Outcome of children and adolescents with central nervous system tumors in phase I trials.

Central nervous system (CNS) tumors are a leading cause of death in pediatric oncology. New drugs are desperately needed to improve survival. We evaluated the outcome of children and adolescents with CNS tumors participating in phase I trials within the Innovative Therapies for Children with Cancer (ITCC) consortium. Patients with solid tumors aged < 18 years at enrollment in their first dose-finding trial between 2000 and 2014 at eight ITCC centers were included retrospectively. Survival was evaluated using univariate/multivariate analyses. Overall, 114 patients were included (109 evaluable for efficacy). Median age was 10.2 years (range 1.0-17.9). Main diagnoses included: medulloblastoma/primitive neuroectodermal tumors (32.5%) and high-grade gliomas (23.7%). Complete/partial responses (CR/PR) were reported in 7.3% patients and stable disease (SD) in 23.9%. Performance status of 90-100%, school/work attendance, normal ALT/AST and CR/PR/SD correlated with better overall survival (OS) in the univariate analysis. No variables assessable at screening/enrollment were associated with OS in the multivariate analysis. Five patients (4.5%) were discontinued from study due to toxicity. No toxic deaths occurred. Median OS was 11.9 months with CR/PR, 14.5 months with SD and 3.7 months with progressive disease (p < 0.001). The enrollment of children and adolescents with CNS tumors in phase I trials is feasible, safe and offers potential benefit for the patients. Sustained disease stabilization has a promising role as a marker of anti-tumor activity in children with CNS tumors participating in phase I trials.

How can the environmental sustainability of healthcare products be taken into account throughout their life cycle?

Healthcare product procurement accounts for around 50% of the French healthcare system's greenhouse gas emissions. This lesson learned from the publication of the Shift Project's work in November 2021 has been a catalyst within the healthcare system, accelerating the consideration and implementation of actions aimed at reducing the environmental impact of the healthcare system, before, during and after care. In addition to their carbon footprint, healthcare products have a wide range of environmental impacts, including on water, air and soil, throughout their entire life cycle. We have chosen to divide this life cycle into four main stages: from research and development to production, distribution and market access, use and finally end-of-life management. Analysis of the regulatory framework at each stage and of existing initiatives described in the literature or by those in the field have structured and fuelled our thinking. We found that existing regulations focus exclusively on the health risk, with little or no consideration of the environmental risk, which is in itself a health risk. Furthermore, the implementation of certain structuring actions during the first 3 stages of the life cycle would make it possible to simplify or even eliminate the major problem of waste management associated with the end-of-life of healthcare products. With this in mind, we have produced 9 recommendations to ensure that the environmental impact of healthcare products is better taken into account throughout their life cycle.

Prognostic factors of overall survival in children and adolescents enrolled in dose-finding trials in Europe: An Innovative Therapies for Children with Cancer study.

OBJECTIVES: Dose-finding trials are fundamental to develop novel drugs for children and adolescents with advanced cancer. It is crucial to maximise individual benefit, whilst ensuring adequate assessment of key study end-points. We assessed prognostic factors of survival in paediatric phase I trials, including two predictive scores validated in adult oncology: the Royal Marsden Hospital (RMH) and the MD Anderson Cancer Center (MDACC) scores. METHODS: Data of patients with solid tumours aged <18 years at enrolment in their first dose-finding trial between 2000 and 2014 at eight centres of the Innovative Therapies for Children with Cancer European consortium were collected. Survival distributions were compared using log-rank test and Cox regression analyses. RESULTS: Overall, 248 patients were evaluated: median age, 11.2 years (range 1.0-17.9); 46% had central nervous system (CNS) tumours and 54% extra-CNS tumours. Complete responses were observed in 2.1%, partial responses in 7.2% and stable disease in 25.9%. Median overall survival (OS) was 6.3 months (95% confidence interval, 5.2-7.4). Lansky/Karnofsky ≤80%, no school/work attendance, elevated creatinine and RMH score ≥1 correlated with worse OS in the multivariate analysis. The RMH and MDACC scores correlated with OS in adolescents (12-17 years), p = 0.002, but not in children (2-11 years). CONCLUSIONS: Performance status of 90-100% and school/work attendance at enrolment are strong indicators of longer OS in paediatric phase I trials. Adult predictive scores correlate with survival in adolescents. These findings provide a useful orientation about potential prognosis and could lead in the future to more paediatric-adapted eligibility criteria in early-phase trials.

Outcomes in paediatric metastatic rhabdomyosarcoma: results of The International Society of Paediatric Oncology (SIOP) study MMT-98.

PURPOSE: Results are presented of the SIOP study MMT-98 for paediatric metastatic rhabdomyosarcoma (RMS), which evaluated intensive chemotherapy followed by low intensity 'maintenance' chemotherapy in standard risk patients (SRG). For poor risk patients (PRG), the value of a therapeutic window study, sequential high dose monotherapy to achieve a complete response (CR) followed by low dose maintenance chemotherapy was examined. PATIENTS AND METHODS: From November 1998 to 2005, 146 patients aged 6 months to 18 years with metastatic RMS were entered. Forty-five were SRG, i.e. age<10 years and no bone marrow or bone involvement. Treatment was a 6-drug regimen with local therapy of surgery and/or radiotherapy followed by maintenance of 9 courses of vincristine, actinomycin D and cyclophosphamide (VAC). One hundred and one patients were PRG, i.e. >10 years, or with bone marrow or bone metastases. An upfront window study, high dose monotherapy, local treatment and then VAC maintenance therapy were given. RESULTS: With a median follow-up of 1.52 years, the 3-year event-free survival (EFS) and overall survival (OS) for SRG were 54.92% and 62.14%, respectively, whilst for the PRG 16.17% and 23.17%. The corresponding adverse hazard ratio (HR) for the PRG was HR=2.65 (95% CI 1.63-4.31, p-value<0.001) for EFS and HR=2.51 (CI 1.53-4.11, p-value<0.001) for OS. CONCLUSION: SRG patients' EFS and OS were comparable to those of previous studies. For PRG patients there was no improvement in survival.