Author:

Jean-Michel Zucker

European pediatric oncology has undergone remarkable transformation since the early 2000s, building on foundations laid by pioneers like Odile Schweisguth who established the first dedicated childhood cancer service in the late 1940s. The establishment of national cooperative groups in the 1970s and the creation of [SIOPE] (@international-society-of-paediatric-oncology) in 1998 enabled large-scale multicenter trials that dramatically improved survival rates, which reached 81% by 2010-2014 according to the EUROCARE-6 study. Major advances include high-resolution MRI and molecular profiling techniques that enable precision medicine, the identification of targetable genetic alterations (such as BRAF V600E in gliomas and ALK mutations in neuroblastoma), and the structuring of early-phase clinical trials through networks like ITCC. Revolutionary treatments have emerged including proton therapy to reduce long-term radiation damage, anti-GD2 immunotherapy for neuroblastoma, and CAR-T cell therapy for lymphomas. Europe has pioneered integrated care centers like SIREDO in Paris and Princess Máxima Center (in Utrecht that combine clinical care with translational research. Alongside therapeutic advances, European institutions have led ethical frameworks for pediatric trials and comprehensive long-term survivorship programs through initiatives like PanCareSurFup, addressing late effects including cardiovascular, neurocognitive, and fertility complications. The future focuses on leveraging real-world data through initiatives like DARWIN EU and artificial intelligence to further refine treatment strategies while maintaining Europe's commitment to scientific excellence, equity, and bioethical leadership in childhood cancer care.

Introduction

European pediatric oncology has experienced considerable advances since the beginning of the 2000s that have profoundly transformed the diagnosis, management, and research of solid tumors in children and adolescents. These advances, which have enabled a spectacular improvement in the survival of children with cancer, are based on the emergence of centers of excellence, the establishment of European collaborative networks, and an increasingly close articulation between clinical trials and translational research, leading to the development of precision medicine. At the same time, consideration of ethical issues and late effects of treatments has broadened the perspective of care to include the long-term quality of life of cured children. This article proposes a journey through these contributions, highlighting Europe's specific contributions and their influence on the international scene.

Chapter 1 – History and Current Cooperative Groups

Europe played a pioneering role in the emergence of pediatric oncology. Odile Schweisguth was the first to organize, from the late 1940s, a service specifically dedicated to childhood cancers at Institut Gustave Roussy (Villejuif, France). She trained generations of specialists, participated in the identification of nosological entities, and was co-founder in 1969 of the International Society of Pediatric Oncology (SIOP). She summarized her experience in the first comprehensive work devoted to solid tumors in children ^[1]. From the 1970s, Europe saw the development of powerful national and international cooperative groups. The SFOP/SFCE (French Society for the Fight Against Cancers and Leukemias in Children and Adolescents) coordinated the majority of pediatric protocols in France. The CCLG (Children's Cancer and Leukaemia Group) established itself as the reference structure in Great Britain. Germany developed the GPOH (Gesellschaft für Pädiatrische Onkologie und Hämatologie), while the Netherlands structured research through the DCOG (Dutch Childhood Oncology Group). In Italy, AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica) established itself as a major player, as did SEHOP in Spain and the Nordic country groups. The federation of these networks made it possible to construct, from the 1980s, European multicenter protocols that were the key to the spectacular improvement in pediatric cancer survival. This historical foundation led in 1998 to the individualization of [SIOPE] (@international-society-of-paediatric-oncology), the European branch of SIOP, promoting the sharing of expertise, the pooling of biological samples, and the development of large-scale European trials. The structuring, at the turn of the 2000s, of large cooperative networks, including "Innovative Therapies for Children with Cancer" (ITCC), has since played a key role in developing early trials and making therapeutic innovations available to young patients ^[2].

Chapter 2 – Diagnostic Progress: Imaging, Pathology, and Cytology

Progress in brain imaging over the past two decades has profoundly transformed the diagnosis of childhood tumors. High-resolution MRI and its advanced techniques (diffusion, perfusion, spectroscopy), and their specific application in pediatric neuro-oncology, have made it possible to better characterize brain lesions and more finely guide therapeutic decisions ^[3]. Nuclear imaging also occupies an important place: MIBG scintigraphy has become a standard for neuroblastoma, contributing to initial staging, evaluation of treatment response, and detection of relapses ^[4]. In parallel, anatomopathology has undergone a major evolution with the standardization of prognostic classifications. A milestone was the development of international recommendations, supported by a strong European contribution, for the examination of enucleated ocular globes in retinoblastoma, whose systematic examination according to consensual criteria has made it possible to refine histological stratification, optimize risk estimation, and considerably improve therapeutic management ^[5]. Finally, significant progress has been made to reduce the invasiveness of diagnostic procedures. The use of percutaneous tumor cytology, often guided by imaging, now allows in many cases, with excellent diagnostic reliability, to avoid a more cumbersome surgical biopsy. This approach, developed in Europe by teams specialized in pediatric cytopathology, has taken its place in establishing initial diagnosis while reducing morbidity ^[6].

Chapter 3 – Prognostic Progress and Translational Research

The multiplication and diversification of molecular biology techniques have exemplarily enabled the progress of translational research. Work coordinated by several European teams has shown in neuroblastoma that specific recurrent chromosomal alterations - particularly MYCN amplification, 1p deletion and 17q gain - determine prognosis, allowing finer patient stratification and adapted therapeutic orientation ^[7]. This dynamic found major expression in the MAPPYACTS trial, a pioneering European study that evaluated the feasibility and interest of systematic molecular profiling of refractory pediatric tumors, and demonstrated the relevance of genomic sequencing to guide personalized therapeutic decisions and open new clinical research perspectives ^[8]. In the European phase II/III trial (BIOMEDE) in children with infiltrating brainstem glioma, molecular profiling at diagnosis on stereotactic biopsy made it possible to classify tumors into 4 distinct groups, with profiles correlated to potential therapeutic targets and different prognosis ^[9].

Chapter 4 – Precision Medicine and Targeted Innovations

Based on the identification of targetable genetic alterations, the rise of precision medicine has marked a turning point in the management of several pediatric solid tumors. In osteosarcoma, recent transcriptomic analyses conducted in Europe have identified molecular signatures associated with treatment response and relapse risk, opening the way to finer patient stratification ^[10]. In pediatric low-grade gliomas, European multicenter studies have highlighted the importance of MAPK pathway alterations, particularly BRAF V600E activating mutations, and have led to the evaluation of targeted inhibitors such as dabrafenib and trametinib, whose efficacy has been confirmed in a recent trial ^[11]. In neuroblastoma, discoveries about ALK gene mutations have led to clinical trials evaluating the efficacy of tyrosine kinase inhibitors such as crizotinib, with promising results in patients carrying this alteration ^[12].

Chapter 5 – Early Clinical Trials

The structuring of early phase I/II clinical trials in pediatric oncology is a major contribution from Europe. Integrating pharmacodynamic biomarkers and molecular characterization platforms, ITCC, which brings together more than 50 centers across the continent, has enabled the implementation of methodologies adapted to pediatric specificities and constraints, promoted young patients' access to new molecules, and strengthened cooperation between clinicians, academic researchers, and industrial partners ^[13]. The randomized VIT-0910 trial, coordinated within this framework, evaluated the combination of vincristine-irinotecan with or without temozolomide in children with relapsed rhabdomyosarcoma. This multicenter phase II trial showed a progression-free survival benefit in certain subgroups, confirming the feasibility and relevance of combined approaches derived from translational research ^[14]. Its results have indeed strengthened the link between biological discoveries and clinical trials, by highlighting the interest of integrative approaches combining genomics, preclinical models and early trials, and by deepening treatment response criteria, pediatric pharmacokinetics and biomarker analysis ^[15].

Chapter 6 – Ethical Reflection on Clinical Trials

Clinical research in pediatric oncology cannot progress without trials, including randomized and early ones. But these protocols raise specific ethical issues, related to the vulnerability of children, family involvement, and disease rarity, whether regarding justification of randomizations, benefit/risk balance in early phases, or the place of child and adolescent assent. A systematic review of European publications between 2003 and 2013 analyzed these issues, highlighted encountered dilemmas - informed consent sometimes difficult to obtain, balance between expected benefits and risks incurred, need to guarantee equitable access to new treatments - and proposed ways to strengthen research ethics in this field ^[16]. More recently, pan-European recommendations have been formulated to harmonize practices regarding information and assent of minors, to improve transparency and confidence in the research process. This guide emphasizes the need for appropriate language and genuine involvement of children in decisions concerning them to offer them informed participation ^[17]. These efforts show that Europe is not limited to medical advances but also plays a driving role in bioethical reflection, essential for maintaining the legitimacy and sustainability of research programs.

Chapter 7 – Surgery and Radiotherapy

In neurosurgery, techniques guided by intraoperative imaging, and more recently by artificial intelligence systems, have improved the safety and radicality of resection in pediatric brain tumors, promoting more complete resection while preserving neurological functions. Surgical platforms integrating intraoperative navigation, real-time MRI, and functional mapping allow reaching areas previously considered inoperable ^[18]. Reconstructive surgery after tumor resection represents another field of innovation. Progress in pediatric orthopedics, particularly for osteosarcomas, now allows personalized bone reconstructions, sometimes assisted by 3D printing of custom surgical guides, offering young patients better functionality and faster reintegration ^[19]. Proton therapy, of which several European centers have been pioneers, has established itself in Europe as a modality of choice for certain pediatric tumors, particularly brain tumors and various sarcomas, thanks to its efficacy and reduction of late side effects related to irradiation, as confirmed by a recent European review, emphasizing its preferred indications ^[20]. In rhabdomyosarcoma, a European retrospective study conducted in specialized centers emphasizes that proton therapy, while maintaining local control equivalent to standard techniques, allows a significant reduction in the dose received by healthy organs, and reduces long-term sequelae ^[21].

Chapter 8 – Immunotherapy and CAR-T

Thanks to trials including strong European participation, immunotherapy has burst into the field of pediatric oncology with emblematic successes. Neuroblastoma was one of the first childhood cancers to benefit from targeted immunotherapy with anti-GD2 antibodies, which have significantly improved disease control and survival in high-risk forms, as confirmed by a recent meta-analysis ^[22]. Beyond neuroblastoma, immunotherapies are rapidly developing in other refractory pediatric tumors. An innovative European study showed that administration of an autologous tumor lysate-based vaccine, combined with lymphocyte infusion, could significantly improve survival of children and adolescents with metastatic or recurrent sarcomas ^[23]. Moreover, cellular therapy approaches are experiencing remarkable growth. While CAR-T have first transformed leukemia management, specific trials for lymphomas in children and adolescents/young adults are currently underway. Recently published, the HSP-CAR30 trial shows the efficacy of CAR-T cells directed against the CD30 protein and opens the way, a therapeutic perspective until now completely unprecedented, to a broader application of these innovative approaches ^[24].

Chapter 9 – Evolution of Survival and Prevention of Sequelae

Since the beginning of the 2000s, overall survival of childhood cancers in Europe has clearly improved. According to the population-based EUROCARE-6 study (2010–2014), based on a comprehensive epidemiological database (31 countries, >135,000 children included), the 5-year survival rate reaches 81%, with continuous progression. Moreover, the percentage of cured patients ("cure fraction") is estimated at about 80%, with considerable dispersion according to the pathology considered and also according to age at diagnosis and country ^[25]. This spectacular improvement is accompanied by new challenges: prevention and management of late sequelae. The PanCareSurFup consortium, associating several European cohorts, has made it possible to identify and well document cardiovascular, neurocognitive, endocrine, or fertility sequelae of different chemotherapies, or secondary to radiotherapy, and to develop recommendations to pediatric oncologists for long-term multidisciplinary follow-up of cured patients integrating adult organ specialists and, when necessary, genetic consultation, placing each survivor in a personalized health pathway ^[26]. Furthermore, Scandinavian studies have explored the long-term quality of life of brain tumor survivors, highlighting persistent challenges in cognition and social integration ^[27]. Finally, international reflection, to which Europe contributes largely, focuses on defining the best strategies for prevention and screening of late effects, in a precision medicine perspective for each survivor ^[28].

Conclusion – Future Perspectives

Since the beginning of the 21st century, European pediatric oncology has entered a new era, notably marked by the integration of molecular data, the structuring of early clinical trials, the rise of proton therapy and immunotherapies. Precision medicine now establishes itself as an unavoidable paradigm based on an even more advanced integration of genomic data and artificial intelligence. The next steps will involve reasonable exploitation of "real-world data," that is, data collected outside clinical trials, from registries, electronic monitoring databases, or national cohorts. Their analysis, combined with artificial intelligence, should make it possible to refine therapeutic indications, better evaluate long-term effects, and promote equitable access to innovations. The DARWIN EU initiative, led by the European Medicines Agency, illustrates this ambition by structuring the use of real-world data for research and therapeutic evaluation ^[29]. It prefigures a new era of continental collaboration, for the benefit of children and adolescents with cancer. In this regard, the development of integrated expert centers combining care, clinical research, and translational research already contributes to improving clinical results and reducing late sequelae. SIREDO, at Institut Curie in Paris, represents in France this first pioneering integrated structure for solid tumors in children, adolescents, and young adults up to 25 years old ^[30]; in the Netherlands, the Princess Máxima Center in Utrecht, which centralizes all pediatric cases in the country, illustrates a similar model ^[31], as do the integrated centers in London, Heidelberg, Rome, Barcelona, Oslo. Thus these centers are a considerable asset for allowing Europe to continue playing a driving role in the fight against childhood cancers, combining scientific excellence, international cooperation, and permanent concern for equity and ethics.