Paediatric Hepatic International Tumour Trial

Primary liver tumours (hepatoblastoma (HB) and hepatocellular carcinoma (HCC))
in children account
for 1% of paediatric tumours. The incidence, however, has been increasing with
improved neonatal
care for preterm infants, who have an increased risk of developing HB. HB has
an annual incidence
of 0.8 per million children. HCC is less common in children.

Currently, the 5 year overall survival (OS) for children with HB is variable
and ranges from about 50-
100% depending on the disease characteristics. Among those *cured*, current
treatment regimens
have a risk of significant toxicities including cisplatin-induced oto-toxicity
and nephrotoxicity,
doxorubicin-induced cardiomyopathy and secondary leukaemia. In patients treated
for HB with 600
mg/m2 of cumulative cisplatin, hearing loss to the point of requiring
augmentation devices occurs in
half of all patients, severely impacting childhood development and quality of
life. The lethal impact
of anthracycline-induced cardiomyopathy and secondary leukaemia is
self-evident.

The Paediatric Hepatic International Tumour Trial (PHITT) trial will
investigate whether reductions in therapy reduce the risk of both short- and
long-term side effects for patients with good prognosis without compromising
their good outcomes and whether intensifying treatments with the introduction
of new agents improves outcomes for those with a poor prognosis.

This study has been transitioned to CTIS with ID 2024-516110-38-00 check the CTIS register for the current data.

Primary Objectives:
-To evaluate if the treatment of Low Risk HB can be reduced (Group B1)
-To compare different induction treatment regimens for Intermediate risk HB
(Group C)
-To compare different post induction treatment regimens for High Risk HB (Group
D2)
-To determine if the outcome is improved when GEMOX is added to PLADO in the
treatment of
unresected hepatocellular carcinoma HCC (Group F)
-To collect samples for biological and toxicity studies. (All groups)

Secondary Objectives:
-To report outcome (including event-free survival (EFS), failure-free survival
(FFS), overall
survival (OS), toxicity and surgical outcome) in all patient groups.
-To validate a new global risk stratification, defined by Children*s Hepatic
Tumours
International Collaboration (CHIC)
-To evaluate clinically relevant factors, including the following:
> Provide a comprehensive and highly-validated panel of diagnostic and
prognostic
biomarkers
> Determine if paediatric HCC is a biologically different entity to adult HCC
> Develop genomic and/or biomarker analysis to predict children who may have an
increased risk of developing toxicity with chemotherapy.
-To establish a collection of clinically and pathologically-annotated
biological samples.
-Evaluate a surgical planning tool for an impact on decision making processes
in POST-TEXT
III and IV HB

The PHITT trial is a collaborative trial involving three major clinical groups
running paediatric liver
tumour trials the International Society of Paediatric Oncology Epithelial Liver
Tumour Group (SIOPEL),
the Liver Tumour Committee of the Children*s Oncology Group, USA (COG), the
Japanese Children*s
Cancer Group (JCCG). The European arm of the study is led by the SIOPEL group
and is sponsored by the University of Birmingham, UK and detailed in this
protocol. It is anticipated that the other trial groups will use a similar
protocol, with an overall analysis of all patients taking place. PHITT is the
clinical trial within the Children*s Liver Tumour European Research Network
(ChiLTERN) Programme. Biology and pathology research will be done in
collaboration with the ChilTERN Programma.

The PHITT is an international, over-arching phase III trial, with four
randomised comparisons, for paediatric, adolescent and young adult patients
with newly diagnosed HB and HCC.

This trial includes a registration phase (trial entry) where patients will give
consent for the analysis of their biological samples, tumour pathology and
imaging reports to determine the grading and status of the disease, before
being allocated in a Treatment Group.

Patients with HB are classed into four risk-stratified groups and treated using
different regimens.
-Group A, very low risk.
Group A1 (WDF-histology); no further treatment.
Group A2 (non-WDF); 2 cycles cisplatin

-Group B, low risk
Group B1 (resected after 2 course cisplatin). Randomisation 2 cycles cisplatin
vs. 4 cycles cisplatin
Group B2 (not resectable after 2 course cisplatin). Patients have further
standard treatment and surgery.

-Group C, intermediate risk
Group C; Randomisation induction chemo therapy: SIOPEL-3HR vs. 5CVD vs. CDDP-M

-Group D, high risk
Group D1 (good respons or non-metastatic); Further standard treatment Carbo-Doxo
Group D2/D3 (poor respons); Carbo-Doxo alternating with randomised carbo-etop
vs. vincr-irinotecan

HCC patients are treated in two risk-stratified groups.
-Group E, completely resected HCC
Group E1 (secondary to underlying liver disease); No further treatment.
Group E2 (de novo HCC); Standard treatment PLADO chemotherapy

-Group F, not resectable HCC
Group F; Randomisation PLADO+S vs. PLADO+S alternating GEMOX+S.

Group A: No intervention.
Group B1: Randomisation between 4 additional cycles versus 2 additional cycles
cisplatin.
Group B2: No intervention.
Group C: Randomisation between SIOPEL-3HR versus C5VD versus CDDP-M.
Group D1: No intervention.
Group D2: Randomisation between carbo-doxo/carbo-etop versus
carbo-doxo/vinc-irinotecan
Group E1: No intervention.
Group E2: No intervention.
Group F: Randomisation between PLADO+S versus PLADO+S alternating with GEMOX+S.

All groups:
In addition to the standard care blood and (tumor)tissue will be collected for
biology and pathology research at diagnosis, end of treatment and relapse. This
will be done in combination with standard care blood sampling and biopsies.
Extra blood and urine will be collected in patients receiving cisplatin,
carboplatin or doxorubicin. These samples will be collected for toxicity
biomarker research. This will be combined with standard sampling as much as
possible.

Patients with a liver tumor should be treated to cure. Also in the current
standard treatment, patients would be hospitalized for several days. The
toxicity and safety will be closely monitored during this study. The treatment
is therefore justified.

In groups A and B, we try to reduce the number of courses and reduce the burden
in this protocol. The advantage may be that patients have fewer side effects
due to this reduction. A disadvantage may be that patients receive not enough
treatment. This is still unknown and subject of this study.
Patients will visit the hospital as many days or less.

Three world-wide commonly used standard treatments are compared in group C. It
is still unknown which one is the best and this is the subject of this study.
The participant has no direct benefit or disadvantage here.

Two new regimes are added to standard therapy in group D. It may be that this
improves the outcome, but that is not proven and subject of this study. The
additional medication can cause other or new toxicity. It is possible that the
additional medication does not give any improvement.

In group E, patients receive the current standard treatment.

In group F, patients receive additional medication. The advantage may be that
this results in a better result in this group with a bad prognosis. However,
this is not proven and subject of this study. The disadvantage may be that the
additional agents do not give a better result and the medication causes other
toxicity. This is justified in patients with this poor prognosis

In addition to the treatment, blood, tissue and urine will be collected for
different studies. In the future this can provide valuable information, the
participant has no benefit here now. The disadvantage may be that the patient
suffers from pain or stress. The decreases are combined as much as possible
with regular decreases, interventions and hospitalization. Patients have an
access device, that is used for standard care, which keeps the number of
injections limited. This part of the study will be terminated if patient oppose
or withdraw consent.