Periodic Reporting for period 4 - ChiLTERN (Children’s Liver Tumour European Research Network)
Berichtszeitraum: 2020-07-01 bis 2021-12-31
The ChiLTERN project aimed to establish effective health care for children with liver cancer, of which there are two types: hepatoblastoma (HB) and hepatocellular carcinoma (HCC).
HB is the main liver tumour in childhood, generally arising in infants <3 years. In contrast, HCC, the main liver tumour in adults and adolescents, is much rarer in children. The outcome for HB patients has dramatically improved over the past 20 years due to the introduction of new chemotherapeutic regimens, combined with efficient surgical approaches. Survival rates of children with liver cancer have increased from 30% in the 1970s to about 75%. Nevertheless, there are still very limited treatment options for patients suffering from certain types of aggressive and chemo-resistant tumours. In addition, survivors can suffer serious side effects due to the high doses of chemotherapy treatments. There was an urgent need to improve the knowledge of these rare cancers, discover new drugs and therapeutic targets to treat high-risk disease and reduce the severity of current chemotherapy-related side effects. The rarity of paediatric liver cancers makes it hard to run good clinical trials to identify the best treatments and the scientific community had limited access to clinical samples. Together this has impaired knowledge of the biology of the disease. Consequently, and in contrast to some other cancers, children with liver cancer have not benefited from the incorporation of biological data into medical practice, which might enable more reliable evidence-based treatments to become established as standard of care.
HB is the main liver tumour in childhood, generally arising in infants <3 years. In contrast, HCC, the main liver tumour in adults and adolescents, is much rarer in children. The outcome for HB patients has dramatically improved over the past 20 years due to the introduction of new chemotherapeutic regimens, combined with efficient surgical approaches. Survival rates of children with liver cancer have increased from 30% in the 1970s to about 75%. Nevertheless, there are still very limited treatment options for patients suffering from certain types of aggressive and chemo-resistant tumours. In addition, survivors can suffer serious side effects due to the high doses of chemotherapy treatments. There was an urgent need to improve the knowledge of these rare cancers, discover new drugs and therapeutic targets to treat high-risk disease and reduce the severity of current chemotherapy-related side effects. The rarity of paediatric liver cancers makes it hard to run good clinical trials to identify the best treatments and the scientific community had limited access to clinical samples. Together this has impaired knowledge of the biology of the disease. Consequently, and in contrast to some other cancers, children with liver cancer have not benefited from the incorporation of biological data into medical practice, which might enable more reliable evidence-based treatments to become established as standard of care.
Central to ChiLTERN is the Paediatric Hepatic International Tumour Trial (PHITT) where 4 randomised treatment questions (3 in HB, 1 in HCC) were addressed. Opening in August 2017 , it has recruited 312 of the European target of 450 patients from 128 hospitals across 13 European countries. Funds have been secured to allow a further 2 years of recruitment in Europe. The US and Japan also continue to recruit, together allowing us to meet the planned global recruitment target of 1200 patients.
CHILTERN established the most complete worldwide biorepository of clinically and pathologically annotated biological samples from children with liver cancer. It includes 2076 high-quality samples (blood, plasma, tissue, urine) obtained at different time points from 277 (89%) of PHITT patients and has established the largest pre-clinical platform of childhood liver cancer with 24 HB patient-derived xenografts, 13 tumour organoids and 15 non-tumour organoids
European Pathology review has been accomplished, which provided urgent pathology review for cases with upfront surgery and cases difficult to diagnose and defined the first WHO Classification of Paediatric Tumours (Pfister et al, Cancer Discovery, 2022).
The CHILTERN Biomarker studies have identified and validated a panel of diagnostics and prognostics using from German, Spanish and French retrospective and the prospective PHITT sample collections. Outcomes included a 16-gene signature as a strong prognostic factor in resected specimens from a series of 174 retrospective HB patients, a 3-protein score to predict the prognosis of adult patients with other cancers including adult HCC and the first Molecular Risk Stratification of HB encompassing 3 main prognostic categories to improve the current clinical risk stratification (Carrillo-Reixach et al, J Hepatol, 2020). Further exploratory studies are uncovering further new molecular features of paediatric liver cancers.
International synergies have been established, including collaborations with 2 EU consortiums: the H2020 individualized Paediatric Cure (iPC) project (GA 826121, 2019-2022, https://ipc-project.eu) creating treatment models for paediatric cancer patients using artificial intelligence tools and the Paediatric Preclinical Proof Of Concept Platform (ITCC-P4) (GA116064, 2017-2021, https://www.itccp4.eu/). Collaborations with the American Children's Oncology Group (COG) and the Japanese Study Group About Paediatric Liver Tumour (JPLT) are developing cross-validation studies.
CHILTERN linked International cooperative groups (SIOPEL, COG, GPOH, and JCCG) to drive the Children’s Hepatic Tumours International Collaboration (CHIC) integrating data from each consortia’s published clinical trials. By interrogating clinical aspects and outcome of 1605 HB patients, the new CHIC HB Stratification (CHIC-HS) has been established.
ChiLTERN’s Surgical Expert Panel established a web platform to enable collection of data and imaging from patients worldwide, including Asia and the US. In response to the COVID19 pandemic, the surgical web platform was modified to enable online case review and evaluation by surgical panel members, which formed the basis for improvements in surgical planning and made an important contribution towards the formulation of clinical recommendations.
Other associated ChiLTERN studies included >350 samples from 55 patients analysed to characterise the pharmacokinetics of total cisplatin in plasma and free drug in plasma ultrafiltrate, 139 urine samples from 74 patients for a kidney toxicity biomarker analysis and 40 plasma samples from 38 patients for cardiac toxicity biomarker analysis. In addition, 62 DNA samples were collected for pharmacogenetic analysis from 30 hospitals across 7 countries. It is anticipated that DNA samples will be available from >100 additional patients by the completion of PHITT.
CHILTERN established the most complete worldwide biorepository of clinically and pathologically annotated biological samples from children with liver cancer. It includes 2076 high-quality samples (blood, plasma, tissue, urine) obtained at different time points from 277 (89%) of PHITT patients and has established the largest pre-clinical platform of childhood liver cancer with 24 HB patient-derived xenografts, 13 tumour organoids and 15 non-tumour organoids
European Pathology review has been accomplished, which provided urgent pathology review for cases with upfront surgery and cases difficult to diagnose and defined the first WHO Classification of Paediatric Tumours (Pfister et al, Cancer Discovery, 2022).
The CHILTERN Biomarker studies have identified and validated a panel of diagnostics and prognostics using from German, Spanish and French retrospective and the prospective PHITT sample collections. Outcomes included a 16-gene signature as a strong prognostic factor in resected specimens from a series of 174 retrospective HB patients, a 3-protein score to predict the prognosis of adult patients with other cancers including adult HCC and the first Molecular Risk Stratification of HB encompassing 3 main prognostic categories to improve the current clinical risk stratification (Carrillo-Reixach et al, J Hepatol, 2020). Further exploratory studies are uncovering further new molecular features of paediatric liver cancers.
International synergies have been established, including collaborations with 2 EU consortiums: the H2020 individualized Paediatric Cure (iPC) project (GA 826121, 2019-2022, https://ipc-project.eu) creating treatment models for paediatric cancer patients using artificial intelligence tools and the Paediatric Preclinical Proof Of Concept Platform (ITCC-P4) (GA116064, 2017-2021, https://www.itccp4.eu/). Collaborations with the American Children's Oncology Group (COG) and the Japanese Study Group About Paediatric Liver Tumour (JPLT) are developing cross-validation studies.
CHILTERN linked International cooperative groups (SIOPEL, COG, GPOH, and JCCG) to drive the Children’s Hepatic Tumours International Collaboration (CHIC) integrating data from each consortia’s published clinical trials. By interrogating clinical aspects and outcome of 1605 HB patients, the new CHIC HB Stratification (CHIC-HS) has been established.
ChiLTERN’s Surgical Expert Panel established a web platform to enable collection of data and imaging from patients worldwide, including Asia and the US. In response to the COVID19 pandemic, the surgical web platform was modified to enable online case review and evaluation by surgical panel members, which formed the basis for improvements in surgical planning and made an important contribution towards the formulation of clinical recommendations.
Other associated ChiLTERN studies included >350 samples from 55 patients analysed to characterise the pharmacokinetics of total cisplatin in plasma and free drug in plasma ultrafiltrate, 139 urine samples from 74 patients for a kidney toxicity biomarker analysis and 40 plasma samples from 38 patients for cardiac toxicity biomarker analysis. In addition, 62 DNA samples were collected for pharmacogenetic analysis from 30 hospitals across 7 countries. It is anticipated that DNA samples will be available from >100 additional patients by the completion of PHITT.
ChiLTERN will have significant impact on the health of children with liver cancer. The results will inform clinicians on the best way to treat individual patients, to allow more children to be cured while exposing fewer to toxic chemotherapy and ensure surgery is both effective and safe.
The challenge of the rarity of HB and HCC resulted in a successful 3-continent collaborative effort. This academic trial sets new standards for international collaboration in paediatric oncology, setting the model for a successor study PHITT 2. It is anticipated that molecular profiling will be performed in real-time in the next study to allow greater precision in risk stratification work that has been validated as part of the ChiLTERN.
Progress beyond the state of the art will be made in terms of availability of new surgical guidelines and a new role of computer assisted surgical planning. This will ultimately lead to considerable improvements and new options in the decision-making process of surgical treatment of PRETEXT III/IV HB and thus have a positive impact on the health and wellbeing of affected children and their families. Based on first data available at the end of the project duration, cautious conclusions can be drawn that the surgical planning and evaluation approach applied in the project contributed to a positive clinical and oncological outcome of the patients, especially considering the fact that these are patients of the highly complex groups POSTEXT III and IV.
The challenge of the rarity of HB and HCC resulted in a successful 3-continent collaborative effort. This academic trial sets new standards for international collaboration in paediatric oncology, setting the model for a successor study PHITT 2. It is anticipated that molecular profiling will be performed in real-time in the next study to allow greater precision in risk stratification work that has been validated as part of the ChiLTERN.
Progress beyond the state of the art will be made in terms of availability of new surgical guidelines and a new role of computer assisted surgical planning. This will ultimately lead to considerable improvements and new options in the decision-making process of surgical treatment of PRETEXT III/IV HB and thus have a positive impact on the health and wellbeing of affected children and their families. Based on first data available at the end of the project duration, cautious conclusions can be drawn that the surgical planning and evaluation approach applied in the project contributed to a positive clinical and oncological outcome of the patients, especially considering the fact that these are patients of the highly complex groups POSTEXT III and IV.