Neuroblastoma

Section editor
	Wayne H. Liang, MD, MS, FAMIA UAB Birmingham, AL LinkedIn WayneLiangMD

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

14 regimens on this page 15 variants on this page

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

N5/N6

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Protocol

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

Chemotherapy, N5 cycles

• Vindesine (Eldisine)
• Cisplatin (Platinol)
• Etoposide (Vepesid)

Chemotherapy, N6 cycles

• Vincristine (Oncovin)
• Dacarbazine (DTIC)
• Ifosfamide (Ifex)
• Doxorubicin (Adriamycin)

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 does not contain protocol 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 III (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

• Busulfan (Myleran) 0.8 to 1.2 mg/kg IV every 6 hours on days -6 to -3 (16 total doses)
• Melphalan (Alkeran) 140 mg/m² IV once on day -2

Stem cells re-infused on day 0

References

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

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 III (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.

Immunotherapy

• 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
• 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

• Isotretinoin (Accutane) 160 mg/m²/day PO on days 14 to 27

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

Isotretinoin monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Matthay et al. 1999	1991-1996	Phase III (E-esc)	No further therapy	Seems to have superior EFS
Yu et al. 2010 (COG ANBL0032)	2001-2009	Phase III (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

• Isotretinoin (Accutane) 80 mg/m² PO twice per day on days 1 to 14

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 III (C)	IL-2, Isotretinoin, Dinutuximab	Did not meet primary endpoint of EFS36

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

Preceding treatment

• Busulfan & Melphalan, then auto HSCT verus Carboplatin, Etoposide, Melphalan, then auto HSCT

Chemotherapy

• Isotretinoin (Accutane)

Immunotherapy

• Dinutuximab (Unituxin)

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

Relapsed or refractory

Cyclophosphamide monotherapy

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Regimen

Study	Evidence
Thurman et al. 1964	Non-randomized

Of historic interest.

Chemotherapy

• Cyclophosphamide (Cytoxan)

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

• Cyclophosphamide (Cytoxan)
• Vincristine (Oncovin)

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 II, <20 pts (E-switch-ooc)	Irinotecan, Temozolomide, Temsirolimus	Superior ORR

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

Chemotherapy

• Irinotecan (Camptosar) 50 mg/m² IV over 90 minutes once per day on days 1 to 5
• Temozolomide (Temodar) 100 mg/m² PO once per day on days 1 to 5

Immunotherapy

• 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

• Sargramostim (Leukine) 250 mcg/m² SC once per day on days 6 to 12

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

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Regimen

Study	Evidence
Study 201 (NCT03363373) Study 12-230 (NCT01757626)	Single-arm, open-label, non-randomized

Immunotherapy

• Naxitamab-gqgk (Danyelza) 3 mg/kg/day (maximum of 150 mg/day) IV once per day on days 1, 3, 5

Supportive medication

• GM-CSF 250 µg/m²/day SQ once per day on days -4 to 0 and 500 µg/m²/day SQ once per day on days 1 to 5

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

References

1. Clinicaltrials.gov Study 201 NCT03363373
2. Clinicaltrials.gov Study 12-230 NCT01757626
3. 11/24/2020 FDA approval
4. Naxitamab-gqgk (Danyelza) package insert