Too many targets, not enough patients: rethinking neuroblastoma clinical trials

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Neuroblastoma is a rare solid tumour of infancy and early childhood with a disproportionate contribution to paediatric cancer mortality and morbidity. Combination chemotherapy, radiation therapy and immunotherapy remains the standard approach to treat high-risk disease, with few recurrent, actionable genetic aberrations identified at diagnosis. However, recent studies indicate that actionable aberrations are far more common in relapsed neuroblastoma, possibly as a result of clonal expansion. In addition, although the major validated disease driver, MYCN, is not currently directly targetable, multiple promising approaches to target MYCN indirectly are in development. We propose that clinical trial design needs to be rethought in order to meet the challenge of providing rigorous, evidence-based assessment of these new approaches within a fairly small patient population and that experimental therapies need to be assessed at diagnosis in very-high-risk patients rather than in relapsed and refractory patients.

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The authors regret that, because of space limitations, they could not cite all original research articles and related references on this topic. Research in the authors’ laboratories is supported by National Health and Medical Research Council (NHMRC) Program Grant APP1016699, Development Grant APP1136278, Project Grants APP1125036 and 1085411 and Cancer Institute New South Wales (NSW) Translational Program Grant 10/TPG/1-03.

Author information

Author notes

  1. These authors contributed equally: Jamie I. Fletcher, David S. Ziegler, Toby N. Trahair


  1. Children’s Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, Australia

    • Jamie I. Fletcher
    • , David S. Ziegler
    • , Toby N. Trahair
    • , Glenn M. Marshall
    • , Michelle Haber
    •  & Murray D. Norris
  2. School of Women’s and Children’s Health, UNSW Sydney, Kensington, NSW, Australia

    • Jamie I. Fletcher
    • , David S. Ziegler
    • , Toby N. Trahair
    •  & Michelle Haber
  3. Kids Cancer Centre, Sydney Children’s Hospital, Randwick, NSW, Australia

    • David S. Ziegler
    • , Toby N. Trahair
    •  & Glenn M. Marshall
  4. University of New South Wales Centre for Childhood Cancer Research, UNSW Sydney, Kensington, NSW, Australia

    • Murray D. Norris


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M.D.N., G.M.M. and M.H. substantially contributed to discussions of content and reviewed and edited the manuscript before submission. J.I.F., D.S.Z. and T.N.T. researched data for the article, substantially contributed to discussions of content, wrote the article and reviewed and edited the manuscript before submission.

Competing interests

M.D.N. and M.H. own stock in Cleveland BioLabs, which is entitled to a portion of the royalties for sale of the Incuron product CBL0137. The other authors declare that they have no competing interests.

Corresponding author

Correspondence to Murray D. Norris.


Children’s Oncology Group

(COG). A childhood and adolescent cancer clinical trial consortium based in North America.

European International Society of Paediatric Oncology Neuroblastoma Group

(SIOPEN). A neuroblastoma clinical trials consortium based in Europe.

GD2 immunotherapy

An anti-neuroblastoma cancer immunotherapy that uses monoclonal antibodies targeting GD2 (for example, dinutuximab), either alone or in conjunction with interleukin-2 and/or granulocyte–macrophage colony-stimulating factor. GD2 is a tumour-associated disialoganglioside found on the surface of neuroblastoma cells.

High-dose therapy–myeloablative transplant

A treatment regimen involving very-high-dose chemotherapy with autologous stem cell transplantation that is used to eradicate residual neuroblastoma following induction chemotherapy.

Innovative Therapies for Children with Cancer

(ITCC). An early-phase clinical trial consortium for paediatric and adolescent cancers that is based in Europe.

Metaiodobenzylguanidine therapy

(MIBG therapy). Targeted radiation therapy using MIBG conjugated to iodinated radionuclides such as 131 I-MIBG.

Metastatic response

A measurable, objective response to therapy at metastatic sites.

MIBG scintigraphy

An imaging technique using metaiodobenzylguanidine (MIBG), which is a noradrenaline precursor that is selectively taken up by neuroendocrine cells via the noradrenaline transporter receptor; when radiolabelled, this uptake can be exploited for functional imaging.

MIBG non-avid disease

Cases of neuroblastoma (5–10%) with low or absent noradrenaline transporter receptor expression and thus no accumulation of metaiodobenzylguanidine (MIBG).

Type 1 error rate

The rate at which the null hypothesis is mistakenly rejected; the threshold is commonly set arbitrarily at 0.05 (5%). Relaxing the type 1 error threshold increases the chance of selecting a new treatment even if it is worse than standard of care but allows for smaller, faster trials and increased progress on average over time, resulting in better treatments and outcomes. As proposed new treatments are rarely worse than the standard of care, P values of 0.05 and 0.15 have only a 3% and a 7% chance, respectively, of selecting a worse treatment.

Window-of-opportunity design

A trial design in which patients receive one or more novel antitumour agents between their cancer diagnosis and standard-of-care therapy. Tumour sampling is undertaken before and after therapy for translational research.