once per day on days 3 to 6
 +
**Cycles 2 & 4: 25 mg/m<sup>2</sup> IV once per day on days 7 to 10
 +
====Immunotherapy====
 +
*[[Sargramostim (Leukine)]] as follows:
 +
**Cycles 1, 3, 5: 250 mcg/m<sup>2</sup> SC once per day on days 0 to 13
 +
*[[Aldesleukin (Proleukin)]] as follows:
 +
**Cycles 2 & 4: 3,000,000 IU/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 0, then 4,500,000 IU/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 7 (total dose per cycle: 30,000,000 IU/m<sup>2</sup>)
 +
====Chemotherapy====
 +
*[[Isotretinoin (Accutane)]] 160 mg/m<sup>2</sup>/day PO on days 14 to 27
 +
'''28-day cycle for 6 cycles'''
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# Carr LL, Mankoff DA, Goulart BH, Eaton KD, Capell PT, Kell EM, Bauman JE, Martins RG. Phase II study of daily sunitinib in FDG-PET-positive, iodine-refractory differentiated thyroid cancer and metastatic medullary carcinoma of the thyroid with functional imaging correlation. Clin Cancer Res. 2010 Nov 1;16(21):5260-8. Epub 2010 Sep 16. [https://doi.org/10.1158/1078-0432.CCR-10-0994 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3063514/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20847059 PubMed]
+
# '''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. [https://doi.org/10.1056/NEJMoa0911123 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3086629/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20879881 PubMed] NCT00026312
−
==Vandetanib monotherapy {{#subobject:a85524|Regimen=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. [https://doi.org/10.1158/1078-0432.ccr-20-3909 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8046731/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33504555/ PubMed]
 +
==Isotretinoin monotherapy {{#subobject:d9be60|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #1, 100 mg/day {{#subobject:148745|Variant=1}}===
+
===Regimen {{#subobject:54059a|Variant=1}}===
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 33%"|Study
+
!style="width: 20%"|Study
−
!style="width: 33%"|Years of enrollment
+
!style="width: 20%"|Years of enrollment
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1056/NEJM199910143411601 Matthay et al. 1999]
 +
|1991-1996
 +
|style="background-color:#1a9851"|Phase 3 (E-esc)
 +
|[[#Observation_88|No further therapy]]
 +
| style="background-color:#91cf60" |Seems to have superior EFS
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2902067/ Robinson et al. 2010 (D4200C00068)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3086629/ Yu et al. 2010 (COG ANBL0032)]
−
|2006-2007
+
|2001-2009
−
| style="background-color:#ffffbe" |Phase 2, <20 patients
+
|style="background-color:#1a9851"|Phase 3 (C)
 +
|[[#GM-CSF.2C_IL-2.2C_Isotretinoin.2C_Dinutuximab|GM-CSF, IL-2, Isotretinoin, Dinutuximab]]
 +
|style="background-color:#fc8d59"|Seems to have inferior OS
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*Matthay et al. 1999: [[Regimen_classes#High-dose_chemotherapy_with_auto_HSCT|HDT with purged auto HSCT]] versus [[#Cisplatin.2C_Doxorubicin.2C_Etoposide_88|cisplatin, doxorubicin, etoposide]] consolidation
 +
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Targeted therapy====
+
====Chemotherapy====
−
*[[Vandetanib (Caprelsa)]] 100 mg PO once per day
+
*[[Isotretinoin (Accutane)]] 80 mg/m<sup>2</sup> PO twice per day on days 1 to 14
−
'''Continued indefinitely'''
+
'''28-day cycle for 6 cycles'''
−
</div>
+
</div></div>
−
<div class="toccolours" style="background-color:#cbd5e7">
+
===References===
−
====Subsequent treatment====
+
# 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. [https://doi.org/10.1056/NEJM199910143411601 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10519894 PubMed]
−
*At progression, eligible patients could increase the dose to 300 mg PO once per day; see paper for details
+
# '''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. [https://doi.org/10.1056/NEJMoa0911123 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3086629/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20879881 PubMed] NCT00026312
−
</div></div><br>
+
##'''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. [https://doi.org/10.1158/1078-0432.ccr-20-3909 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8046731/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33504555/ PubMed]
 +
==Isotretinoin & Dinutuximab {{#subobject:d0nx60|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #2, 300 mg/day {{#subobject:e75f4f|Variant=1}}===
+
===Regimen {{#subobject:59ab1a|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
!style="width: 20%"|Study
 
!style="width: 20%"|Study
Line 156: Line 700:
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834392/ Wells et al. 2010]
+
|[https://doi.org/10.1016/S1470-2045(18)30578-3 Ladenstein et al. 2018 (HR-NBL1 part 2)]
−
|2004-2006
+
|2009-2013
−
| style="background-color:#91cf61" |Phase 2
+
|style="background-color:#1a9851"|Phase 3 (C)
−
| style="background-color:#d3d3d3" |
+
|[[#Interleukin-2.2C_Isotretinoin.2C_Dinutuximab_99|IL-2, Isotretinoin, Dinutuximab]]
−
| style="background-color:#d3d3d3" |
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of EFS36
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3675689/ Wells et al. 2011 (ZETA)]
 
−
|2006-2007
 
−
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 
−
|[[#Placebo_2|Placebo]]
 
−
| style="background-color:#1a9850" |Superior PFS<br>Median PFS: NYR vs 19.3 mo<br>(HR 0.46, 95% CI 0.31-0.69)
 
 
|-
 
|-
 
|}
 
|}
 +
''Note: this was a second randomization and second cohort of patients enrolled in HR-NBL1.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#Busulfan_.26_Melphalan.2C_then_auto_HSCT|Busulfan & Melphalan, then auto HSCT]] versus [[#Carboplatin.2C_Etoposide.2C_Melphalan.2C_then_auto_HSCT_88|Carboplatin, Etoposide, Melphalan, then auto HSCT]]
 +
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Isotretinoin (Accutane)]]
 
====Targeted therapy====
 
====Targeted therapy====
−
*[[Vandetanib (Caprelsa)]] 300 mg PO once per day
+
*[[Dinutuximab (Unituxin)]]
−
'''Continued indefinitely'''
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# Wells SA Jr, Gosnell JE, Gagel RF, Moley J, Pfister D, Sosa JA, Skinner M, Krebs A, Vasselli J, Schlumberger M. Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Oncol. 2010 Feb 10;28(5):767-72. Epub 2010 Jan 11. [https://doi.org/10.1200/jco.2009.23.6604 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834392/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20065189 PubMed]
+
# '''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. [https://doi.org/10.1016/S1470-2045(18)30578-3 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30442501 PubMed] NCT01704716
−
# '''D4200C00068:''' Robinson BG, Paz-Ares L, Krebs A, Vasselli J, Haddad R. Vandetanib (100 mg) in patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Endocrinol Metab. 2010 Jun;95(6):2664-71. Epub 2010 Apr 6. [https://doi.org/10.1210/jc.2009-2461 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2902067/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20371662 PubMed] content property of [http://hemonc.org HemOnc.org] NCT00358956
+
=Relapsed or refractory=
−
# '''ZETA:''' Wells SA Jr, Robinson BG, Gagel RF, Dralle H, Fagin JA, Santoro M, Baudin E, Elisei R, Jarzab B, Vasselli JR, Read J, Langmuir P, Ryan AJ, Schlumberger MJ. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012 Jan 10;30(2):134-41. Epub 2011 Oct 24. [https://doi.org/10.1200/jco.2011.35.5040 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3675689/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22025146 PubMed] NCT00410761
+
==Cyclophosphamide monotherapy {{#subobject:ea894c|Regimen=1}}==
−
=Advanced or metastatic disease=
 
−
==Axitinib monotherapy {{#subobject:73fcb6|Regimen=1}}==
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:aff447|Variant=1}}===
+
===Regimen {{#subobject:9134b2|Variant=1}}===
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
+
{| class="wikitable" style="width: 40%; text-align:center;"
−
!style="width: 33%"|Study
+
!style="width: 25%"|Study
−
!style="width: 33%"|Years of enrollment
+
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
|-
 +
|[https://doi.org/10.1056/NEJM196406182702503 Thurman et al. 1964]
 +
| style="background-color:#91cf61" |Non-randomized
 +
|-
 +
|}
 +
''Of historic interest.''
 +
====Chemotherapy====
 +
*[[Cyclophosphamide (Cytoxan)]]
 +
</div></div>
 +
===References===
 +
# Thurman WG, Fernbach DJ, Sullivan MP. Cyclophosphamide therapy in childhood neuroblastoma. N Engl J Med. 1964 Jun 18;270:1336-40. [https://doi.org/10.1056/NEJM196406182702503 link to original article] [https://pubmed.ncbi.nlm.nih.gov/14140265 PubMed]
 +
==Cyclophosphamide & Vincristine {{#subobject:f725b0|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:fecc86|Variant=1}}===
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
!style="width: 25%"|Study
 +
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://jamanetwork.com/journals/jama/article-abstract/343795 Evans et al. 1969]
 +
| style="background-color:#91cf61" |Non-randomized
 +
|-
 +
|}
 +
''Of historic interest.''
 +
====Chemotherapy====
 +
*[[Cyclophosphamide (Cytoxan)]]
 +
*[[Vincristine (Oncovin)]]
 +
</div></div>
 +
===References===
 +
# 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. [https://jamanetwork.com/journals/jama/article-abstract/343795 link to original article] [https://pubmed.ncbi.nlm.nih.gov/5818324 PubMed]
 +
==Irinotecan, Temozolomide, Dinutuximab {{#subobject:00704b|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:431f39|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Years of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://doi.org/10.1002/cncr.28766 Locati et al. 2014 (A4061027)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5527694/ Mody et al. 2017 (COG ANBL1221)]
−
|2006-2008
+
|2013-2015
−
| style="background-color:#91cf61" |Phase 2
+
|style="background-color:#91cf61"|Randomized Phase 2, <20 pts (E-switch-ooc)
 +
|[[#Irinotecan.2C_Temozolomide.2C_Temsirolimus_88|Irinotecan, Temozolomide, Temsirolimus]]
 +
|style="background-color:#1a9850"|Superior ORR
 
|-
 
|-
 
|}
 
|}
 +
''Note: this dinutuximab dose is based on a mid-protocol revision.''
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Irinotecan (Camptosar)]] 50 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1 to 5
 +
*[[Temozolomide (Temodar)]] 100 mg/m<sup>2</sup> PO once per day on days 1 to 5
 
====Targeted therapy====
 
====Targeted therapy====
−
*[[Axitinib (Inlyta)]] 5 mg PO twice per day
+
*[[Dinutuximab (Unituxin)]] 17.5 mg/m<sup>2</sup> IV over 10 hours once per day on days 2 to 5
−
'''Continued indefinitely'''
+
**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/m<sup>2</sup> SC once per day on days 6 to 12
 +
'''21-day cycle for up to 17 cycles'''
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''A4061027:''' Locati LD, Licitra L, Agate L, Ou SH, Boucher A, Jarzab B, Qin S, Kane MA, Wirth LJ, Chen C, Kim S, Ingrosso A, Pithavala YK, Bycott P, Cohen EE. Treatment of advanced thyroid cancer with axitinib: Phase 2 study with pharmacokinetic/pharmacodynamic and quality-of-life assessments. Cancer. 2014 Sep 1;120(17):2694-703. Epub 2014 May 20. [https://doi.org/10.1002/cncr.28766 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/24844950 PubMed] NCT00389441
+
# '''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. [https://doi.org/10.1016/S1470-2045(17)30355-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5527694/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28549783 PubMed] NCT01767194
−
==Sunitinib monotherapy {{#subobject:8d6c5|Regimen=1}}==
+
==Naxitamab monotherapy {{#subobject:ac2e27|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:d1cea4|Variant=1}}===
+
===Regimen {{#subobject:bf9b29|Variant=1}}===
−
{| class="wikitable sortable" style="width: 80%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
!style="width: 25%"|Study
+
!style="width: 33%"|Study
−
!style="width: 25%"|Years of enrollment
+
!style="width: 33%"|Years of enrollment
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
+
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6440722/ Kushner et al. 2018 (Study 12-230)]
 +
|2012-2016
 +
| style="background-color:#ffffbe" |Phase 1 (RT)
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3063514/ Carr et al. 2010]
+
|[https://www.clinicaltrials.gov/ct2/show/NCT03363373 Awaiting publication (Study 201)]
−
|2007-2009
+
|2018-ongoing
−
| style="background-color:#91cf61" |Phase 2
+
| style="background-color:#91cf61" |Phase 2 (RT)
−
|ORR: 31% (95% CI: 16-47)
 
 
|-
 
|-
 
|}
 
|}
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Targeted therapy====
 
====Targeted therapy====
−
*[[Sunitinib (Sutent)]] 37.5 mg PO once per day
+
*[[Naxitamab (Danyelza)]] 3 mg/kg (maximum of 150 mg/day) IV once per day on days 1, 3, 5
−
'''Continued indefinitely'''
+
====Supportive therapy====
 +
*[[Sargramostim (Leukine)|GM-CSF]] 250 mcg/m<sup>2</sup>/day SC once per day on days -4 to 0, then 500 mcg/m<sup>2</sup>/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.
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# Carr LL, Mankoff DA, Goulart BH, Eaton KD, Capell PT, Kell EM, Bauman JE, Martins RG. Phase II study of daily sunitinib in FDG-PET-positive, iodine-refractory differentiated thyroid cancer and metastatic medullary carcinoma of the thyroid with functional imaging correlation. Clin Cancer Res. 2010 Nov 1;16(21):5260-8. Epub 2010 Sep 16. [https://doi.org/10.1158/1078-0432.CCR-10-0994 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3063514/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20847059 PubMed]
+
# '''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. [https://doi.org/10.1001/jamaoncol.2018.4005 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6440722/ link to original article] [https://pubmed.ncbi.nlm.nih.gov/30326045/ PubMed] NCT01757626
−
[[Category:Thyroid cancer regimens]]
+
#'''Study 201:''' NCT03363373
 +
[[Category:Neuroblastoma regimens]]
 
[[Category:Disease-specific pages]]
 
[[Category:Disease-specific pages]]
−
[[Category:Endocrine cancers]]
+
[[Category:Pediatric solid tumors]]
−
[[Category:Head and neck cancers]]
 

Revision as of 23:43, 9 February 2023

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Section editor transclusions Are you looking for a regimen, but can't find it here? It is possible that we've moved it to the historical regimens page. If you still can't find it, please let us know so we can add it!

Neuroblastoma
0 regimens on this page
0 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

  • Dinutuximab (Unituxin) 25 mg/m2 IV over 10 to 20 hours once daily on days 3 through 6
  • 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

  • Dinutuximab (Unituxin) 25 mg/m2 IV over 10 to 20 hours once daily on days 3 through 6
  • 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
  • Topotecan (Hycamtin) 1.2 mg/m2 IV over 30 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
  • Topotecan (Hycamtin) 1.2 mg/m2 IV over 30 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)

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

  • Dinutuximab (Unituxin) 25 mg/m2 IV over 10 to 20 hours once daily on days 3 through 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

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
  • Dinutuximab (Unituxin) 17.5 mg/m2 IV over 10 hours (may be extended up to 20 hours) on days 2 through 5

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
  • Dinutuximab (Unituxin) 17.5 mg/m2 IV over 10 hours (may be extended up to 20 hours) on days 2 through 5

21-Day Cycle

Immunotherapy, Cycle 4 (GM-CSF)

21-Day Cycle

Supportive Therapy, Cycle 4

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
  • Dinutuximab (Unituxin) 17.5 mg/m2 IV over 10 hours (may be extended up to 20 hours) on days 2 through 5

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)

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
  • Carboplatin (Paraplatin) by the following criteria:
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

  • Dinutuximab (Unituxin) 17.5 mg/m2 IV over 10 hours (may be extended up to 20 hours) on days 4 through 7
  • 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
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