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The outcomes of adolescents/young adults with osteosarcoma have not improved in decades. The chaotic karyotype of this rare tumor has precluded the identification of prognostic biomarkers and patient stratification. We reasoned that transcriptomic studies should overcome this genetic complexity. RNA sequencing (RNA-seq) of 79 osteosarcoma diagnostic biopsies identified stable independent components that recapitulate the tumor and microenvironment cell composition. Unsupervised classification of the independent components stratified this cohort into favorable (G1) and unfavorable (G2) prognostic tumors in terms of overall survival. Multivariate survival analysis ranked this stratification as the most influential variable. Functional characterization associated G1 tumors with innate immunity and G2 tumors with angiogenic, osteoclastic, and adipogenic activities as well as PPARγ pathway upregulation. A focused gene signature that predicted G1/G2 tumors from RNA-seq data was developed and validated within an independent cohort of 82 osteosarcomas. This signature was further validated with a custom NanoString panel in 96 additional osteosarcomas. This study thus proposes new biomarkers to detect high-risk patients and new therapeutic options for osteosarcoma. Significance: These findings indicate that the osteosarcoma microenvironment composition is a major feature to identify hard-to-treat patient tumors at diagnosis and define the biological pathways and potential actionable targets associated with these tumors.

Supplementary Figure from Immune Infiltrate and Tumor Microenvironment Transcriptional Programs Stratify Pediatric Osteosarcoma into Prognostic Groups at Diagnosis

Supplementary Table from Immune Infiltrate and Tumor Microenvironment Transcriptional Programs Stratify Pediatric Osteosarcoma into Prognostic Groups at Diagnosis

The outcomes of adolescents/young adults with osteosarcoma have not improved in decades. The chaotic karyotype of this rare tumor has precluded the identification of prognostic biomarkers and patient stratification. We reasoned that transcriptomic studies should overcome this genetic complexity. RNA sequencing (RNA-seq) of 79 osteosarcoma diagnostic biopsies identified stable independent components that recapitulate the tumor and microenvironment cell composition. Unsupervised classification of the independent components stratified this cohort into favorable (G1) and unfavorable (G2) prognostic tumors in terms of overall survival. Multivariate survival analysis ranked this stratification as the most influential variable. Functional characterization associated G1 tumors with innate immunity and G2 tumors with angiogenic, osteoclastic, and adipogenic activities as well as PPARγ pathway upregulation. A focused gene signature that predicted G1/G2 tumors from RNA-seq data was developed and validated within an independent cohort of 82 osteosarcomas. This signature was further validated with a custom NanoString panel in 96 additional osteosarcomas. This study thus proposes new biomarkers to detect high-risk patients and new therapeutic options for osteosarcoma.Significance:These findings indicate that the osteosarcoma microenvironment composition is a major feature to identify hard-to-treat patient tumors at diagnosis and define the biological pathways and potential actionable targets associated with these tumors.

Desmoplastic small round cell tumor (DSRCT) is an aggressive sarcoma occurring in the young, teenager, and adult populations. The aim of this study is to compare initial tumor presentation, therapeutic management and scalability between pediatric and adult DSRCT patients and investigate the possibility of specific therapeutic approaches. A multicenter retrospective study of 81 Franco-Belgian medical files with DSRCT harboring Ewing sarcoma-Wilm tumor transcript was made. Median age was 17 years (3 to 58) with 42 children (13.5 y [3;17]) and 39 adults (28 y [18;58]). No significant differences were found between the 2 groups regarding initial symptoms and metastasis at diagnosis. The therapeutic approaches were similar for both groups: use of neoadjuvant chemotherapy (78.6% vs. 79.5%, P=1), primary surgery (71.4% vs. 69.2%, P=0.73), adjuvant chemotherapy (54.8% vs. 61.5%, P=0.99), radiotherapy (23.8% and 10.3%, P=0.11) and intraperitoneal chemotherapy (14.3% vs. 2.6%; P=0.11). Median time to recurrence was 12 versus 18 months (P=0.13). Overall survival at 2 years and recurrence free were 46.4% versus 60.1% (P=0.83) and 14.3% versus 16%, respectively (P=0.16). Clinical presentation, initial therapeutics and outcome of DSRCT are equivalent suggesting that similar management should be considered for children and adults with DSRCT.

Mucositis is defined as inflammatory and/or ulcerative lesions of the oral and/or gastrointestinal tract. It occurs in approximately 40% to 50% of adults patients receiving conventional chemotherapy and up to 75% of patients receiving high dose chemotherapy as conditioning for hematopoietic stem cell transplantation. It is a toxic side effect, which strongly impairs quality of life and leads to refractory pain, increasing risk of infection and even therapeutic modifications. Despite improvements made, the management of mucositis remains a challenge and is still not consensual. A multicentric survey of practices concerning the preventive and curative management of chemo-induced mucositis in pediatric oncology department in France was carried out using a standardized questionnaire. Results confirm heterogeneous practices and the small progress made during the last decade. This national survey and an analysis of the recent literature leads to propose guidelines for the prevention and treatment of oral mucositis in children receiving treatment for cancer.

Background/Objectives About 1,000,000 new cases of cancer in Adolescent and Young Adults (AYAs) are diagnosed annually worldwide. . While their long term survival is about 80%, they are six times more likely to develop a second primary cancer (SPC) compared to their peers. This risk is multifactorial and depends on the type of first cancer, treatment received and prevalence of risk factors. PREVAPAJA aimed to implement a clinical program based on physical activity (PA) and cancer prevention recommendations for AYAs with cancer at Centre Léon Bérard-AYAs Department. Methods The study was conducted at Leon Berard Comprehensive Cancer Centre among patients aged 15-25 years. AYAs attended PA sessions during the active treatment period and were individually informed on SPC risk prevention. PA, sedentary, anthropometrics, quality of life and fatigue were assessed at baseline (T1) and at the end of treatment (T2). PA level and intention of changes in health behaviors were assessed by phone 1 year after T1. Results 68 AYAs (median age=19 years) were enrolled in 2016-2017). The results showed an improvement in PA level during and at distance of the intervention, with also a reduction of sitting time. Fatigue decreased between T1 and T2 (p>0.003) and overall quality of life improved significantly between T1 and T2 (p>0.001). Conclusions This study showed the feasibility of implementing a clinical program based on PA intervention and cancer prevention recommendations for AYAs with cancer. It responded to AYAs' needs for support and discussions regarding PA recommendations and ways to prevent SPC. Beneficial outcomes of this program should encourage to systematically proposing PA intervention in combination with information exchanges with AYAs with cancer.

Objective: Regarding the efficiency of Bu-Mel-based high-dose-chemotherapy (Bu-Mel-HDCT) and whole lung irradiation (WLI), the objective was to evaluate the efficiency and safety of this salvage sequence in Ewing sarcoma (ES) lung relapses. Methods: All eligible pediatric ES patients (1991–2020) identified in SFCE departments were retrospectively reviewed. Seven patients were (1) diagnosed with a pulmonary relapse, isolated or not, (2) naïve from both HCDT and WLI (3) treated by the salvage sequence of conventional chemotherapy, Bu-Mel-HDCT and WLI. The main endpoint was OS evaluation. WLI toxicities were scored using CTC-V5. Results: With a 13 years median follow-up (FU), 5/7 patients are alive and in complete remission. 10y-EFS is 71.4%. Three patients experienced transitory radio-induced pneumopathy (RIP). A patient developed RIP (gr.3) and finally progressive lung fibrosis leading to death. Conclusion: This study reports seven ES patients treated for lung metastatic relapses, using an aggressive strategy, with favorable survival long-term results which should be balanced with the risk of lung toxicity. Advances in knowledge: The approach of surgery, Bu-Mel HDCT followed by WLI can be discussed in selected ES patients with lung relapse, naive from HDCT or WLI, providing an optimal chemosensitivity. A special vigilance is necessary regarding the incidence rate of lung toxicity which can be mitigated by limiting the radiotherapy dose, and observing optimal timing of radiotherapy after HDCT.

Sarcomas are a rare heterogeneous group of malignant neoplasms that can arise in almost any anatomic site and any age. Close collaboration among adult and pediatric cancer specialists in the management of these tumors is of foremost importance. In this review, we present the current multidisciplinary organization in care of patients with sarcoma in France and we review the main advances made in the last decades in systemic and radiotherapy treatment in the main sarcoma types diagnosed in children, adolescents and young adults (AYA), thanks to the international collaboration.

Purpose: The French standard chemotherapy for osteosarcoma combines high-dose methotrexate (HDM) and etoposide–ifosfamide (EI) in children and adolescents, and API-AI (doxorubicin–cisplatin–ifosfam...

Online Ahead of Print:October 30, 2019; International audience; Purpose: Treatment of pediatric cancers and hematological malignancies requires long periods of isolation in a sterile room. To promote family connections, telepresence robots have been made available in the homes of hospitalized patients. Our aim was to evaluate the perceived benefits and difficulties encountered by users and their families in terms of family dynamics. We also evaluated the presence of the robot on the medical caregivers' therapeutic relationship and organization of daily care. Methods: An observational study was undertaken with semistructured face-to-face interviews of 17 patients (aged 7 to 25 years) and their parents conducted by a psychologist on day +15 after provision of the robot and then after the patients had gone home, as well as face-to-face interviews of 15 caregivers by a philosopher before the robots were made available and at day +21. Results: One of the main perceived benefits expressed by the patients was maintenance of a connection with their siblings and retention of their role in the family. For parents, the device provided reassurance of being able to stay in touch with their child. The nursing staff indicated that the devices allowed them to develop more than a professional relationship with the child and to interact with their extended family. Limitations of the virtual nature of the nursing staff/family relationship were also noted, such as potential frustration for patients when they witness things that they cannot access and a degree of concern for the parents during periods of disconnection. Conclusions: This study revealed an overall perceived benefit for patients, their families, and caregivers. It also highlighted relevant issues and it provides guidelines for broader application of such devices.

Complementary and Alternative Medicines (CAM) are increasingly used in the therapeutic arsenal, particularly for pain management. Foot reflexology (FR) is still poorly evaluated, specifically in the pediatric population. The aim of this study was to evaluate the effectiveness of FR sessions in children experiencing chronic or persistent pain.We conducted a prospective study in two pediatric centers from January 2011 to January 2014. Sessions of FR were offered to children regardless of their age, experiencing persistent pain (72h) or chronic pain (3 months). A form was completed by the patient before and after each FR sessions. The effectiveness of the session was evaluated using a Visual Analogue Scale (VAS) for both pain and anxiety.One hundred and twenty-two patients suffering from persistent pain were included. We observed a significant decrease of mean VAS pain scores after each session (respectively P0.001, P0.001 and P=0.015) and of mean VAS anxiety scores (P0.001) for all sessions). Seventy patients suffering from chronic pain were included. Decrease in VAS pain scores was statistically significant after each reflexology session for children suffering from headache and musculoskeletal pain (P0.001). Anxiety was significantly lower after each session (P0.001).In 192 pediatric patients, FR significantly reduce pain and anxiety in children suffering from persistent or chronic pain. This CAM could have a place in pain management in children but needs to be evaluated in larger cohorts.

Resume Introduction Le Kyste Osseux Anevrysmatique (KOA) est une tumeur benigne qui implique la voie RANK/RANKL. La chirurgie est le traitement de reference, mais comporte certains risques selon la localisation kystique. Le denosumab, anticorps monoclonal humain de type IgG2 ciblant le systeme RANK/RANKL, pourrait avoir une efficacite antiproliferative sur cette tumeur. Le but de l’etude est d’evaluer l’interet du denosumab dans la prise en charge des kystes osseux anevrysmatiques inoperables chez l’enfant. Hypothese Le denosumab est un traitement utilisable chez l’enfant porteur d’un KOA resistant aux traitements dits classiques. Materiel et methode Les dossiers des patients traites par denosumab pour un KOA, dans les 32 centres pediatriques affilies a la SFCE (Societe Francaise du Cancer de l’Enfant) et au GSF-GETO (Groupe sarcome Francais), ont ete revus retrospectivement. Cinq cas ont ete declares, traites entre mars 2015 et juin 2018. La mediane d’âge etait de 8 ans (7–17 ans). Tous les patients presentaient des douleurs, et trois un deficit neurologique. Trois patients ont fait l’objet d’une chirurgie avant traitement, un apres traitement. Un n’a pas ete opere. Ils ont recu des injections mensuelles de denosumab de 70 mg/m2 pendant une duree mediane de 12 mois [4–23 mois]. L’evolution clinique et l’imagerie (scanner, IRM) ont ete analysees. Resultats Des anomalies secondaires du bilan phosphocalcique etaient identifiees pour deux cas. Avec un suivi median de 24 mois [0–28 mois] depuis la mise en route du traitement, les douleurs avaient disparu pour tous les patients, les deficits neurologiques etaient en amelioration. Des modifications radiologiques etaient observees dans tous les cas (remineralisation centrale, recorticalisation). Discussion Le denosumab est une alternative therapeutique pour certains kystes anevrysmatiques inaccessibles a la chirurgie. La toxicite immediate est acceptable. Une etude plus large et un suivi plus long seraient souhaitables pour confirmer cette indication. Niveau de preuve IV.

Background Aneurysmal bone cyst (ABC) is a benign tumour whose progression involves the RANK/RANKL signalling pathway. Surgery is the reference standard treatment but carries risks that vary with the site of the tumour. Denosumab is a human monoclonal IgG2 antibody that targets the RANK/RANKL pathway and may therefore hold promise for inhibiting ABC progression. The objective of this study was to evaluate denosumab use in paediatric patients (younger than 18 years) with ABC and to describe the clinical and radiological outcomes, as well as the side effect profile. Hypothesis Denosumab is a viable option in children with ABC refractory to standard treatments. Material and methods We retrospectively reviewed the medical files of paediatric patients given denosumab to treat ABC in any of 32 centres affiliated with the French Paediatric Cancer Society (Societe Francaise du Cancer de l’Enfant, SFCE) and French Sarcoma Group (Groupe Sarcome Francais, GSF-GETO). We identified 5 patients treated between March 2015 and June 2018. Median age was 8 years (range, 7–17 years). Pain was a symptom in all 5 patients and neurological deficits were present in 3 patients. Surgery was performed in 4 patients, either before (n = 3) or after (n = 1) denosumab therapy; the remaining patient had no surgery. Denosumab was given as monthly injections in a dosage of 70 mg/m2 for a median of 12 months (range, 4–23 months). The clinical outcomes and changes in computed tomography and/or magnetic resonance imaging findings were evaluated. Results Abnormalities in calcium and phosphate levels secondary to the ABC occurred in 2 patients. At median of 24 months (range, 0–28 months) after denosumab initiation, all 5 patients were free of pain, and the neurological deficits in 3 patients had improved. Central remineralisation and cortical reconstitution were demonstrated consistently by the imaging studies. Discussion Denosumab is a viable treatment option in selected paediatric patients with inoperable ABC. The immediate adverse effect profile is acceptable. A larger study with a longer follow-up would be welcome to further assess the contribution of denosumab to the treatment of ABC. Level of evidence IV.

Mucositis, an acute inflammation of the digestive mucosa, is one of the main toxicities secondary to oncological treatments. Among its consequences, mucositis-related pain is an important complication due to its intensity and repercussion, especially on quality of life. Treatment of pain plays a central role in management of mucositis. It must be multimodal, combining local and general opioid or non-opioid treatments, adapted to pain intensity and based on international recommendations updated in 2014. A systemic analgesic treatment with morphine with a patient-controlled analgesia device is often necessary in severe mucositis. In case of insufficient analgesia, use of co-analgesics (paracetamol, ketamine, anticonvulsants, and antidepressants) can improve analgesic control and reduce morphine doses. Non-drug strategies (distraction, relaxation, hypnosis) and preventive measures must be a major concern. Among them, laser therapy using a low power athermal laser beam, is a promising therapeutic strategy whose effectiveness is based on its analgesic, anti-inflammatory, and healing properties. Despite many available studies, there is a limited number of clinically effective therapies. New therapeutic agents for the prevention and treatment of mucositis and its pain, based on the biological phenomena involved, must be further developed to improve the efficacy of analgesia.

Resume Contexte L’utilisation d’un compte rendu standardise est indispensable pour repondre aux exigences de la certification des centres de references « sarcome osseux » par l’Institut national du cancer (INCa). Les classifications de reference, de la Musculoskeletal Tumor Society (MSTS), de l’American Joint Committee on Cancer (classification R du TNM/AJCC/IUCC) et du college americain des pathologistes, manquant de precision n’integrant pas l’effet de la chimiotherapie sur les cellules tumorales dans la mesure des marges chirurgicales, menant a une interpretation equivoque des marges par les equipes qui traitent les sarcomes osseux. Cette analyse de la litterature est destinee a evaluer les limites des classifications existantes pour etablir un compte rendu standardise de la prise en charge des pieces de resection osseuse des patients traites par chimiotherapie neoadjuvante et atteints d’osteosarcome ou de sarcome d’Ewing, en repondant aux questions : (1) quelle est la valeur pronostique des marges et de la reponse a la chimiotherapie dans les classifications ? ; (2) quelles sont les modifications histologiques induites par la chimiotherapie et leur impact sur l’interpretation des marges ? Methode Une analyse de la litterature ciblee sur la valeur pronostique des marges de resections chirurgicales, en utilisant le moteur de recherche PubMed a ete realisee en septembre 2018. Les recommandations du Groupe francais des pathologistes osseux, et internationales, de prise en charge des pieces de resection osseuses ont ete considerees pour choisir les items du compte rendu standardise. Sur 523 articles, 8 repondent aux criteres d’eligibilite. Resultats La mesure de la plus petite distance entre la tumeur et le trait chirurgical avec un seuil > 2 mm semblent les plus performants pour evaluer le risque de recidive locale. Une bonne reponse a la chimiotherapie et la localisation au squelette appendiculaire diminuent la probabilite de recidives locales. Aucune des classifications n’integre les modifications microscopiques induites par la chimiotherapie dans l’interpretation des marges chirurgicales. Discussion Pour uniformiser les pratiques, les membres du GROUPOS ont etabli collegialement un compte rendu standardise des pieces de resection des sarcomes osseux qui tient compte des modifications histopathologiques de la tumeur apres chimiotherapie. Le systeme R du TNM a ete adapte et une distance > 2 mm entre la tumeur et le plan de dissection a ete valide pour definir une marge saine R0. Le statut R1, ≤ 2 mm, a ete subdivise en 3 sous-groupes (a, b, c) pour integrer la mesure des marges par rapport a la cicatrice post-chimiotherapie : R1a, resection dans la « cicatrice » ; R1b, resection dans du tissu normal a ≤ 2 mm de la cicatrice et/ou de cellules viables residuelles ; R1c, resection intralesionnelle au contact de cellules viables ou dans des territoires de necrose de coagulation. Les membres du GROUPOS ont construit ce compte rendu standardise pour etablir un langage unique et ainsi ameliorer la prise en charge des sarcomes osseux dans les centres specialises. Des donnees fiables pourront etre etablies pour mener des etudes multicentriques nationales et internationales. Niveau de preuve IV.

ObjectivesKetamine, anN-methyl-D-aspartate receptor antagonist, is effective at relieving adult cancer pain, although there have been very few reports to date regarding its use in children and in adolescents and young adults (AYA). This study assessed the efficacy, safety and opioid-sparing effects of low doses of ketamine added to opioid analgesics to alleviate persistent cancer pain.MethodsThis prospective, multicentre, observational trial collected data regarding demographics, pain characteristics, pain score assessment within the first 48 hours of ketamine administration, tolerance and satisfaction from 38 patients aged 2–24 years prescribed with ketamine as an adjuvant antalgic for refractory cancer pain in 10 French paediatric oncology centres.ResultsThe mean visual analogue scale pain score decreased from 6.7 to 4.3 out of 10 (n=39, pConclusionsLow doses of ketamine as an adjuvant to opioids significantly reduced the intensity of pain in half of the study population. A tendency towards better pain control is shown, although a lack of statistical power somewhat limits our conclusions, especially in children. Nevertheless, ketamine may be a useful option for improving the treatment of refractory pain in children and AYA with cancer.

Pediatric sarcoma patients with pleuropulmonary lesions have a dismal prognosis because the impossibility to obtain local control. The aim of this study was to determine if pleuropneumonectomy (PP) could be a therapeutic option. We retrospectively reviewed nine patients who underwent salvage PP for pleuropulmonary localization of primary localized sarcoma or metastatic recurrence. Surgery and complications were analyzed, pulmonary function tests were conducted, and quality of life was determined with EORTC-QLQ-C30 questionnaire. At the time of PP age was between 9–17 years. Underlying disease included metastatic osteosarcoma (n = 5), Ewing sarcoma (two metastatic, one primary), and one primary undifferentiated sarcoma. Early complications occurred in three patients. Mean postoperative hospitalization stay was 14.5 days. Pulmonary function test showed 19–66% reduction of total lung capacity which led to mild exercise intolerance but did not affect daily life. Four patients died of multi-metastatic relapse &lt, 14 months after PP, one patient had a local recurrence, and four patients are in complete remission between 1.5 and 12 years after PP. In conclusion, in this small patient group treated with a pleuropneumonectomy for primary or metastatic lesions, outcome is variable, however, this extended surgical technique was generally quite well tolerated. Postoperative lung function seems well preserved, and it seems to lead to at least an extension of life with good quality and therefor can be considered as salvage therapy.

Purpose: In Europe, 20,000 Adolescent and Young Adults (AYAs) aged 15–25 years are diagnosed with cancer annually. Although prognosis is good, AYA cancer survivors are at greater risk of second pri...

Simple Summary Osteosarcoma is the most common primary malignant bone tumour in adolescents and young adults. The survival of osteosarcoma patients has not improved for four decades. The purpose was to describe first and subsequent relapses in patients from the OS2006/Sarcome-09 trial, to help future trial design. Among the 434 patients with a confirmed osteosarcoma who achieved CR1 during first line treatment, 157 patients experienced at least one relapse. The 3-year progression-free and overall survival rates were 21% and 37%, respectively. Only a quarter of the patients were included in clinical trials at first recurrence. We want to promote randomised phase-II trials in osteosarcoma relapses, with broad inclusion criteria at study entry in terms of age and disease status, and PFS as primary endpoint. Surgery/local treatment of all residual lesions should be allowed when feasible. Single-arm trial design could be used for subsequent relapses. Abstract The purpose was to describe first and subsequent relapses in patients from the OS2006/Sarcome-09 trial, to help future trial design. We prospectively collected and analysed relapse data of all French patients included in the OS2006/Sarcome-09 trial, who had achieved a first complete remission. 157 patients experienced a first relapse. The median interval from diagnosis to relapse was 1.7 year (range 0.5–7.6). The first relapse was metastatic in 83% of patients, and disease was not measurable according to RECIST 1.1 criteria in 23%. Treatment consisted in systemic therapy (74%) and surgical resection (68%). A quarter of the patients were accrued in a phase-II clinical trial. A second complete remission was obtained for 79 patients. Most of them had undergone surgery (76/79). The 3-year progression-free and overall survival rates were 21% and 37%, respectively. In patients who achieved CR2, the 3y-PFS and OS rates were 39% and 62% respectively. Individual correlation between subsequent PFS durations was poor. For osteosarcoma relapses, we recommend randomised phase-II trials, open to patients from all age categories (children, adolescents, adults), not limited to patients with measurable disease (but stratified according to disease status), with PFS as primary endpoint, response rate and surgical CR as secondary endpoints.

Background Tyrosine kinase inhibitors have shown activity in osteosarcoma and might enhance the efficacy of chemotherapy. We aimed to determine the recommended phase 2 dose and antitumour activity of lenvatinib with etoposide plus ifosfamide in patients with refractory or relapsed osteosarcoma. Methods This multicentre, open-label, multicohort, phase 1/2 trial was done at 17 hospitals in six countries. Eligible patients were aged 2-25 years, had relapsed or refractory osteosarcoma, measurable or evaluable disease per Response Evaluation Criteria in Solid Tumors version 1.1, Lansky play-performance score or Karnofsky performance score of 50% or higher, up to one previous VEGF or VEGF receptor-targeted therapy, and a life expectancy of at least 3 months. This study includes a combination dose-finding phase 1 part (cohort 3A) and a phase 2 combination expansion in patients with osteosarcoma (cohort 3B). Lenvatinib was administered orally at a starting dose of 11 mg/m(2) per day, capped at 24 mg per day, and etoposide (100 mg/m(2) per day) plus ifosfamide (3000 mg/m(2) per day) were administered intravenously on days 1-3 of each 21-day cycle for a maximum of five cycles. Lenvatinib monotherapy continued after these five cycles until disease progression, toxic effects, or patient choice to discontinue. The phase 1 primary endpoint was to determine the recommended phase 2 dose by evaluating dose-limiting toxicity and the phase 2 primary endpoint was progression-free survival at 4 months. Progression-free survival was measured in the full analysis set, which included all patients enrolled for efficacy outcomes; safety was assessed in all patients who received any study drug. This study is registered with ClinicalTrials.gov, NCT02432274. Findings 30 patients were screened for enrolment into cohort 3A between May 9, 2016, and June 3, 2019, and 22 patients for enrolment into cohort 3B between Sept 13, 2018, and July 18, 2019. Eight patients from cohort 3A and two from cohort 3B were ineligible for enrolment in the study. In phase 1, dose-limiting toxicities were observed in three patients (one in the lenvatinib 11 mg/m(2) combination group and two in the 14 mg/m2 combination group) and the recommended phase 2 dose was determined as lenvatinib 14 mg/m(2) per day (with daily dose cap of 24 mg) and etoposide 100 mg/m(2) per day plus ifosfamide 3000 mg/m2 per day administered intravenously on days 1-3 of each 21-day cycle for a maximum of five cycles. 35 patients from phase 1 (cohort 3A; n=15) and phase 2 (cohort 3B; n=20) were treated at the recommended phase 2 dose and their results were pooled. Progression-free survival at 4 months was 51% (95% CI 34-69) in 18 of 35 patients per the binomial estimate. The most common grade 3-4 treatment-emergent adverse events were neutropenia (27 [77%] of 35), thrombocytopenia (25 [71%]), anaemia (19 [54%]), and decreased white blood cell count (19 [54%]). 26 [74%] of 35 patients had serious treatment-emergent adverse events and no treatment-related deaths occurred. Interpretation Lenvatinib with etoposide plus ifosfamide shows promising antitumour activity with no new safety signals in patients with refractory and relapsed osteosarcoma. These findings warrant further investigation in an ongoing randomised phase 2 study (NCT04154189). Copyright (C) 2021 Elsevier Ltd. All rights reserved.

Sequencing of cell-free DNA in the blood of cancer patients (liquid biopsy) provides attractive opportunities for early diagnosis, assessment of treatment response, and minimally invasive disease monitoring. To unlock liquid biopsy analysis for pediatric tumors with few genetic aberrations, we introduce an integrated genetic/epigenetic analysis method and demonstrate its utility on 241 deep whole-genome sequencing profiles of 95 patients with Ewing sarcoma and 31 patients with other pediatric sarcomas. Our method achieves sensitive detection and classification of circulating tumor DNA in peripheral blood independent of any genetic alterations. Moreover, we benchmark different metrics for cell-free DNA fragmentation analysis, and we introduce the LIQUORICE algorithm for detecting circulating tumor DNA based on cancer-specific chromatin signatures. Finally, we combine several fragmentation-based metrics into an integrated machine learning classifier for liquid biopsy analysis that exploits widespread epigenetic deregulation and is tailored to cancers with low mutation rates. Clinical associations highlight the potential value of cfDNA fragmentation patterns as prognostic biomarkers in Ewing sarcoma. In summary, our study provides a comprehensive analysis of circulating tumor DNA beyond recurrent genetic aberrations, and it renders the benefits of liquid biopsy more readily accessible for childhood cancers., Liquid biopsies enable minimally invasive applications for diagnosis and treatment monitoring. Here the authors analyse fragmentation patterns of circulating tumour DNA on multiple levels and develop a bioinformatic tool, LIQUORICE, to accurately detect and classify paediatric cancers with low mutational burden.

Mucositis is defined as inflammatory and/or ulcerative lesions of the oral and/or gastrointestinal tract. It occurs in approximately 40% to 50% of adults patients receiving conventional chemotherapy and up to 75% of patients receiving high dose chemotherapy as conditioning for hematopoietic stem cell transplantation. It is a toxic side effect, which strongly impairs quality of life and leads to refractory pain, increasing risk of infection and even therapeutic modifications. Despite improvements made, the management of mucositis remains a challenge and is still not consensual. A multicentric survey of practices concerning the preventive and curative management of chemo-induced mucositis in pediatric oncology department in France was carried out using a standardized questionnaire. Results confirm heterogeneous practices and the small progress made during the last decade. This national survey and an analysis of the recent literature leads to propose guidelines for the prevention and treatment of oral mucositis in children receiving treatment for cancer.

Purpose: This study aimed to explore and identify the factors associated with problematic substance use (alcohol, tobacco, and cannabis) and behavioral addictions (internet and eating disorders) over time in adolescents and young adults (AYAs) treated for cancer. Methods: AYAs newly diagnosed with cancer, 15-25 years of age, completed a questionnaire during their hospitalization (T1), assessing their consumption of alcohol, tobacco, and cannabis (The Alcohol Use Disorders Identification Test; The Smoking Behavior Questionnaire; and The Cannabis Abuse Screening Test), their internet use (The Internet Addiction Test), their body preoccupations (The Eating Attitudes Test), as well as their coping strategies (Brief COPE) and emotional adjustment (The Hospital Anxiety and Depression Scale). Questionnaires were completed again 6 months later (T2). Results: Seventy-three AYAs were included at T1 and 21 AYAs at T2. Nearly one out of two (46.58%) AYAs had a problematic substance use or behavioral addiction after cancer diagnosis (T1). Problematic use of internet was frequently reported (23.29%), as well as harmful alcohol consumption or addiction (16.44%) and cannabis dependence (12.33%). The main factor related to problematic substance use was being older, while the main factor related to behavioral addiction was having a higher anxiety score. Substance use as a coping strategy was used more frequently by AYAs with problematic substance use and emotional support as a coping strategy was used more frequently by AYAs with a behavioral addiction. Conclusions: High rates of problematic substance use and behavioral addiction were reported in our sample. AYAs surveyed had high problematic use of cannabis and high internet use. Attention to substance use and addictive behaviors is recommended to ensure optimal care.

TPS11585 Background: Primary metastatic osteosarcoma (OS) patients are treated with a curative intent following the same principles of non-metastatic OS, while the treatment of recurrent OS is primarily surgical in the case of isolated lung metastases. When complete removal of all metastases cannot be achieved, the prognosis remains poor, with a median Progression-Free Survival (PFS) between 3 to 8 months, and therefore there is a clinical need to reduce the risk of progression after the initial treatment sequence. The REGOBONE study reported a significant PFS benefit of regorafenib (REG) compared to placebo (in osteosarcomas: median PFS: 16.4 versus 4.1 weeks) and a manageable safety profile in patients with histologically confirmed HGBS (i.e., osteosarcoma or other bone sarcomas with the exception of Ewing sarcomas, chondrosarcoma and chordoma). Methods: This multicenter trial is ongoing to study the efficacy and safety of maintenance REG in pts > = 16 years old with HGBS, without complete remission but with no progressive disease after standard treatment, either at diagnosis or at relapse. Sixty pts will be randomly allocated in a 1:1 ratio to receive either oral REG at a daily dose of 120mg or its matching placebo, continuously for a maximum of 12 months. Randomization is stratified according to the setting of the disease: initial diagnosis versus relapse. The primary objective is to compare the efficacy (PFS) between the 2 arms. The expected 4-month PFS rates are 30% in the control arm and 60% in the REGO arm (HR = 0.42). Fifty-two events will provide 87% power to show significant improvement in PFS, using a 2-sided log-rank test at a 5% level. Secondary endpoints include Overall Response Rate (ORR), Disease Control Rate (DCR), Time to Treatment Failure (TTF), Overall Survival (OS), Quality of Life (QoL), and safety profile. Radiological endpoints will be evaluated using the RECIST 1.1 with tumor assessments every 2 months (first 6 months) and then every 3 months. Translational objectives will identify predictive biomarkers for efficacy of REG as maintenance therapy. Pts of the control arm who experience disease progression may switch to receive open label REG. As of Feb 1st, 2022, 3 patients have been randomized. 14 sites of the French Sarcoma Group will participate. An amendment is being implemented to lower the age limit (12 years old) and to expand tumor types to other HGBS (Ewing sarcomas, chondrosarcomas, Undifferentiated Pleomorphic Sarcomas, Leiomyosarcomas and angiosarcomas). Clinical trial information: NCT04698785.

Background, Methods To describe the characteristics, treatments (systemic/local), and outcome (oncological/functional) of French patients with head and neck Ewing's sarcomas (HNES) registered in the Euro‐Ewing 99 (EE99) database. Specific patient‐level data were reviewed retrospective. Results Forty‐seven HNES patients in the EE99 database had a median age of 11 years, 89% had bone tumors (skull 55%, mandible 21%, maxilla 11%), 89% had small tumors (

Background We report results from the phase I dose-finding and phase II expansion part of a multicenter, open-label study of single-agent lenvatinib in pediatric and young adult patients with relapsed/refractory solid tumors, including osteosarcoma and radioiodine-refractory differentiated thyroid cancer (RR-DTC) (NCT02432274). Patients and methods The primary endpoint of phase I was to determine the recommended phase II dose (RP2D) of lenvatinib in children with relapsed/refractory solid malignant tumors. Phase II primary endpoints were progression-free survival rate at 4 months (PFS-4) for patients with relapsed/refractory osteosarcoma; and objective response rate/best overall response for patients with RR-DTC at the RP2D. Results In phase I, 23 patients (median age, 12 years) were enrolled. With lenvatinib 14 mg/m2, three dose-limiting toxicities (hypertension, n = 2; increased alanine aminotransferase, n = 1) were reported, establishing 14 mg/m2 as the RP2D. In phase II, 31 patients with osteosarcoma (median age, 15 years) and 1 patient with RR-DTC (age 17 years) were enrolled. For the osteosarcoma cohort, PFS-4 (binomial estimate) was 29.0% [95% confidence interval (CI) 14.2% to 48.0%; full analysis set: n = 31], PFS-4 by Kaplan–Meier estimate was 37.8% (95% CI 20.0% to 55.4%; full analysis set) and median PFS was 3.0 months (95% CI 1.8-5.4 months). The objective response rate was 6.7% (95% CI 0.8% to 22.1%). The patient with RR-DTC had a best overall response of partial response. Some 60.8% of patients in phase I and 22.6% of patients in phase II (with osteosarcoma) had treatment-related treatment-emergent adverse events of grade ≥3. Conclusions The lenvatinib RP2D was 14 mg/m2. Single-agent lenvatinib showed activity in osteosarcoma; however, the null hypothesis could not be rejected. The safety profile was consistent with previous tyrosine kinase inhibitor studies. Lenvatinib is currently being investigated in osteosarcoma in combination with chemotherapy as part of a randomized, controlled trial (NCT04154189), in pediatric solid tumors in combination with everolimus (NCT03245151), and as a single agent in a basket study with enrollment ongoing (NCT04447755)., Highlights • The recommended phase II dose of lenvatinib in children with relapsed/refractory solid malignant tumors is 14 mg/m2. • This dose is equivalent to the recommended dose of 24 mg/day for single-agent lenvatinib in adults with DTC. • Single-agent lenvatinib showed activity of interest in children and young adults with osteosarcoma. • Based on this initial report, lenvatinib is currently being investigated in combination with chemotherapy in osteosarcoma.

[Background] Although there have been multiple randomised trials in newly diagnosed Ewing sarcoma family of tumours (ESFT) and these have been conducted over many years and involved many international cooperative groups, the outcomes for all stages of disease have plateaued. Internationally, the standard treatment of ESFT is not defined, and there is a need to add new agents other than conventional chemotherapy to improve outcomes. This trial will compare two different induction/consolidation chemotherapy regimens: (1) vincristine, ifosfamide, doxorubicin and etoposide (VIDE) induction and vincristine, actinomycin D, ifosfamide or cyclophosphamide, or busulfan and mephalan (VAI/VAC/BuMel) consolidation and (2) vincristine, doxorubicin, cyclophosphamide, ifosfamide and etoposide (VDC/IE) induction and ifosfamide and etoposide, vincristine and cyclophosphamide, vincristine, actinomycin D and ifosfamide, or busulfan and mephalan (IE/VC/VAI/BuMel) consolidation (randomisation 1, or R1). A second randomisation (R2) will determine whether the addition of zoledronic acid to consolidation chemotherapy, as assigned at R1, is associated with improved clinical outcome., [Methods] EURO EWING 2012 is an international, multicentre, phase III, open-label randomised controlled trial. There are two randomisations: R1 and R2. Patients are randomly assigned at two different time points: at entry to the trial (R1) and following local control therapy (R2). The primary outcome measure is event-free survival. The secondary outcome measures include overall survival, adverse events and toxicity, histological response of the primary tumour, response of the primary tumour, regional lymph nodes or metastases (or both), and achievement of local control at the end of treatment., [Discussion] This study will establish which is the “standard regimen” of chemotherapy, taking into account both clinical outcomes and toxicity. This will form the chemotherapy backbone for future interventional studies where we may want to add new targeted agents. It will also determine the role of zoledronic acid in conjunction with the separate EE2008 trial. Any trial in ESFT needs to take into account the rarity of the tumour and consider that international cooperation is needed to provide answers in a timely manner., [Trial registration] Registered with EudraCT number 2012-002107-17 on 26 February 2012. Registered with ISRCTN number 92192408 on 4 November 2013., This project has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement n°602856. The NCC in France, CLB, receives additional funding from SFCE and Ligue contre le cancer. The coordinating sponsor (the University of Birmingham, Birmingham, UK) is funded by Cancer Research UK (grant award reference C5952/A14745).

Introduction: This study evaluates the management of patients aged 0 to 30 years treated for sarcoma with data registered in the NETSARC French national database and compared the survival of adolescents and young adults (AYA) patients managed in reference sarcoma national centers (AYA in NC) and in non-NC (AYA outside NC). Patients and Methods: NETSARC (netsarc.org) is a network of 26 reference sarcoma centers funded by the French National Cancer Institute. Patients’ characteristics and follow-up are prospectively collected in a database regularly monitored and updated. Patients’ survival was compared between groups. The primary endpoint was overall survival (OS). Secondary endpoints were local progression-free survival (LPFS), progression-free survival (PFS), and the quality of initial surgery. Results: Among 3,972 patients aged 0 to 30 years diagnosed between 2010 and 2017, 714 children, 1,290 AYAs in NC and 937 AYAs outside NC were included. Compliance to guidelines between AYAs treated in versus outside reference centers was significantly different (p

BackgroundPatients with Ewing sarcoma or osteosarcoma have a median overall survival of less than 12 months after diagnosis, and a standard treatment strategy has not yet been established. Pharmacological inhibition of MET signalling and aberrant angiogenesis has shown promising results in several preclinical models of Ewing sarcoma and osteosarcoma. We aimed to investigate the activity of cabozantinib, an inhibitor of MET and VEGFR2, in patients with advanced Ewing sarcoma and osteosarcoma.MethodsWe did a multicentre, single-arm, two-stage, phase 2 trial in patients with advanced Ewing sarcoma or osteosarcoma recruited from ten centres in the French Sarcoma Group. Key eligibility criteria were aged 12 years or older, Eastern Cooperative Oncology Group performance status of 0–1, and documented disease progression (according to Response Evaluation Criteria in Solid Tumors version 1.1) before study entry. The number of previous lines of treatment was not limited. Patients received cabozantinib (adults 60 mg, children [

International audience; Introduction > L'ostéosarcome est la tumeur osseuse maligne la plus fréquente avant 25 ans. La réponse à la chimiothérapie néo-adjuvante influe la suite du traitement et est un facteur pronostique majeur. Il n'existe pas, actuellement, de moyens fiables de l'évaluer précocement. L'objectif de cette étude est de développer une méthode de prédiction de cette réponse à partir des données radiomiques issues de l'IRM diagnostique. Méthodes > Les caractéristiques cliniques et radiologiques de patients traités pour un ostéosar-come localisé ou métastatique en région Rhône-Alpes entre 2007 et 2016 ont été recueillies. Sur les IRM initiales, chaque tumeur était segmentée par un radiologue expert puis 87 caractéristiques radiomiques étaient extraites automatiquement. Une analyse univariée était réalisée pour évaluer l'association des caractéristiques avec la réponse histologique à la chimiothérapie néo-adjuvante. Pour distinguer les bons des mauvais répondeurs, nous avons construit des modèles prédictifs basés sur des machines à vecteurs de support. Leur performance de classification était évaluée par l'aire sous la courbe sensibilité/spécificité (AUROC). Résultats > L'analyse a porté sur les examens IRM de 69 patients dont 55,1 % (38/69) étaient bons répondeurs. Le modèle de prédiction obtenu à partir des données radiomiques issues de l'IRM diagnostique obtenait une aire sous la courbe de 0,98 avec une sensibilité de 100 % (IC 95 % [100 %-100 %]) et spécificité de 86 % (IC 95 % [59,7 %-111 %]). Discussion > Les caractéristiques radiomiques de l'IRM diagnostique pourraient permettre de prédire la réponse à la chimiothérapie des patients présentant un ostéosarcome avant de débuter la chimiothérapie néo-adjuvante.

Survival of adolescents and young adults (AYA) with sarcoma is lower than in younger patients. The objective of this study was to describe the regional healthcare circuits, the differences in the management between adult, paediatric and mixed units and to assess the prognostic impact of compliance with clinical practice guidelines (CPGs) on overall survival (OS) and on relapse free survival (RFS).Retrospective analysis of the management and long term follow-up of all 13-25 year old patients with a sarcoma diagnosed in the Rhône-Alpes area between 2000 and 2005.140 patients satisfied inclusion criteria and were selected. The majority of 13-25 year old patients were treated in paediatric units. Joint management resulted in a higher rate of discussion in multidisciplinary tumour board, inclusion in clinical trials, and fertility preservation. Non-compliance with guidelines was observed in 65% of cases. Overall compliance was not reported to correlate to survival. Compliance of radiotherapy with CPG's seemed associated with a better prognosis for OS (HR = 0.20, 95% CI = [0.10-0.40]; p 0.0001) and RFS (HR = 0.18, 95% CI = [0.09-0.37; p 0.0001) as well as compliance of surgery for OS (HR = 0.43, 95% CI = [0.23-0.81]; p = 0.01). Multivariate Cox regression analysis revealed other independent predictors of OS like age at diagnosis, stage and histological subtype.Management of AYA in joint units seems to improve the quality of care. Compliance of surgery and radiotherapy with CGP's seems to improve survival.

Purpose There are some lines of evidence suggesting a potential role of immunotherapy for treating patients with osteosarcomas. Patients and methods This was an open-label, multicentre, phase 2 study of pembrolizumab in combination with metronomic cyclophosphamide in patients with advanced osteosarcomas. All patients received 50 mg b.i.d. of cyclophosphamide one week on and one week off and 200 mg of intravenous pembrolizumab (every 3 weeks). There was a dual primary end-point, encompassing both the non-progression and objective responses at 6 months per Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1. An objective response rate of 20% and/or a 6-month non-progression rate of 60% were determined as reasonable objectives for treatment with meaningful effect. Correlative studies of immune biomarkers were planned from the patients' tumour samples. Results Between October 13 2015 and July 3 2017, 17 patients were included. Fifty were assessable for the efficacy end-point. Four patients experienced tumour shrinkage, resulting in a partial response (PR) in one patient (6.7%). The 6-month non-progression rate was 13.3% (95% confidence interval [CI]: 1.7–40.5). The most frequent adverse events were grade I or II nausea, anaemia, anorexia and fatigue. programmed death-ligand 1 (PD-L1) expression rate was low, observed in only 2 cases of 14 with available tumour material. The only patient who experienced PR had a PD-L1–negative tumour. Conclusion Programmed cell death 1 (PD-1) inhibition has limited activity in osteosarcomas. Further studies investigating PD-1 inhibitor in combination with agents modulating the microenvironment are warranted. Trial registration This study is registered with ClinicalTrials.gov, number NCT02406781 .

Background The role of high-dose chemotherapy in relapsing osteosarcomas has not been established. We evaluated the efficacy and tolerance of high-dose thiotepa (HDTp) after standard chemotherapy (SCT) in patients with relapsed osteosarcoma. Patients and methods This randomised open-label phase II study enrolled patients 1–50 years, with local or metastatic relapse of a high-grade osteosarcoma, not progressive after two cycles of SCT, for whom a complete surgery can be achievable following treatment. The trial assigned enrolled patients in a 1:1 ratio to receive two additional courses of SCT + HDTp and autologous transplantation (Arm A), or SCT alone (Arm B). Surgery for complete resection was scheduled as soon as feasible. Primary endpoint was overall survival (OS). Secondary objectives included progression-free survival (PFS) and safety. Results From September 2009 to November 2016, 44 patients were randomised (A:22; B:22). In total, 54.5% were males, and the median age was 16 years (9-32years). The two-year OS rate was 66.7% (95% CI 42.5–82.5) (SCT + HDTp, Arm A) versus 50.0% (95% CI 28.2–68.4) for SCT alone (Arm B). Median OS was 27.4 and 24.8 months, respectively (hazard ratio [HR] 0.826, 95% CI 0.393–1.734; p = 0.6123). Median PFS was 15.6 (8.9–24.9) months in Arm A versus 7.2 (4.8–33.3) months in Arm B, p = 0.3845. Among the 22 patients treated with SCT + HDTp, 16 (72.7%) experienced at least one grade ≥3 adverse events versus 18/22 (81.8%) patients treated with SCT. No toxic death occurred. Conclusion Adjuvant HDTp failed to significantly improve OS and PFS in resectable relapsed osteosarcomas. Despite a trend of prolonged survival and an acceptable toxicity, thiotepa cannot be recommended. Key message HDTp and autologous transplantation added to SCT did not improve OS and PFS in patients with resectable relapsed osteosarcomas. Despite a trend of prolonged survival, thiotepa cannot be recommended.