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Children’s Liver Tumour European Research Network

Periodic Reporting for period 3 - ChiLTERN (Children’s Liver Tumour European Research Network)

Reporting period: 2019-01-01 to 2020-06-30

The ChiLTERN project has the goal of establishing effective health care for children with liver cancer, of which there are two types: hepatoblastoma (HB) and hepatocellular carcinoma (HCC). Seven Work Packages (WP) address different aspects of the collaboration.

HB is the main liver tumour occurring in childhood, generally arising in infants under 3 years of age. In contrast, HCC, the main liver tumour in adults, is much rarer in children. The outcome for HB patients has dramatically improved over the past 20 years due to the introduction of new chemotherapy regimens, combined with efficient surgical approaches. Accordingly, survival rates of paediatric patients with liver cancer have increased from 30% in the 1970s to about 75% nowadays. Nevertheless, there are still very limited treatment options for patients suffering from certain types of aggressive liver tumours because of their resistance to chemotherapy. Survivors can suffer serious side effects due to the high doses of chemotherapy administered to young children. Therefore, there is an urgent need to improve the knowledge of this rare cancer and discover new drugs and therapeutic targets to treat high-risk disease and reduce the severity of current chemotherapy-related side effects.

The rarity of liver cancer in children makes it hard to run good clinical trials to identify the best treatments. Furthermore, the scientific community has had limited access to biological samples from patients and this has impaired our 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 reliably evidence-based treatments to become established as the standard of care.
The core part of ChiLTERN is the Paediatric Hepatic International Tumour Trial (PHITT) (WP2) to which the consortium partners in Europe will contribute. Parallel trials are being run in USA and Japan, with all data being merged into a single database housed in Europe. The University of Birmingham is the trial’s sponsor for European and the statistical analysis centre.

The PHITT trial will address four randomised treatment questions (three in HB, one in HCC):

1. Can low risk patients’ treatment be reduced from six courses to four?

2. In standard risk patients, which of three chemotherapy regimens is the best?

3. In high risk patients, which of two novel chemotherapy regimens is the better?

4. In HCC, is more intensive chemotherapy better?

Due to the complexity of PHITT (including the non-EU international aspects of parallel trials in USA and Japan), it has taken longer than anticipated to open. This extra time was needed to ensure that the Sponsor worked effectively with multiple parties on the many tasks needed for the success of PHITT. The trial is now open in eight European countries, with six more scheduled to open.

In WP3, we will create the first European collection of biological samples from children with liver cancer enrolled in PHITT (WP3). The ChiLTERN consortium has worked hard to set up the processes for obtaining and analysing the associated patient samples. On-line control of the processes for sample collection is essential given the numerous different hospitals collaborating around Europe. The samples will be part of the Childhood Liver Cancer Network (CLCN) collection and will be linked with clinical information from PHITT. This sample collection will be studied intensively, including to discover new disease-related factors that predict outcome, potentially enabling development of new targeted drugs. Specific aims of WP3 aims include: i) to study the biology of very rare and aggressive liver cancers to discover new bio-markers and therapeutic targets; ii) to determine if paediatric HCC is a biologically and genetically different disease from adult HCC.

WP4 will validate the CHIC-HS, which is a risk index that defines the prognosis for patients depending on their clinical features. It was built out of a data-set collected from eight previous trials. The first step in the validation will be performed with data that was also retrospectively collected from more recent completed trials. The second step in the validation will use data collected within the PHITT trial.

We will also establish surgical guidelines with respect to extended tumour resection versus liver transplantation, to define factors influencing surgical and clinical outcome and to define the role of computer assisted surgical planning (WP5). For establishing the guidelines, an expert panel has been created, which will evaluate the imaging data and analyse the factors necessary for the decision making process. Information packages for study sites have been compiled and standardised protocols for scans established to achieve optimal imaging quality. Based on the groundwork laid in the first period, the second period was dedicated to the start and roll out of imaging data collection. The first data sets were received at the end of the second reporting period.

WP6 has the overall remit of identifying biological factors that determine the likelihood of suffering from drug-induced toxicities. While significant advances have been made in the treatment of paediatric liver cancer, there is an urgent need to reduce side-effects of chemotherapy, without jeopardising the chances of achieving a positive clinical outcome. This includes a reduction in the late effects of chemotherapy while maintaining efficacy in low risk groups, while balancing increases in toxicity associated with greater dose intensity and improved cure rates in poor risk patients. An important step to achieving these aims will be to identify biological factors that correlate with clinical toxicity in patients. Work so far has included the generation of standard protocols for the obtaining and analysis of samples.

WPs 3 to 6 are reliant on the samples collected in conjunction with the PHITT trial and the patients’ clinical data. Hence, given the limited number of patients currently in PHITT, there will be more detailed and comprehensive reporting for period 3.

The administrative procedures for the management of ChiLTERN (WP1) – e.g. data management plans, independent oversight committees – have been set up, along with those for the important aspects of dissemination and communication (WP7), which will enable us to inform our collaborators and the wider world about the progress of ChiLTERN.
ChiLTERN will have significant impact on the health of children with liver cancer. The socio-economic impact of this project is difficult to assess at this stage, but we believe the results will inform clinicians on the best way to treat individual patients, to allow us to cure more children, expose fewer to toxic chemotherapy and ensure their surgery is both effective and safe. At this stage of the project, we have established processes and protocols are in place for the PHITT trial and the associated laboratory studies. We have made substantial progress in setting up and developing the platforms needed and, with recruitment to PHITT now increasing, we anticipate publications and increased dissemination activities to start in the next period.
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