Randomized Trial of Prophylactic Granulocyte Colony-Stimulating Factor During Rapid COJEC Induction in Pediatric Patients With High-Risk Neuroblastoma: The European HR-NBL1/SIOPEN Study

Ladenstein, Ruth; Valteau-Couanet, D; Brock, Pénélope; Yaniv, Isaac; Castel, Victoria; Laureys, Geneviève; Malis, J; Papadakis, Vassilios; Lacerda, Ana Forjaz de; Ruud, Ellen; Kogner, Per; Garami, Miklós; Balwierz, Walentyna; Schrøeder, Henrik; Beck‐Popovic, Maja; Schreier, G.; Machin, David; Pötschger, Ulrike; Pearson, Andrew D.J.

doi:10.1200/jco.2009.27.3524

Cited by 113 publications

(89 citation statements)

References 49 publications

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“…S2). All patients with high-risk neuroblastomas are subjected to the same induction treatment before surgical excision of the tumor (Table S3) (33), and all patients had at least 2 wk off chemotherapy before surgery. Any effect of the chemotherapeutic drugs on prostaglandin levels would have affected the patients in both of the high-risk subgroups (i.e., patients with 11q-deleted tumors and those with MYCN-amplified tumors) similarly.…”

Section: Discussionmentioning

confidence: 99%

COX/mPGES-1/PGE ₂ pathway depicts an inflammatory-dependent high-risk neuroblastoma subset

Larsson

Kock

Idborg

et al. 2015

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

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The majority of solid tumors are presented with an inflammatory microenvironment. Proinflammatory lipid mediators including prostaglandin E 2 (PGE 2 ) contribute to the establishment of inflammation and have been linked to tumor growth and aggressiveness. Here we show that high-risk neuroblastoma with deletion of chromosome 11q represents an inflammatory subset of neuroblastomas. Analysis of enzymes involved in the production of proinflammatory lipid mediators showed that 11q-deleted neuroblastoma tumors express high levels of microsomal prostaglandin E synthase-1 (mPGES-1) and elevated levels of PGE 2 . High mPGES-1 expression also corresponded to poor survival of neuroblastoma patients. Investigation of the tumor microenvironment showed high infiltration of tumor-promoting macrophages with high expression of the M2-polarization markers CD163 and CD206. mPGES-1-expressing cells in tumors from different subtypes of neuroblastoma showed differential expression of one or several cancer-associated fibroblast markers such as vimentin, fibroblast activation protein α, α smooth muscle actin, and PDGF receptor β. Importantly, inhibition of PGE 2 production with diclofenac, a nonselective COX inhibitor, resulted in reduced tumor growth in an in vivo model of 11q-deleted neuroblastoma. Collectively, these results suggest that PGE 2 is involved in the tumor microenvironment of specific neuroblastoma subgroups and indicate that therapeutic strategies using existing anti-inflammatory drugs in combination with current treatment should be considered for certain neuroblastomas.

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Section: Discussionmentioning

confidence: 99%

COX/mPGES-1/PGE ₂ pathway depicts an inflammatory-dependent high-risk neuroblastoma subset

Larsson

Kock

Idborg

et al. 2015

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

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“…If the pediatric regulation would have been running for the past 30 years, a class waiver could potentially have been obtained and none of these drugs would have been studied in pediatric malignancies, including neuroblastoma. Fortunately, large academic phase III trials have been run in Europe and in the United States to establish standard treatments for high-risk neuroblastoma using those chemotherapy drugs that are not licensed in this disease, a practice widespread in pediatric medicine (8,9). We cannot afford to allow the good intentions of the Pediatric Medicine regulation to hamper this academic endeavor.…”

Section: Discussionmentioning

confidence: 99%

Is the European Pediatric Medicine Regulation Working for Children and Adolescents with Cancer?

Vassal

Geoerger

Morland

2013

Clinical Cancer Research

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The European Pediatric Medicine Regulation was launched in 2007 to provide better medicines for children. Five years later, the number of new anticancer drugs in early development in the pediatric population remains low, and most children with cancer are still largely denied access to innovative drugs in Europe, as compared with the United States. We analyzed individual pediatric investigation plan (PIP) and waiver decisions for oncology drugs and all oncology drugs that have been approved for marketing authorization since 2007 in Europe. Among the 45 approved PIPs, 33% concern leukemias and lymphomas, 29% solid tumors, 13% brain tumors, and 20% a drug for supportive care. No specific PIP exists for lifethreatening diseases such as high-risk neuroblastoma, whereas there are several PIPs in extremely rare malignancies in children and adolescents such as gastrointestinal stromal tumor, melanoma, thyroid cancer, and chronic myeloid leukemia. This paradoxical situation is due to approval of a PIP being driven by the adult indication. Twenty-six of 28 authorized new oncology drugs have a potentially relevant mechanism of action for pediatric malignancies, but 50% have been waived because the adult condition does not occur in children. The most striking example is crizotinib. Implementation of the pediatric regulation should no longer be driven by the adult indication but should be guided instead by the biology of pediatric tumors and the mechanism of action of a drug. This change will be achievable through voluntary PIPs submitted by Pharma or revocation of the oncology class waiver list.

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“…1,[34][35][36] It is noteworthy that the criteria required to receive HDC differed from those applied in the HR-NBL1/SIOPEN trial. We included patients with a CR or PR of metastases after several lines of chemotherapy ('poor response'), whereas in the SIOPEN study eligibility criteria after Rapid COJEC induction (±2 courses of topotecan with vincristine and doxorubicin) 13,37 were a CR of BM and a PR on MIBG scan with ⩽ 3 residual positive spots.…”

Section: Discussionmentioning

confidence: 99%

“…Patient characteristics are described in Table 1. Before HDC, patients received a median number of six courses of conventional chemotherapy (range [4][5][6][7][8][9][10][11][12][13][14], over a median duration of 6 months (range 3-23). Good and poor responses after the first line of conventional chemotherapy were obtained in 73 (34%) and 142 (66%) patients, respectively.…”

Section: Patient Characteristicsmentioning

confidence: 99%

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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Randomized Trial of Prophylactic Granulocyte Colony-Stimulating Factor During Rapid COJEC Induction in Pediatric Patients With High-Risk Neuroblastoma: The European HR-NBL1/SIOPEN Study

Abstract: Following these results, PPG-GSF was advised for all patients on rapid COJEC induction.

Cited by 113 publications

References 49 publications

COX/mPGES-1/PGE ₂ pathway depicts an inflammatory-dependent high-risk neuroblastoma subset

COX/mPGES-1/PGE ₂ pathway depicts an inflammatory-dependent high-risk neuroblastoma subset

Is the European Pediatric Medicine Regulation Working for Children and Adolescents with Cancer?

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

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Randomized Trial of Prophylactic Granulocyte Colony-Stimulating Factor During Rapid COJEC Induction in Pediatric Patients With High-Risk Neuroblastoma: The European HR-NBL1/SIOPEN Study

Abstract: Following these results, PPG-GSF was advised for all patients on rapid COJEC induction.

Cited by 113 publications

References 49 publications

COX/mPGES-1/PGE 2 pathway depicts an inflammatory-dependent high-risk neuroblastoma subset

COX/mPGES-1/PGE 2 pathway depicts an inflammatory-dependent high-risk neuroblastoma subset

Is the European Pediatric Medicine Regulation Working for Children and Adolescents with Cancer?

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

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Product

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COX/mPGES-1/PGE ₂ pathway depicts an inflammatory-dependent high-risk neuroblastoma subset

COX/mPGES-1/PGE ₂ pathway depicts an inflammatory-dependent high-risk neuroblastoma subset