Standard-of-care with complete resection upfront: observation vs sorafenib vs PLADO vs PLADO and sorafenib?
Katzenstein et al12 reported an 88% 5-year EFS in patients with completely resected HCC receiving either cisplatin, 5-fluorouracil, and vincristine or PLADO (n=8). The German HB99 study11 used two cycles of carboplatin/etoposide postoperatively, which translated into 5-year EFS and OS probabilities of 72% and 89% (n=14), respectively. Thus, there seems to be no difference in survival based on the chemotherapy used. Whether postoperative sorafenib has a survival benefit remains unclear. In adults, it was recently shown that sorafenib is not effective as an adjuvant treatment following resection or ablation.25 An enhanced chemotherapeutic response to sorafenib and PLADO was demonstrated in the small series of patients with advanced HCC (PR in four out of seven). However, further data regarding sorafenib are urgently needed in the pediatric HCC population.24
The problem is that it is impossible to realize Phase II to III studies in an entity as rare as HCC in childhood. In the SIOPEL 1, 2, and 3 studies1,10 recruiting patients between 1990 and 2004, 15/121 had an HCC with complete resection at diagnosis. Internationally, the estimated number of primary resectable patients would be about 10/year. With such low numbers, a study randomizing patients after upfront complete surgical resection to observation vs sorafenib vs PLADO vs PLADO and sorafenib, and even to a two-arm study, will never be feasible within an adequate amount of time.
Thus, only recommendations can be given. Pediatric liver tumor specialists currently recommend that children with HCC should receive PLADO with or without sorafenib, as more intensive regimens have not yielded better results. But the role of postoperative chemotherapy and the amount (PLADO for two or four cycles? sorafenib at all or for 6 or 12 months?) for a stage I disease that has demonstrated chemotherapeutic sensitivity in pediatric patients are unknown.
Current therapeutic options in newly diagnosed patients with unresectable tumors and/or metastatic disease
Pediatric patients with unresectable or primarily metastatic HCC do not survive unless the disease can be rendered resectable. Given preexisting evidence that pediatric HCC is chemotherapy responsive in nearly 50% of the patients (Table 1), PLADO has been established as the standard chemotherapy. Intensification of platinum and doxorubicin agents, as in the SIOPEL 2 and 3 studies,13 did not result in improved survival. However, 5-year EFS rates still remain between 10%–34% since response mostly does not translate into complete surgical resection. Better tumor shrinkage is needed to facilitate surgery. Hopefully, sorafenib in addition to PLADO improves the resectability rate, EFS, and OS.24
In a recently published multicenter study from France, 204 adults with advanced HCC received gemcitabine (1,000 mg/m² on d1) and oxaliplatin (100 mg/m² on d2) (GEMOX), with promising response and tumor control rates of 22% and 66%, respectively.26 In 44% of the patients, grade 3–4 toxicities were reported, especially neutropenia, thrombocytopenia, neurotoxicity, and diarrhea. In a retrospective survey within the international liver tumor community, the response to GEMOX was 30% in heavily pretreated pediatric patients (personal communication).