Abstract: Hepatocellular carcinoma (HCC) is a very rare entity in children, making it nearly impossible to orchestrate Phase II/III studies even as multinational cooperative trials. In contrast to adults, nearly 50% of the children have a response (α-fetoprotein decline and/or tumor shrinkage) to chemotherapeutic agents such as cisplatin and doxorubicin (PLADO), demonstrating that HCC in childhood can be chemotherapy sensitive. As a result, the main treatment options in pediatric HCC focus on systemic drug therapies and resection as the central therapy. In nonmetastatic patients with complete resection upfront, the 5-year event-free survival and overall survival has reached 80%–90%. In almost all reported studies, children received adjuvant chemotherapy (mostly PLADO), but it has never been proven that postoperative chemotherapy is superior to observation. No data are available for the effects of sorafenib. The 3-year survival is <20% in children with unresectable HCC independent of the chemotherapy given preoperatively. Currently, PLADO in combination with sorafenib is recommended with the goal of achieving operability status. Alternatively, data are promising for the combination of sorafenib with gemcitabine and oxaliplatin. For children with nonresectable and nonmetastastic liver tumors, it has been shown that the Milan criteria regarding liver transplantation are not applicable – individual decisions have to be made. Transarterial chemoembolization could be offered to patients with chemotherapy-resistant liver tumors for palliative care or potentially to achieve surgical resectability, and therefore cure. Information about the feasibility or effects of new agents or approaches as discussed in adult HCC patients is not available for childhood HCC. Research has to be done for characterizing the molecular and genomic mechanisms of pediatric HCC to support the development of novel therapeutic approaches and the implementation of personalized medicine.

Keywords: hepatocellular carcinoma, pediatric, sorafenib, cisplatin, doxorubicin 

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Primary malignant liver tumors are rare in childhood with an incidence of about 1.6 cases per million children (0–14 years).1,2 While hepatoblastoma (HB) represents 80% of the hepatic-related cancer affecting children predominantly between 6 months and 3 years, hepatocellular carcinoma (HCC) is more uncommon, with incidence increasing with age. Only about 0.5%–1% of all pediatric tumors are HCC.1,2 In hepatoblastoma, event-free survival (EFS) and overall survival (OS) was increased from roughly 30% in the 1970s to 70%–90% these days, especially due to advances of chemotherapy regimens and surgical approaches.3 In HCC, the results with unresectable tumor especially are rather dismal.

Contrary to adults, in the majority of children or adolescents, no etiologic factors can be detected. However, in areas with a high prevalence of hepatitis B virus (HBV) infection rate, the lifetime risk of HCC in chronic HBV carriers is estimated to be 10%–25%.4 For example, in Taiwan and Hong Kong, 100% and 64%, respectively, of all children with HCC were chronic HBV carriers. It can be expected that universal newborn vaccination will have an effect in reducing the incidence of HCC.5,6 Only a minority of HCC cases are associated with cirrhosis or other chronic liver diseases such as glycogen storage disease type III, tyrosinemia type I, Wilson disease, or biliary atresia. This indicates that the pathogenesis of HCC in childhood is different compared with that in adults.7–9