Clinical TrialThe Children's Hepatic tumors International Collaboration (CHIC): Novel global rare tumor database yields new prognostic factors in hepatoblastoma and becomes a research model
Introduction
Hepatoblastoma is a rare pediatric tumor, and even though it remains the most common liver tumor in children, with an increasing annual incidence of 1.2–1.5/million population/year, even major tertiary children's cancer centers may encounter only 1 or 2 newly diagnosed patients a year [1] Historically, four separate cooperative multicenter trial groups have undertaken the systematic treatment studies of this disease: the International Childhood Liver Tumour Strategy Group (SIOPEL); the Children's Oncology Group (COG), and its legacy groups the Children's Cancer Group (CCG) and the Pediatric Oncology Group (POG); the German Society for Pediatric Oncology and Haematology (GPOH); and the Japanese Study Group for Pediatric Liver Tumors (JPLT) [2]. Although each of these groups has made significant contributions to improving the treatment and outcomes for patients with hepatoblastoma, they have developed and used disparate, yet variably overlapping, staging systems. This fact has made any outcome and prognostic factor comparisons between groups challenging and unreliable.
Each of the four cooperative groups have collected data that have been used to relate patient characteristics to disease outcome. Common poor prognostic factors, such as metastatic disease at diagnosis, have been identified across groups [3], [4], [5], [6]. Some risk factors achieved statistical significance in certain cooperative group studies, while remaining non-significant in others [3], [4], [5], [6]. Other potential risk factors were postulated, but due to low patient numbers, never achieved statistical significance [5], [6].The Children's Hepatic tumors International Collaboration (CHIC) was pursued specifically to address this challenge by combining the data of published clinical trials that were started on or after 1988 to reflect the results of prospective clinical trials that employ modern therapeutic approaches to the treatment of hepatoblastoma from which prognostic factors, related to either disease, host or treatment, could be established.
Efforts to identify such prognostic factors in the setting of a rare tumor have been hampered by the extensive fragmentation of relatively small cohorts of patients. Classical rare cancers definitions are based on their prevalence, which does not properly reflect their true health burden: the Italian TREP project defined pediatric rare tumors as “any malignancy characterized by an annual incidence less than 2/million” [7]. Moreover, these definitions do not reflect the added complexity of studying rare tumors in children, where individual treatment centers often treat limited numbers of patients annually. One potential response to this challenge is the organization of global networks of researchers sharing data collaboratively.
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Strategy for worldwide collaboration and definitions used
As the result of collaborative decisions four groups (SIOPEL, COG, GPOH and JPLT) embarked on an effort to merge the data collected in the conduct of eight clinical trials into one database for analysis. Trials, conducted between 1989 and 2008 and included in this database, are presented in Table 1 [8], [9], [10], [11], [12], [13], [14], [15], [16], [17]. All data on 1605 subjects were obtained through the studies which were IRBs approved. Ongoing trials, where results were not yet published at
Results
The spectrum of patients' demographics and univariate survival analysis of the prognostic variables at diagnosis included in the CHIC dataset is presented in Table 4. The Kaplan-Meier plots for factors considered significantly related to prognosis are presented in Fig. 1, Fig. 2, Fig. 3, Fig. 4, Fig. 5, Fig. 6, Fig. 7, Fig. 8, Fig. 9.
In our cohort less than 20% of patients presented with metastatic disease which was strongly associated with poor outcome (Fig. 2). Low AFP serum levels at
Discussion
The clinical research in rare pediatric tumors constitutes a significant challenge. This effort requires the creation of large common databases, and the development of a uniform scientific language which leads to the standardization of risk criteria and patient stratification. However, this alone may be insufficient as global cooperation is limited by financial constraints and busy agendas of researchers. Thus, novel e-environments need to be constructed to facilitate cooperation at the global
Conflict of interest statement
To be confirmed.
Acknowledgments
We are greatly indebted to the significant contributions from all of the co-authors who, as a group, comprise the CHIC steering committee. The dedicated time of statistical analysis from our statisticians, data management from our colleagues at CINECA, and clinical guidance from our oncologists, surgeons, and pathologists has fostered a true collaborative spirit of collective effort. B Haeberle and E Hiyama, in particular, should be recognized as co-first authors for their extensive
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