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Sainte-Foy-lès-Lyon, France

Aim: This phase II study evaluated efficacy, safety and pharmacokinetics (PK) profile of combination intravenous vinorelbine (VNL) and continuous low doses oral cyclophosphamide (CPM) combination in children and young adults with a recurrent or refractory solid tumour. Methods: A total of 117 patients (median age, 12 years) within six disease strata received intravenous VNL 25 mg/m 2 on days 1, 8 and 15 of each 28-day cycle combined with continuous daily oral CPM 25 mg/m2. Tumour response was assessed every two cycles according to WHO (World Health Organisation) criteria. PK of VNL was investigated in a subset of 18 patients aged 4-15 years. Results: In rhabdomyosarcoma (RMS) (n = 50), the best overall response rate (ORR) was 36% with four complete (8%) and 14 partial responses (28%). The best ORR was 13% in Ewing's sarcoma (n = 15), 6% in non-RMS soft tissue sarcoma (n = 16) and 6% in neuroblastoma (n = 16). No response was observed in osteosarcoma (n = 10) and medulloblastoma (n = 7). The main grade 3/4 toxicity was neutropenia (38%). Other severe toxicities were limited with 3% of peripheral neuropathy and no haemorrhagic cystitis. The PK analysis revealed equivalent blood exposure to VNL between children >4 years and adult series when the VNL dose was based on the body surface area-based dosing. Concluding statement: In heavily pre-treated children, VNL combined with CPM showed an interesting response rate in RMS and an acceptable toxicity profile supporting further evaluation of these agents in phase III trials. © 2012 Elsevier Ltd. All rights reserved.

Corradini N.,Nantes University Hospital Center | Laurence V.,University Pierre and Marie Curie | Dreno L.,Nantes University Hospital Center | Picherot G.,Nantes University Hospital Center | Marec-Berard P.,Institute dHematologie Oncologie Pediatrique
Oncologie | Year: 2011

The population of adolescents and young adults (AYA) in France has derived little benefit from the advances in oncology in recent decades. Nevertheless, the number of epidemiological studies and publications in the field of cancer for this age group have increased recently. This has allowed identification of specific needs in terms of cancer treatments, supportive care and psychosocial care, during and after the treatment. Only an improvement in the structure of care, especially the link between adult and paediatric medicine, will improve the results in terms of survival, and physical and psychological well-being in the short and long term, for this population. © 2011 Springer Verlag.

Couec M.-L.,Nantes University Hospital Center | Andre N.,Service dOncologie Pediatrique | Thebaud E.,Center Oscar Lambret | Minckes O.,Service dOncologie Pediatrique | And 6 more authors.
Pediatric Blood and Cancer | Year: 2012

Background: Bevacizumab, a monoclonal antibody targeting the vascular endothelial growth factor, has proven efficacy in some adult tumors; it is now proposed as a new therapeutic strategy for refractory or recurrent brain tumors in some children, either alone or combinated. Procedure: We retrospectively analyzed 28 children who received bevacizumab on a compassionate basis for refractory or recurrent brain tumors between June 2007 and August 2010 in 7 French centers. Among them, 12 had high-grade gliomas, 7 low-grade gliomas, 4 ependymomas, 2 primitive neurectodermal tumors, 3 neuroglial tumors. The median age at start of bevacizumab was 11.0 years. Bevacizumab was administered at 5-10mg/kg every 2 weeks, with concomitant chemotherapy for 27 patients. Results: Bevacizumab was used in combination with irinotecan in 27 patients. Bevacizumab-related toxicity was mild. Toxicities reported were grade I-II hypertension (n=4), proteinuria (n=1), lymphopenia (n=2), wound healing delay (n=2). Whereas tumor reduction could be observed in 6:7 patients with low-grade gliomas, no efficacy could be documented in patients with high-grade glioma, nor PNET nor ependymoma. Conclusion: Bevacizumab-related acute toxicity appears to be low in children, even in combination with irinotecan. Further prospective trials are required to confirm the hypothetical efficacy of bevacizumab and to assess the risk of long-term toxicity especially in the youngest children. © 2012 Wiley Periodicals, Inc.

Geoerger B.,University Paris - Sud | Hargrave D.,Royal Marsden Hospital | Thomas F.,Institute Claudius Regaud | Ndiaye A.,University Paris - Sud | And 15 more authors.
Neuro-Oncology | Year: 2011

This multicenter phase I study aimed to establish the recommended dose (RD) of the epidermal growth factor receptor (EGFR) inhibitor erlotinib, givenasmonotherapy or with radiotherapy to children with malignant brain tumors. Group 1 included patients with refractory or relapsing brain tumors receiving erlotinib alone, and group2 included newly diagnosed patients with brainstem gliomas receiving radiotherapy and erlotinib. A conventional 3 1 3 dose escalation and a continual reassessment method, respectively, were utilized in 4 dose levels: 75, 100, 125, and 150 mg/m2 per day. Fifty-one children were enrolled (30 and 21, respectively); 50 received treatment. The RD of erlotinib was 125 mg/m2 per day as monotherapy or in combination with radiotherapy. Overall, 230 adverse events in 44 patients were possibly treatment related (216, grades 1 and 2; 9, grade 3; 1, grade 4; 4, grade 5). Dermatologic and neurologic symptoms were common; intratumoral hemorrhage was confirmed in 3 patients. In group 1, 8 of 29 patients (28%) had stable disease with tumor regression approaching 50% in a malignant glioma and an anaplastic oligoastrocytoma. In group 2, overall survival was 12.0 months. EGFR overexpression by immunohistochemistry was found in 17 of 38 (45%) tumor samples analyzed, with a partial gain of 7p11.2 in 1 glioblastoma; phosphate and tensin homolog loss was frequent in brainstem glioma (15 of 19). Mean (95% CI) apparent clearance and volume of distribution for erlotinib were 4.0 L/h (3.4-4.5 L/h) and 98.6 L (69.8-127.0 L), respectively, and were independent of the dose level; mean half-life was 16.6 hours. Thus, erlotinib 125 mg/m 2 per day has an acceptable tolerability profile in pediatric patients with brain tumors and can be combined with radiotherapy. © The Author(s) 2010.

Ducassou S.,Institute dHematologie Oncologie Pediatrique | Ferlay C.,Center Leon Berard | Bergeron C.,Institute dHematologie Oncologie Pediatrique | Girard S.,Service dhematologie biologie | And 8 more authors.
British Journal of Haematology | Year: 2011

In children, lymphoblastic lymphomas represent 30% of Non-Hodgkin lymphomas (NHL), and approximately 15% are precursor B-cell lymphomas (PBLL). Our study evaluated their main clinical characteristics, evolution, and prognosis in three trials. From 1989 to 2008, 53 children with PBLL (median age 7·75years) were included in three protocols: Malignant Lymphoma Therapy (LMT) 96, European Organization for Research and Treatment of Cancer (EORTC) 58881, and EORTC 58951 using Berlin-Frankfürt-Münster-derived acute lymphoblastic leukaemia (ALL) therapy. There were 10 stage I disease, 9 stage II, 9 stage III and 25 stage IV. Clinical presentation was heterogeneous with a majority of bone lesions and cutaneous or subcutaneous manifestations. At diagnosis 23 patients had bone marrow involvement, and only three had central nervous system involvement. The median follow-up was 74months. At last follow-up, 45 patients were in continuous complete remission, whereas eight had progressed or had relapsed (7 Stages IV and 1 Stage III) and died. Two patients had a secondary neoplasia, and are still alive. Disease stage was a major prognostic factor, with better overall survival (OS) and event-free survival (EFS) (P<0·05) rates observed in patients with Stage I to III as compared to those with Stage IV. Treatment with protocols derived from ALL therapy are efficient with an 82% EFS and an 85% OS at 5years. © 2011 Blackwell Publishing Ltd.

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