Management of HCC remains difficult since complete surgical resection is fundamental for cure. However, in pediatric HCC, <20% of the patients are considered eligible for initial resection. Various studies have been conducted using different combinations of chemotherapeutic agents to reduce tumor load, thereby helping patients become suitable candidates for resection. Historically, HCC patients were treated with the same protocols as HB patients, and so, primarily, cisplatin, doxorubicin, carboplatin, 5-fluorouracil, and vincristine were used.1,10 However, to date, there is no convincing data that this approach results in a benefit for survival.

The 3-year EFS and OS for children with complete tumor excision upfront and two courses of carboplatin (200 mg/m2/d × 4) and etoposide (100 mg/m2/d × 4) were 72% and 89%, respectively, in the HB99 study (1999–2008)11 conducted by the German Society for Pediatric Oncology and Hematology (GPOH). However, the prognosis remained poor, with 3-year EFS and OS rates of 12% and 20% in those patients who had inoperable or metastatic disease. Intensifying preoperative chemotherapy with two courses of carboplatin and etoposide followed by two courses of high-dose carboplatin (500 mg/m2/d × 4) and etoposide (300 mg/m2/d  × 4) with autologous stem cell transplantation did not translate into a satisfactory operability rate, EFS, or OS.

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Similar findings were reported by the North American Intergroup Hepatoblastoma Study (INT-0098) (1989–1992).12 The 5-year EFS (OS) for pediatric patients (26/46 patients ≥10 years) with inoperable tumor upfront was 8% (23%), and for those with metastases it was 0% (19%). There was no difference based on whether the children received cisplatin (90 mg/m2 on d0) and doxorubicin (20 mg/m2/d × 4 from d2) or cisplatin (90 mg/m2 on d0), 5-fluorouracil (600 mg/m2 on d2), and vincristine (1.5 mg/m2 on d2).

Importantly, the first International Society of Pediatric Oncology Liver Tumor Study (SIOPEL-1 study, 1990–1994)1 demonstrated that HCC in childhood (4–15 years, median: 12 years) can be chemotherapy sensitive. They proved this by showing that 49% of the children responded to cisplatin (80 mg/m2 on d1) and doxorubicin (30 mg/m2/d on d2+3) (PLADO). However, taking into consideration that complete resection is the cornerstone of cure, only 36% had complete tumor excision, and so the 5-year EFS was only 17%. The next attempt (SIOPEL-2 study, 1995–1998)10,13 tried was rapidly switching between cisplatin (80 mg/m2 on d1) and carboplatin (500 mg/m2 on d1)/doxorubicin (30 mg/m2/d on d2+3) (SuperPLADO) every 14 days, but this did not improve the response rate after preoperative chemotherapy (46%), and therefore also not 3-year OS (22%).

Thus, to date, for children with inoperable liver tumor and/or with metastases, the complete resection (and so the EFS and OS) have not improved although different strategies have been attempted.

Sorafenib is an inhibitor of several tyrosine protein kinases such as VEGFR, PDGFR, and Raf kinases.14–16 In preclinical models, sorafenib demonstrated antitumor activity alone and in combination with, for instance, doxorubicin, gemcitabine, and cisplatin.17,18 In adult patients with advanced HCC, sorafenib significantly improved both time to tumor progression and OS from a median of 2.8 to 5.5 months and from 7.9 to 10.7 months, respectively, compared with placebo. The most important grade 3 adverse effects were diarrhea, hand–foot skin reaction, and fatigue.19 Therefore, sorafenib has become the standard therapy for adult patients with HCC.20 Furthermore, in a randomized, double-blind, Phase II study combining sorafenib with doxorubicin, the progression-free survival (PFS) was significantly better in patients receiving sorafenib and doxorubicin than in those receiving doxorubicin and placebo (median: 4.8 vs 8.6 months).21,22 Moreover, tumor reduction was achieved in 62% vs 29% of the patients. This effect could be due to the fact that combining sorafenib with doxorubicin translated into an increased mean values of doxorubicin Cmax and area under the curve by 33% and 21%, respectively.23 In the recent study with 12 children (seven with unresectable liver tumor, age 7–16 years), it was demonstrated that sorafenib (244–602 mg/m2/d, median: 288 mg/m2/d) added to PLADO is a promising new therapeutic option with hand–foot skin reaction being the most relevant toxicity.24 With this combination, four of the seven children with inoperable liver tumor achieved a partial response (PR), two a stable disease, and one a progression. Three patients were alive without evidence of tumor after complete tumor excision at 12 months (with second-line chemotherapy after two courses sorafenib and PLADO), 12 months, and 18 months (both patients had six courses sorafenib and PLADO), respectively, after primary diagnosis. The elevated α-fetoprotein levels seen in four patients at diagnosis markedly declined after two courses of therapy. Since then, some pediatric liver tumor specialists have recommended PLADO with sorafenib as a “standard” chemotherapy.

Thus, there are big challenges to be solved for pediatric patients with HCC, namely: 1) What is the standard-of-care in children with newly diagnosed HCC with complete resection upfront: observation vs sorafenib vs PLADO vs PLADO and sorafenib? 2) What are the therapeutic options in newly diagnosed patients with unresectable tumors and/or metastatic disease? 3) Are there new approaches on the horizon for HCC in children? 4) Must the Milan criteria for a liver transplantation be strictly adhered to? and 5) Does transarterial chemoembolization (TACE) play a role in pediatric patients?