Neuroblastoma

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

14 regimens on this page
15 variants on this page


Low-risk

Intermediate-risk, all lines of therapy

COG A3961 regimen

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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

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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

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Protocol

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

Chemotherapy, N5 cycles (1, 3, 5)

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

21-day cycle, alternating with N6 cycles

Chemotherapy, N6 cycles (2, 4, 6)

21-day cycle, alternating with N5 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 verified protocol in supplement PubMed NCT03042429

High-risk, consolidation

Busulfan & Melphalan, then auto HSCT

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Ladenstein et al. 2017 (HR-NBL1) 2002-2010 Phase 3 (E-switch-ic) 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: 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 protocol PubMed NCT01704716

GM-CSF, IL-2, Isotretinoin, Dinutuximab

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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 verified protocol PubMed NCT00026312

Isotretinoin monotherapy

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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

  • Matthay et al. 1999: HDT with purged auto HSCT versus cisplatin, doxorubicin, etoposide consolidation

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 verified protocol 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 verified protocol PubMed

Isotretinoin & Dinutuximab

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Ladenstein et al. 2018 (HR-NBL1) 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: 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

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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

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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

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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 medications

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 verified protocol PubMed NCT01767194

Naxitamab monotherapy

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Regimen

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

Targeted therapy

Supportive medication

  • 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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