Off-label use of targeted therapies in osteosarcomas: data from the French registry OUTC'S (Observatoire de l'Utilisation des Thérapies Ciblées dans les Sarcomes):

BACKGROUND: The objective of this study is to explore the off-label use of targeted therapies (TTs) for patients with osteosarcoma registered within the French Sarcoma Group--Bone Tumor Study Group (GSF-GETO) national registry. METHODS: All patients with an osteosarcoma, registered between January 1, 2009 and July 15, 2013 were analyzed. RESULTS: Twenty-nine patients with refractory relapsed osteosarcomas received 33 treatment lines of TTs. The median age at the beginning of treatment was 19 years (range 9-72). The median number of previous lines of chemotherapy was 3 (range 1-8). Before inclusion, 3 patients were in second complete remission, 26 were in progression for metastatic relapse. Twenty-three patients received sirolimus (in combination with cyclophosphamide for 18); 5, sunitinib; 4, sorafenib; and one, pazopanib. Stable disease was observed for 45.5% of patients (95% Confidence Interval (CI) [20-52.8]). The median Progression-Free Survival (PFS) was 3 months (95% CI [2-5.4]) for patients treated by sirolimus and 1.8 months (95% CI [1.3-2.8]) for patients receiving multi-targeted tyrosine kinase inhibitors; 6-month PFS 15%. The median Overall Survival (OS) was 6.8 months (95% CI [4.7-12.1]), and one-year OS was 24%. In a multivariate analysis, PFS was superior for patients receiving sirolimus compared to other TTs (Hazard Ratio (HR) = 2.7, 95% CI [1.05-7.1]). No toxic death was reported. Grade 3 and 4 toxicities were observed in 27 and 6% of cases respectively. CONCLUSION: Off-label TTs, especially sirolimus, reported benefit in the treatment of refractory osteosarcomas with an acceptable toxicity profile, including in pediatric population

Le médecin consultant pour les limitations et les arrêts de traitement en pédiatrie

International audienceIn 2005, the French law on patients’ rights at the end of life ratified that decisions to withdraw or withhold life-sustaining treatments must be made and carried out by the physician in charge of the patient, after obtaining the advice of an independent consulting colleague. The purpose of this text is to put forward the perspective of a pediatric multidisciplinary workshop regarding the role of the consulting physician and to propose guidelines to help choose this consultant.La loi du 22 avril 2005 relative aux droits des malades et à la fin de vie (dite « loi Leonetti ») a donné un cadre légal aux décisions de limitation et d’arrêt de traitement (LAT) et a instauré l’obligation d’une délibération collégiale pour les patients hors d’état d’exprimer leur volonté. Les modalités de cette collégialité ont été précisées par le décret du 6 février 2006 qui impose au médecin en charge du patient de prendre l’avis motivé d’un consultant avant toute décision de LAT. Ces dispositions qui ont été intégrées dans l’article 37 du Code de déontologie médicale, nécessitent leur appropriation dans des disciplines dont la culture et la temporalité sont très différentes. En pédiatrie, l’application de cette loi doit tenir compte du rôle des parents puisque, sur le plan légal, l’enfant est représenté par ses parents, qu’il soit ou non en état d’exprimer sa volonté. L’objectif de ce texte est de définir les situations requérant la présence d’un consultant au sens de la loi Leonetti en pédiatrie, de préciser son positionnement et son rôle, et de proposer des éléments d’orientation pour en guider le choix en pratique

A Pharmacokinetic and Pharmacogenetic Analysis of Osteosarcoma Patients Treated With High-Dose Methotrexate: Data From the OS2006/Sarcoma-09 Trial

International audienc

Pixel-Bit

Resumen tomado de la publicaciónSe presenta una investigación sobre la utilización de dispositivos móviles de apoyo a la interpretación instrumental del alumnado de música de Educación Secundaria. El principal objetivo de esta investigación radica en analizar la eficacia de la utilización del teléfono móvil con microcontenidos para mejorar el rendimiento interpretativo de los alumnos.A través de la grabación en vídeo de los alumnos participantes y del diseño de partituras de control se ha logrado hacer un seguimiento minucioso de la interpretación instrumental, lo que ha permitido contar con datos valiosos del impacto del uso de las tecnologías móviles en este ámbito musical.Las conclusiones de este artículo demuestran que los alumnos que utilizan dispositivos móviles con microcontenidos cometen menos errores en la concatenación de dichos micro-contenidos que aquellos que no los utilizan, consiguiendo una mayor musicalidad. Igualmente, se pone en evidencia que dichos alumnos cometen menos errores puntuales de nota, lo que demuestra un mayor domino con el instrumento.ES

Results of methotrexate-etoposide-ifosfamide based regimen (M-EI) in osteosarcoma patients included in the French OS2006/sarcome-09 study

International audienceBACKGROUND:In most countries, reference chemotherapy for osteosarcoma is MAP regimen (M = high-dose methotrexate, AP = doxorubicin-cisplatinum). In France, the standard preoperative chemotherapy for children/adolescents combines M and etoposide-ifosfamide (EI), based on the OS94-trial. We report the safety and efficacy results of patients ≤25 years treated with preoperative M-EI regimen enroled in the French OS2006-study, between 2007 and 2014.METHODS:Treatment comprised preoperative chemotherapy with the 7 M-courses and 2 EI-courses, then surgery and postoperative chemotherapy assigned by risk's groups: standard-risk (good histological response without metastases) received 12 M-courses, 3 EI-courses; high-risk (poor histologic response, initial metastases or unresectable primary) received 5 M-courses alternated with 5 AP-courses. 253 patients were randomised to receive (n = 128) or not (n = 125) zoledronate.RESULTS:409/522 patients enroled in the OS2006 study who received preoperative M-EI were analysed. Median age was 14.3 years (4.7-24.5), with 55 patients aged 18-25 years. Primary tumour location was limb in 383 patients (94%) and 85 (21%) presented metastases. Median chemotherapy duration was 37.4 weeks. 381 (96%) patients underwent surgery, 258 patients (65%) had a good histologic response. 187/324 patients (58%) with localised disease did not receive doxorubicin nor cisplatinum. Toxicity was evaluated in the randomised study: most patients experienced ≥1 severe toxicity (grade IV haematological or grade III/IV extra-haematological). Median follow-up was 4.8 years, and 168 patients had events. Five-year event-free survival was 56% (95% CI, 51-62%) and overall survival 71% (66-76%).CONCLUSION:M-EI regimen/strategy was feasible for patient aged ≤25 years with survival rates are comparable to those obtained with MAP regimen

Additional file 5: of Prognostic impact of blood and urinary angiogenic factor levels at diagnosis and during treatment in patients with osteosarcoma: a prospective study

Table S3. Association between serum VEGF and bFGF and urinary bFGF levels at diagnosis and the risk of a poor histological response or treatment failure (multivariable analysis) (DOCX 16 kb

Zoledronate in combination with chemotherapy and surgery to treat osteosarcoma (OS2006): a randomised, multicentre, open-label, phase 3 trial

International audienceBACKGROUND:Based on preclinical data for the antitumour effect of zoledronate in osteosarcoma, we assessed whether zoledronate combined with chemotherapy and surgery improved event-free survival in children and adults with osteosarcoma.METHODS:In this randomised, multicentre, open-label, phase 3 trial (OS2006), patients aged between 5 years and 50 years with newly diagnosed high-grade osteosarcoma were randomly assigned to receive standard chemotherapy with or without ten zoledronate intravenous infusions (four preoperative and six postoperative). Adults older than 25 years received 4 mg zoledronate per infusion, patients aged 18-25 years received 0·05 mg/kg for the first two infusions and 4 mg for the remaining eight infusions, and younger patients received 0·05 mg/kg per infusion. Chemotherapy comprised high-dose methotrexate based chemotherapy in patients younger than 18 years, and doxorubicin, ifosfamide, and cisplatin in adults older than 25 years; patients aged 18-25 years were treated with either regime at the discretion of the treating centre. Balanced randomisation between the two groups was done centrally with online randomisation software, based on a minimisation algorithm taking into account centre, age, combined with chemotherapy regimen, and risk group (resectable primary and no metastasis vs other). Patients and investigators were not masked to treatment assignment, but the endpoint adjudication committee members who reviewed suspected early progressions were masked to group allocation. The primary endpoint was event-free survival, estimated from the randomisation to the time of first failure (local or distant relapse, progression, death) or to the last follow-up visit for the patients in first complete remission, analysed on a modified intention-to-treat population, which excluded patients found not to have a malignant tumour after central review. Three interim analyses were planned. This trial is registered with ClinicalTrials.gov, number NCT00470223.FINDINGS:Between April 23, 2007, and March 11, 2014, 318 patients, median age 15·5 years (range 5·8-50·9), were enrolled from 40 French centres; of whom 158 were assigned to the control group (chemotherapy alone) and 160 to the zoledronate group, including 55 (17%) patients with definite metastases. The trial was stopped for futility after the second interim analysis. With a median follow-up of 3·9 years (IQR 2·7-5·1), 125 events occurred (55 in the control group and 70 in the with zoledronate group). Event-free survival at 3 years for all 315 randomly assigned patients was 60·3% (95% CI 64·5-65·9); 3-year event-free survival was 63·4% (55·2-70·9) for the control group and 57·1% (48·8-65·0) for the zoledronate group. The risk of failure was not reduced and was even marginally higher in the zoledronate group than in the control group (hazard ratio [HR] 1·36 [95% CI 0·95-1·96]; p=0·094). No major increase in severe toxic effects of grade 3 or higher associated with zoledronate, barring expected hypocalcaemia (45 [29%] of 153 participants in the zoledronate group vs ten [6%] of 155 participants in the control group; p<0·0001) and hypophosphataemia (61 [40%] of 151 in the zoledronate group vs 26 [17%] of 156 in the control group; p<0·0001). No significant difference in orthopaedic complications was noted between the two groups (27 in the control group and 29 in the zoledronate group). Two treatment-related deaths were reported (one from cardiomyopathy in the control group and one from multiorgan failure in the zoledronate group before the first zoledronate infusion).INTERPRETATION:From the results observed in this study, we do not recommend zoledronate in osteosarcoma patients. Further biological studies are required to understand the discordance between the results of OS2006 trial and preclinical data.FUNDING:French National Cancer Institute (INCa), Novartis, Chugai, Ligue Nationale contre le Cancer, Fédération Enfants et Santé, Société Française des Cancers et Leucémies de l'Enfant

Late toxicity comparison of alkylating-based maintenance regimen with cyclophosphamide (VAC) vs ifosfamide (VAI) in Ewing sarcoma survivors treated in the randomized clinical trial Euro-EWING99-R1 in France

International audienceIn Euro-EWING99-R1 randomized trial, cyclophosphamide was shown to be noninferior to ifosfamide in the consolidation of standard-risk Ewing sarcoma (SR-EWS) after a common induction with VIDE (vincristine-ifosfamide-doxorubicin-etoposide). We present the results of the late effects analysis of VAC (vincristine-dactinomycin-cyclophoshamide) vs VAI (vincristine-dactinomycin-ifosfamide) conducted in Euro-EWING99-R1 French cohort. Of 267 French randomized patients, 204 were alive and free-of-relapse at 5-years including 172 with available long-term follow-up data concerning cardiac, renal and/or gonadal functions (sex-ratio M/F = 1.3, median age at diagnosis = 14 years): 84 randomized in VAC (median cumulative doses: cyclophosphamide = 9.7 g/m2, ifosfamide = 59.4 g/m2) and 88 in VAI (ifosfamide = 97.1 g/m2). With a median follow-up of 10 years (range = 5-17), five late relapses and five second malignancies were recorded. The 10-year event-free survival among 5-year free-of-relapse survivors was similar between VAC and VAI (93% vs 95%, P =.63). We estimated the 10-year cumulative probabilities of cardiac and kidney toxicities at 4.4% (95% confidence interval [95% CI] = 1.1%-7.6%) and 34.8% (95% CI = 26.8%-42.0%), respectively. Cardiac toxicity cumulative probability was similar in both arms, whereas kidney toxicity was higher in VAI (at 10 years, 43.0% vs 25.7%, P =.02), resulting from significant difference in glomerular toxicity (31.1% vs 13.1%, P &lt;.01). At 10 years, gonadal toxicity was observed in 27% and 28% of pubertal men and women, respectively, without significant difference between VAC and VAI. Kidney and gonadal toxicities represent major issues in Euro-EWING99-R1, with significantly higher risk of kidney toxicities with VAI, without significant gonadal toxicity reduction. These results support the need to limit cumulative doses of both alkylating agents and to use mixed regimen as in VIDE-VAC or VDC/IE (vincristine-doxorubicin-cyclophoshamide/ifosfamide-etoposide)