Advances in Risk Classification and Treatment Strategies for Neuroblastoma - PubMed (original) (raw)

Review

. 2015 Sep 20;33(27):3008-17.

doi: 10.1200/JCO.2014.59.4648. Epub 2015 Aug 24.

Mark A Applebaum 1, Samuel L Volchenboum 1, Katherine K Matthay 1, Wendy B London 1, Peter F Ambros 1, Akira Nakagawara 1, Frank Berthold 1, Gudrun Schleiermacher 1, Julie R Park 1, Dominique Valteau-Couanet 1, Andrew D J Pearson 1, Susan L Cohn 2

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Review

Advances in Risk Classification and Treatment Strategies for Neuroblastoma

Navin R Pinto et al. J Clin Oncol. 2015.

Abstract

Risk-based treatment approaches for neuroblastoma have been ongoing for decades. However, the criteria used to define risk in various institutional and cooperative groups were disparate, limiting the ability to compare clinical trial results. To mitigate this problem and enhance collaborative research, homogenous pretreatment patient cohorts have been defined by the International Neuroblastoma Risk Group classification system. During the past 30 years, increasingly intensive, multimodality approaches have been developed to treat patients who are classified as high risk, whereas patients with low- or intermediate-risk neuroblastoma have received reduced therapy. This treatment approach has resulted in improved outcome, although survival for high-risk patients remains poor, emphasizing the need for more effective treatments. Increased knowledge regarding the biology and genetic basis of neuroblastoma has led to the discovery of druggable targets and promising, new therapeutic approaches. Collaborative efforts of institutions and international cooperative groups have led to advances in our understanding of neuroblastoma biology, refinements in risk classification, and stratified treatment strategies, resulting in improved outcome. International collaboration will be even more critical when evaluating therapies designed to treat small cohorts of patients with rare actionable mutations.

© 2015 by American Society of Clinical Oncology.

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Conflict of interest statement

Authors' disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.

Figures

Fig 1.

Fig 1.

Current standard-of-care treatment strategy for high-risk neuroblastoma. Therapy consists of three treatment blocks: induction (chemotherapy and primary tumor resection); consolidation (high-dose chemotherapy with autologous stem-cell rescue and external-beam radiotherapy [XRT]); and postconsolidation (anti–ganglioside 2 immunotherapy with cytokines and _cis_-retinoic acid). ch, chimeric; CHO, Chinese hamster ovary; GM-CSF, granulocyte macrophage colony-stimulating factor; IL-2, interleukin-2; IV, intravenous; mAB, monoclonal antibody.

Fig 2.

Fig 2.

Probability of overall survival (OS) among 3,352 Children's Oncology Group (COG) patients with high-risk neuroblastoma diagnosed between 1990 and 2010 according to era. Five-year OS rates (+ SE) for patients diagnosed between 1990 and 1994 (n = 356), 1995 to 1999 (n = 497), 2000 to 2004 (n = 1,015), and 2005 to 2010 (n = 1,484) are 29% + 0.02, 34% + 0.02, 47% + 0.02, and 50% + 0.02, respectively. Data from COG Statistics and Data Center.

Fig 3.

Fig 3.

Current clinical approaches in targeting neuroblastoma. Iodine-131 (131I) plus metaiodobenzylguanidine (MIBG) is carried through norepinephrine transporter allowing for targeted radiotherapy. Small-molecule inhibitors of anaplastic lymphoma kinase (ALK) selectively bind constitutively phosphorylated mutant ALK receptors, leading to decreased signaling through phosphatidylinositol 3-kinase (PI3K)/AKT, mitogen-activated protein kinase (MAPK)/extracellular regulated kinase (ERK), and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways. Bromodomain and extraterminal domain (BET) bromodomain inhibitors (BDI) bind BRD4 protein, preventing DNA binding and transcription of MYCN. MYCN/MAX transcription complex directly targets ornithine decarboxylase (ODC), rate-limiting enzyme in production of polyamines, which plays role in cell replication, translation, growth, and survival. ODC inhibitors such as antihelmenthic agent difluoromethylornithine (DFMO) reduce polyamine synthesis. Aurora kinase inhibitors reduce ability of aurora kinase to bind to and stabilize MYCN protein, leading to its degradation. Immunotherapeutic approaches include use of chimeric antigen receptor (CAR) T cells against both L1-CAM and ganglioside 2 (GD2) cell surface antigens to promote host antitumor response. Anti-GD2 antibodies (ABs) bind GD2 and cause cell death by activating both complement-dependent cytotoxicity (CDC) and AB-dependent cellular cytotoxicity (ADCC) from natural-killer cells.

Fig 4.

Fig 4.

Workflow of interactive International Neuroblastoma Risk Group (INRG) database cohort discovery tool. (1) User builds query using interface. (2) Server executes query, returning cohort of patients to user. (3) Multiple affiliated data sources can be simultaneously queried. (4) Results are returned to server. (5) Aggregated results of query are presented back to researcher. GEO, Gene Expression Omnibus; GWAS, genome-wide association study; TARGET, Therapeutically Applicable Research to Generate Effective Treatments.

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