PHITT

Newly diagnosed hepatic cancers: primary paediatric hepatic malignancies Hepatoblasoma;(HB) and Hepatocellular Carcinoma (HCC)

An international, over-arching trial, with four randomised comparisons, for paediatric, adolescent and young adult patients with newly diagnosed hepatoblastoma (HB) and hepatocellular carcinoma (HCC)

Primary objectives

• To evaluate if the treatment of Low Risk HB can be reduced (Group B1).
• To compare different 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 interval compressed GEMOX is added to PLADO in the treatment of unresected HCC (Group F).
• To collect samples for biological and toxicity studies. (all groups)

Hepatoblasoma

Group A- Very low Risk
These patients will have a primary resection of their tumour. Patients in this group will be divided into two cohorts depending on the result of the histology subtype:
Group A1: Patients with WDF histology will receive no further adjuvant chemotherapy (follow up for disease progression and death only)
Group A2: Patients with Non-WDF histology will receive 2 cycles of standard dose cisplatin.

Group B - Low Risk
These patients will have a tumours deemed unresectable at diagnosis but no other adverse features. The main aim of this group is to compare treatment with 2 or 4 cycles of post-operative chemotherapy. Patients resected after 2 cycles of chemotherapy will be eligible for a randomisation comparing 2 vs. 4 cycles of post-operative chemotherapy. Patients not resected after 2 cycles of chemotherapy should continue to receive cisplatin in the absence of disease progression and follow the standard approach of resection after 4 cycles of chemotherapy followed by 2 post-operative cycles.

Group C - Intermediate Risk
Patients in Group C will have locally advanced tumours including PRETEXT I-III tumours with a positive annotation factor and all PRETEXT IV tumours. Patients will be randomised to one of 3 chemotherapy arms SIOPEL-3HR, C5VD or higher dose CDDP-M. The resection of the primary tumour can be considered at ANY point during therapy. The protocol gives an outline of the timing of response evaluations and possible surgical intervention but this is not mandated.

Group D - High Risk
These patients may have pulmonary metastatic disease. Often patients will also have challenging primary tumours and a significant number may be considered suitable for transplantation (assuming a lung CR can be achieved). Patients will receive initial chemotherapy according to the cisplatin-intensive SIOPEL-4 regimen. Following 3 blocks of chemotherapy patients will be stratified into 2 risk groups. In Group D1, patients will either have had a chemotherapy-induced lung CR, or will be rendered a lung CR by surgical metastectomy (recommended before resection of the primary tumour). These patients will have chemotherapy consolidation with carboplatin/doxorubicin. The timing of the resection of the primary tumour (including transplant) can be planned at any time after completion of the A blocks of induction therapy.
Patients who have not achieved a lung CR (either with chemotherapy and/or surgery) at the end of block A3 will be randomised (Group D2) to intensified consolidation therapy of carboplatin/doxorubicin with either carboplatin/etoposide or vincristine/irinotecan.

Hepatocellular Carcinoma

Group E - Resected HCC
These patients have primary completely resected HCC with microscopically uninvolved surgical margins. Patients fall into two groups:
E1) Patients who have an underlying predisposition to HCC through genetic, viral or metabolic conditions and have primary completely resected HCC with microscopically uninvolved surgical margins. No further chemotherapy but only observation.
E2) Patients with de novo HCC, which includes fibrolamellar. Patients will receive 4 cycles of PLADO chemotherapy.

Group F - unresactable / incomplete resected / metastatic HCC
Patients will be randomised to preoperative chemotherapy consisting of either PLADO+sorafenib or PLADO/GEMOX+sorafenib.
Given the surgical challenges posed by these tumours and the need to consider transplantation as an option, early referral (at the time of diagnosis) to a transplant centre is encouraged so that sufficient time can be allowed for the surgical planning and/or transplant workup to take place.

• Clinical diagnosis of HB* and histologically defined diagnosis of HB or HCC. *Histological confirmation of HB is required except in emergency situations where: a) the patient meets all other eligibility criteria, but is too ill to undergo a biopsy safely, the patient may be enrolled without a biopsy; b) there is anatomic or mechanical compromise of critical organ function by tumour (e.g., respiratory distress/failure, abdominal compartment syndrome, urinary obstruction, etc.); c) uncorrectable coagulopathy.
• Age ≤30 years.
• Written informed consent for trial entry.

Patients must meet the specific eligibility criteria for their allocated treatment group.

• Any previous chemotherapy or currently receiving anti-cancer agents.
• Recurrent disease
• Previously received a solid organ transplant; other than orthotopic liver transplantation (OLT)
• Uncontrolled infection
• Unable to follow or comply with the protocol for any reason
• Second malignancy
• Pregnant or breastfeeding women

There are also Treatment Group Specific Exclusion Criteria, see protocoll.