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.
10056 Background: Larotrectinib is an FDA and EMA approved TRK inhibitor for TRK fusion solid tumors in patients with locally advanced or metastatic disease, or where surgical resection is likely to ...result in severe morbidity. Here we report the real-world activity and safety data on compassionate use and post-marketing authorization of larotrectinib collected in the SACHA-France study (NCT04477681), following the French Health Technology Assessment institution (HAS) request. Methods: All larotrectinib prescriptions made in France outside clinical trials since April 2019 for patients’ < 25 years-old were registered in the SACHA-France study. Safety and activity data were collected, with data cut-off of 23/01/2024. SACHA-France is open in all 31 French Society of Pediatric Oncology (SFCE) centers, it is approved as a real-world data source by the HAS and supported by the French National Agency for the Safety of Medicines and Health Products (ANSM). Results: 21 patients were included (4 compassionate use, 17 post-marketing authorization). Main cancer types were soft-tissue sarcomas (n=13, of them 7 infantile fibrosarcoma), followed by central nervous system (CNS) tumors (n= 7), and other solid extra-CNS tumors (n=1). All patients except one had a TRK fusion tumor: NTRK3 (n=10), NTRK2 (n=6, all CNS tumor) and NTRK1 (n=4). Median age at start of larotrectinib was 2.8 years (range: 0.2 -21.1). Ten patients had received no prior systemic therapy. Main reasons to start larotrectinib were to avoid mutilating surgery (n=9) and disease progression (n=9). Best objective response was reported as partial response in 13 out of 19 patients with evaluable disease (10/12 patients with soft tissue sarcomas, 2/6 patients with CNS tumors), with median time to response of 57 days. Of them, five patients with soft tissue sarcomas achieved a complete response after non mutilating surgery. Median treatment duration was 219 days (range: 10-1368, 5 patients still on therapy). Seven patients with soft tissue sarcomas stopped larotrectinib, after a median duration of 242 days (range: 122-1190), three of them after tumor surgery; none presented with tumor recurrence (follow-up: 350 days; range 40-636). At data cut-off, 8 patients had disease progression on-therapy (5/7 CNS tumors, 3/13 soft tissue sarcomas), with a NTRK resistance mutation identified in 2 out 3 patients with tumor biopsy. Adverse drug reaction (ADR) were reported in 2/21 patients (9%), including a grade 2 weight gain and a grade 3 neutrophil count decreased (1 patient each). Both ADRs were expected and required neither corrective treatment nor action on larotrectinib. Conclusions: Our real-world data confirm the favorable safety profile of larotrectinib with rapid and durable tumor-agnostic efficacy.
•Systematic review of 19 years phase-II trials in recurrent/refractory osteosarcoma.•Increase in yearly registered trials eligible for recurrent/refractory osteosarcoma.•Increase in the use of ...survival endpoints in recent, mostly single-arm, trials.•Increase over time in trials investigating targeted and immune-directed therapy.•Ongoing need for improved, harmonized, randomized, phase-II trial design.
To analyze changes in recurrent/refractory osteosarcoma phase II trials over time to inform future trials in this population with poor prognosis.
A systematic review of trials registered on trial registries between 01/01/2017–14/02/2022. Comparison of 98 trials identified between 2003 and 2016. Publication search/analysis for both periods, last update on 01/12/2022.
Between 2017 and 2022, 71 phase-II trials met our selection criteria (19 osteosarcoma-specific trials, 14 solid tumor trials with and 38 trials without an osteosarcoma-specific stratum). The trial number increased over time: 13.9 versus 7 trials/year (p = 0.06). Monotherapy remained the predominant treatment (62% vs. 62%, p = 1). Targeted therapies were increasingly evaluated (66% vs. 41%, P = 0.001). Heterogeneity persisted in the trial characteristics. The inclusion criteria were measurable disease (75%), evaluable disease (14%), and surgical remission (11%). 82% of the trials included pediatric or adolescent patients. Biomarker-driven trials accounted for 25% of the total trials. The survival endpoint use (rather than response) slightly increased (40% versus 31%), but the study H1/H0 hypotheses remained heterogeneous. Single-arm designs predominated over multiarm trials (n = 7). Available efficacy data on 1361 osteosarcoma patients in 58 trials remained disappointing, even though 21% of these trials were considered positive, predominantly those evaluating multi-targeted kinase inhibitors.
Despite observed changes in trial design and an increased number of trials investigating new therapies, high heterogeneity remained with respect to patient selection, study design, primary endpoints, and statistical hypotheses in recently registered phase II trials for osteosarcoma. Continued optimization of trial design informed by a deeper biological understanding should strengthen the development of new therapies.
Background
Previous studies have shown that neutrophil‐to‐lymphocyte (NLR) ratio at diagnosis and early lymphocytes recovery on doxorubicin‐based chemotherapy, may impact the outcome in patients with ...osteosarcoma (OST). This study aimed to evaluate the prognostic value of hemogram parameters in patients with OST treated with high‐dose methotrexate and etoposide/ifosfamide (M‐EI) chemotherapy.
Materials and methods
We retrospectively analyzed the prognostic value of various hemogram parameters at diagnosis and during therapy in a large consecutive cohort of patients with OST included in the French OS2006 trial and treated with M‐EI chemotherapy.
Results
A total of 164 patients were analyzed. The median age was 14.7 years (interquartile range IQR: 11.7–17). Median follow‐up was 5.6 years (IQR: 3.3–7.7 years). Three‐year event‐free survival (EFS) and overall survival (OS) were 71.5% (95% confidence interval CI: 64%–78%) and 86.4% (95% CI: 80%–91%), respectively. In univariate analysis, blood count parameters at diagnosis and early lymphocyte recovery at Day 14 were not found prognostic of survival outcomes. By contrast, an increase of NLR ratio at Day 1 of the first EI chemotherapy (NLR‐W4) was associated with reduced OS in univariate (p = .0044) and multivariate analysis (hazards ratio HR = 1.3, 95% CI: 1.1–1.5; p = .002), although not with EFS. After adjustment on histological response and metastatic status, an increase of the ratio NLR‐W4 of 1 was associated with an increased risk of death of 30%.
Conclusions
We identified NLR‐W4 as a potential early biomarker for survival in patients with OST treated with M‐EI chemotherapy. Further studies are required to confirm the prognostic value of NLR and better identify immune mechanisms involved in disease surveillance.
In 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 < .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).
What's new?
The Euro‐EWING99‐R1 trial compared the alkylating agents cyclophosphamide with ifosfamide in combination treatment for Ewing sarcoma. Here, the authors compare the late events between the two combination treatments using data from 172 patients enrolled in Euro‐EWING99‐R1. The combination containing ifosfamide carried a higher risk of kidney toxicity, but both regimens carried high rates of gonadal toxicity. Some of this toxicity could be avoided, they suggest, by using a mixed regimen to limit the dose of both alkylating agents.
Shortages and unequal access to anticancer medicines for children and adolescents are a reality in Europe. The aim of the European Society for Paediatric Oncology (SIOPE) Essential Anticancer ...Medicines Project was to provide a list of anticancer medicines that are considered essential in the treatment of paediatric cancers to help ensure their continuous access to all children and adolescents with cancer across Europe.
This pan-European project, done between Jan 20, 2020, and Feb 18, 2022, was designed to be a systematic collection and review of treatment protocols and strategies that are used to treat childhood cancer in Europe. We formed 16 working groups on the basis of paediatric cancer types, and which were based on the existing SIOPE Clinical Trial Groups. Workings groups consisted of representatives from the SIOPE Clinical Trial Groups, Young SIOPE members, and senior paediatric oncology experts. Each group collected existing treatment protocols that are used to treat the respective cancer types in Europe. Medicines from the standard group of each protocol were extracted. For medicines not on the WHO Essential Medicines List for children (EMLc) 2017, working groups did a literature search to determine whether the medicines should be defined as essential, promising, or neither essential nor promising. Each group provided an individual summary, and all medicines that were considered essential by at least one group were combined in a joint list.
The working groups identified 73 treatment protocols used in Europe and defined 66 medicines as essential. For several newer medicines, such as kinase inhibitors or tisagenlecleucel, the supporting evidence was insufficient to consider them essential, so these medicines were defined as promising. 25 medicines were considered promising by at least one working group. 22 (33%) of the 66 essential and none of the promising medicines were included in the WHO EMLc 2017. The WHO EMLc 2021 included two new medicines (everolimus and vinorelbine) following applications we made as a result of this project.
Medicines that were defined as essential within this project should be available for the treatment of childhood and adolescent cancer continuously and across Europe. This list can be used to support and guide stakeholders and policy makers in negotiations on a national and European level regarding shortages, accessibility, and affordability of these medicines.
None.
Innovative anticancer therapies for children, adolescents, and young adults are regularly prescribed outside their marketing authorization or through compassionate use programs. However, no clinical ...data of these prescriptions is systematically collected.
To measure the feasibility of the collection of clinical safety and efficacy data of compassionate and off-label innovative anticancer therapies, with adequate pharmacovigilance declaration to inform further use and development of these medicines.
This cohort study included patients treated at French pediatric oncology centers from March 2020 to June 2022. Eligible patients were aged 25 years or younger with pediatric malignant neoplasms (solid tumors, brain tumors, or hematological malignant neoplasms) or related conditions who received compassionate use or off-label innovative anticancer therapies. Follow up was conducted through August 10, 2022.
All patients treated in a French Society of Pediatric Oncology (SFCE) center.
Collection of adverse drug reactions and anticancer activity attributable to the treatment.
A total of 366 patients were included, with a median age of 11.1 years (range, 0.2-24.6 years); 203 of 351 patients (58%) in the final analysis were male. Fifty-five different drugs were prescribed, half of patients (179 of 351 51%) were prescribed these drugs within a compassionate use program, mainly as single agents (74%) and based on a molecular alteration (65%). Main therapies were MEK/BRAF inhibitors followed by multi-targeted tyrosine kinase inhibitors. In 34% of patients at least a grade 2 clinical and/or grade 3 laboratory adverse drug reaction was reported, leading to delayed therapy and permanent discontinuation of the innovative therapy in 13% and 5% of patients, respectively. Objective responses were reported in 57 of 230 patients (25%) with solid tumors, brain tumors, and lymphomas. Early identification of exceptional responses supported the development of specific clinical trials for this population.
This cohort study of the SACHA-France (Secured Access to Innovative Medicines for Children with Cancer) suggested the feasibility of prospective multicenter clinical safety and activity data collection for compassionate and off-label new anticancer medicines. This study allowed adequate pharmacovigilance reporting and early identification of exceptional responses allowing further pediatric drug development within clinical trials; based on this experience, this study will be enlarged to the international level.
The aim of this study was to identify early clinical and laboratory features that distinguish acute lymphoblastic leukemia (ALL) from juvenile idiopathic arthritis (JIA) in children presenting with ...persistent bone or joint pain for at least 1 month.
We performed a multicenter case-control study and reviewed medical records of children who initially presented with bone or joint pain lasting for at least 1 month, all of whom were given a secondary diagnosis of JIA or ALL, in four French University Hospitals. Each patient with ALL was paired by age with two children with JIA. Logistic regression was used to compare clinical and laboratory data from the two groups.
Forty-nine children with ALL and 98 with JIA were included. The single most important feature distinguishing ALL from JIA was the presence of hepatomegaly, splenomegaly or lymphadenopathy; at least one of these manifestations was present in 37 cases with ALL, but only in 2 controls with JIA, for an odds ratio (OR) of 154 95%CI: 30-793 (regression coefficient: 5.0). If the presence of these findings is missed or disregarded, multivariate analyses showed that non-articular bone pain and/or general symptoms (asthenia, anorexia or weight loss) (regression coefficient: 4.8, OR 124 95%CI: 11.4-236), neutrophils < 2 × 10
/L (regression coefficient: 3.9, OR 50 95%CI: 4.3-58), and platelets < 300 × 10
/L (regression coefficient: 2.6, OR 14 95%CI: 2.3-83.9) were associated with the presence of ALL (area under the ROC curve: 0.96 95%CI: 0.93-0.99).
Based on our findings we propose the following preliminary decision tree to be tested in prospective studies: in children presenting with at least 1 month of osteoarticular pain and no obvious ALL in peripheral smear, perform a bone marrow examination if hepatomegaly, splenomegaly or lymphadenopathy is present. If these manifestations are absent, perform a bone marrow examination if there is fever or elevated inflammatory markers associated with non-articular bone pain, general symptoms (asthenia, anorexia or weight loss), neutrophils < 2 × 10
/L or platelets < 300 × 10
/L.
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