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Weeda et al. Hepatoma Res 2021;7:43 https://dx.doi.org/10.20517/2394-5079.2021.10 Page 3 of 7

[11]
Furthermore, in adult HCC, the angiogenesis and apoptosis pathways are frequently affected . These
signaling pathways are significant as the only targeted agents with some efficacy in adult HCC are sorafenib
[13]
and its generational successors which are multi kinase inhibitors targeting these pathways . Despite a lack
of evidence that these pathways are significantly aberrant in pediatric HCC, results from a small pediatric
series using sorafenib combined with cisplatin and doxorubicin have been encouraging . Although results
[14]
from adult HCC studies cannot be directly extrapolated to the pediatric patient group, the efficacy of
sorafenib in pediatric HCC may indicate overlap and potentially similar tumor subtypes. Further
development of targets and biomarkers in pediatric HCC is warranted.

SURGICAL AND SYSTEMIC TREATMENT
Complete surgical resection - including orthotopic liver transplant - is essential to cure pediatric HCC. In
contrast to findings in hepatoblastoma , a negative resection margin has the potential to affect long-term
[15]
survival in pediatric HCC. Ziogas et al. analyzed the National Cancer Database (106 children with HCC
[16]
treated between 2004 and 2015) and demonstrated the negative impact of resection with a tumor positive
margin on overall survival. The difference in overall survival between patients undergoing liver
transplantation and patients undergoing resection was not significantly different (P = 0.20). In both groups,
however, increased overall survival compared to resection with a tumor positive margin was found (P =
0.001 for transplantation vs. positive margin resection and P = 0.003 for negative vs. positive margin
resection). Although the difference between liver transplantation and resection with a negative margin was
not significantly different, there is a clear trend toward better survival after transplantation, especially in
higher tumor stages. These findings reiterate the importance of early referral for transplant evaluation.
Furthermore, no difference was shown between patients who underwent liver transplant within or outside
[16]
the Milan criteria , once again emphasizing these criteria may not be applicable to this patient group.

However, only a small fraction of patients is eligible for surgery (~20%) or transplantation at diagnosis.
Thus, efficacious systemic treatments are urgently needed. HCC is relatively chemoresistant with a response
rate below 50%, which does not translate into satisfactory long-term survival. Previous trials from pediatric
liver tumor study groups have treated HCC with the same chemotherapy regimens as hepatoblastoma.
Although there has been great progress in the outlook of high risk and advanced hepatoblastoma, efficacy in
pediatric HCC is limited and there have not been significant improvements in survival due to these
treatments [17,18] .

The presently run collaborative trial on pediatric liver tumors, the Paediatric Hepatic International Tumour
Trial (PHITT), has a separate treatment approach for HCC (https://clinicaltrials.gov/ct2/-
show/NCT03017326). In the PHITT trial, patients (younger than 30 years of age) with HCC are divided into
two groups: a group of resectable HCC and a group of unresectable and/or metastatic HCC.

Patients with resectable HCC will be observed without chemotherapy after resection or transplantation if
they have an underlying metabolic, genetic, or viral infection-mediated predisposing condition. The
rationale behind this approach is that (1) current studies in adult HCC do not support a role of adjuvant
chemotherapy, and (2) tolerance for chemotherapy in the context of possible liver dysfunction/cirrhosis is
decreased. However, it is important to note that the potential role and the optimal regimen of adjuvant
[19]
chemotherapy for HCC in the context of underlying disease are unknown . In case of “de novo” HCC
(including FL-HCC), patients will be treated with 4 cycles of cisplatin and doxorubicin (“PLADO”), as that
is the only regimen pediatric tumor groups have reported some effectiveness with and no other efficacious
chemotherapy is available at the moment [17,20] .