The International Neuroblastoma Risk Group (INRG) Staging System: An INRG Task Force Report

Monclair, Tom; Brodeur, Garrett M.; Ambros, Peter F.; Brisse, H.; Cecchetto, Giovanni; Holmes, Keith; Kaneko, Michio; London, Wendy B.; Matthay, Katherine K.; Nuchtern, Jed G.; Schweinitz, Dietrich von; Simon, Thorsten; Cohn, Susan L.; Pearson, Andrew D.J.

doi:10.1200/jco.2008.16.6876

Cited by 881 publications

(680 citation statements)

References 20 publications

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“…EFS according to treatment period. High-dose busulfan in high-risk neuroblastoma S Proust-Houdemont et al BM involvement at diagnosis was associated with a worse prognosis, as already demonstrated by Hartmann et al, 32 and a good response to induction therapy seems to be another important prognostic factor in the HR-NBL population, as recently reported by other studies. 1,[34][35][36] It is noteworthy that the criteria required to receive HDC differed from those applied in the HR-NBL1/SIOPEN trial.…”

Section: Discussionsupporting

confidence: 62%

Busulfan–melphalan in high-risk neuroblastoma: the 30-year experience of a single institution

Pasqualini

Blanchard

et al. 2016

Bone Marrow Transplant

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High-dose chemotherapy (HDC) was investigated in high-risk neuroblastoma (HR-NBL) to reduce the risk of relapse. We report the results of the 30-year experience of a cohort of patients with HR-NBL treated with high-dose (HD) busulfan (Bu)-containing regimens. From 1980From to 2009 patients aged 41 year with stage 4 NBL were treated with HD Bu-containing regimens at Gustave Roussy. These data were prospectively recorded in the Pediatric Transplantation Database. The median age at diagnosis was 40 months (12-218 months). All patients had a stage 4 neuroblastoma. NMYC amplification was displayed in 24% of the tumors. The hematopoietic support consisted of bone marrow or PBSCs in 46% and 49% of patients, respectively. The 5-year eventfree survival and overall survival rates of the whole cohort were 35.1% and 40%, respectively. Age at diagnosis, bone marrow involvement and tumor response after induction chemotherapy were significant prognostic factors. Toxicity was manageable and decreased over time, owing to both PBSC administration and better supportive care. Based on this experience, HD Bu-melphalan (Mel) has been implemented in Europe and compared with Carboplatin-Etoposide-Mel in the European SIOP Neuroblastoma (SIOPEN)/HR-NBL randomized protocol. It has now become the standard HDC in the SIOPEN HR strategy. INTRODUCTIONThe improved survival rates of patients with high-risk (HR) neuroblastoma (NBL) observed during the past decades are related to the intensification of induction therapy, high-dose chemotherapy (HDC) and better supportive care. 1 In the HR-NBL population, a correlation between survival and dose intensity has been reported, and three randomized studies showed that HDC followed by autologous stem cell transplantation (ASCT) or autologous bone marrow transplantation (ABMT) improved survival rates. [2][3][4] As NBL is notoriously radiosensitive, hyperfractionated TBI was incorporated into the conditioning regimen and has yielded encouraging results. 5 Alkylating agents were demonstrated to produce a log-linear dose response against tumor cells in vitro. 6 Since the mid-1980s, HDC with alkylating agents and ASCT has been the treatment strategy used at Gustave Roussy. HD busulfan (Bu) was selected because of its specific cytotoxicity against quiescent cells, 7 as an alternative to TBI in HR-NBL patients to avoid its side-effects, 8 especially in this very young population, and to achieve better survival rates.We report here the results of our 30-year experience on patients with HR-NBL treated with HD Bu-containing regimens. Bu was combined with melphalan (Mel) or Mel plus cyclophosphamide, and HDC was followed by stem cell (SC) or bone marrow (BM) transplantation. These results provided the rationale to widely implement the use of HD Bu-Mel, which was then compared with Carboplatin-Etoposide-Mel (CEM) in the European SIOP Neuroblastoma (SIOPEN)/HR-NBL randomized trial. HD Bu-Mel has now become the standard HD regimen in the SIOPEN HR strategy.

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Section: Discussionsupporting

confidence: 62%

Busulfan–melphalan in high-risk neuroblastoma: the 30-year experience of a single institution

Pasqualini

Blanchard

et al. 2016

Bone Marrow Transplant

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“…In our neuroblastoma cohort, 69% (27/39) were defined as high-risk disease (defined according to classification systems) (12,13). Among the high-risk patients, 37% (10/27) had mutations in Rho/Rac-associated genes, whereas patients with Rho/Rac gene mutations were found in 25% (3/12) of patients with intermediate-and low-risk neuroblastoma (Table 1).…”

Section: Resultsmentioning

confidence: 99%

Rho-associated kinase is a therapeutic target in neuroblastoma

Dyberg

Fransson

Andonova

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Neuroblastoma is a peripheral neural system tumor that originates from the neural crest and is the most common and deadly tumor of infancy. Here we show that neuroblastoma harbors frequent mutations of genes controlling the Rac/Rho signaling cascade important for proper migration and differentiation of neural crest cells during neuritogenesis. RhoA is activated in tumors from neuroblastoma patients, and elevated expression of Rho-associated kinase (ROCK)2 is associated with poor patient survival. Pharmacological or genetic inhibition of ROCK1 and 2, key molecules in Rho signaling, resulted in neuroblastoma cell differentiation and inhibition of neuroblastoma cell growth, migration, and invasion. Molecularly, ROCK inhibition induced glycogen synthase kinase 3β-dependent phosphorylation and degradation of MYCN protein. Small-molecule inhibition of ROCK suppressed MYCN-driven neuroblastoma growth in TH-MYCN homozygous transgenic mice and MYCN gene-amplified neuroblastoma xenograft growth in nude mice. Interference with Rho/Rac signaling might offer therapeutic perspectives for high-risk neuroblastoma.N euroblastoma is a childhood tumor of the peripheral sympathetic nervous system, causing 6% of all childhood cancers but 9% of deaths from malignant tumors in children (1, 2). Approximately half of patients present with high-risk disease characterized by unresectable primary lesions and multiple metastases (2, 3). Although survival in this group has improved, the majority of the tumors show resistance to therapy with poor patient survival despite intensive multimodal therapy, necessitating the search for new therapeutic options (2).Compared with adult tumors, pediatric cancers exhibit significantly fewer genomic aberrations and mutations. In neuroblastoma, somatically acquired amplification of MYCN, hemizygous deletions of 1p and 11q, and gain of 17q are the most common chromosomal aberrations associated with a poor prognosis (3). Exome-and whole-genome sequencing analysis of neuroblastoma has reported an overall low somatic mutation count (12 to 18, median 15), with ALK being the most frequently mutated gene (7 to 10%) (4-6). In addition, chromothripsis, PHOX2B, and ATRX mutations have also been detected in a subset of highrisk tumors (4,5).Neuritogenesis is initiated during embryogenesis by a transient population of cells called the neural crest. During embryonic development, neural crest cells migrate throughout the embryo and eventually differentiate into multiple cell types, such as neurons and glial cells of the peripheral nervous system, pigment cells, fibroblasts, smooth muscle cells, and odontoblasts. The failure of neural crest cells to differentiate can result in development of cancers such as neuroblastoma and melanoma (7). A combination of Wingless (Wnt), bone morphogenetic protein, and fibroblast growth factor (FGF) signals is required to induce the formation of the neural crest and to initiate migration of neural crest cells by acquiring cell motility through epithelialmesenchymal transition (8). The no...

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“…The INRG staging system (INRGSS) uses preoperative radiological features and image-defined risk factors (IDRFs) to distinguish low-risk tumors from high-risk tumors [48,49]. The INRG classification system was developed based on analysis of 13 clinical and biological variables for effects on event-free survival rates, including patient age at diagnosis, INRGSS tumor stage, serum lactate dehydrogenase and ferritin levels, tumor histological category, grade of differentiation, tumor [51,52] (Figure 3).…”

Section: Prognosis and Risk Stratificationmentioning

confidence: 99%

Overview and recent advances in the treatment of neuroblastoma

Whittle

Smith

Doherty

et al. 2017

Expert Review of Anticancer Therapy

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Introduction: Children with neuroblastoma have widely divergent outcomes, ranging from cure in >90% of patients with low risk disease to <50% for those with high risk disease. Recent research has shed light on the biology of neuroblastoma, allowing for more accurate risk stratification and treatment reduction in many cases, although newer treatment strategies for children with high-risk and relapsed neuroblastoma are needed to improve outcomes. Areas covered: Neuroblastoma epidemiology, diagnosis, risk stratification, and recent advances in treatment of both newly diagnosed and relapsed neuroblastoma. Expert commentary: The identification of newer tumor targets and of novel cell-mediated immunotherapy agents may lead to novel therapeutic approaches, and clinical trials for regimens designed to target individual genetic aberrations in tumors are underway. A combination of therapeutic modalities will likely be required to improve survival and cure rates for patients with high-risk neuroblastoma.ARTICLE HISTORY

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The International Neuroblastoma Risk Group (INRG) Staging System: An INRG Task Force Report

Cited by 881 publications

References 20 publications

Busulfan–melphalan in high-risk neuroblastoma: the 30-year experience of a single institution

Busulfan–melphalan in high-risk neuroblastoma: the 30-year experience of a single institution

Rho-associated kinase is a therapeutic target in neuroblastoma

Overview and recent advances in the treatment of neuroblastoma

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