Our data indicate that, compared with placebo, conventional TACE followed by sorafenib administration led to a significantly longer median TTP in HCC patients. To substantiate the beneficial effect of sorafenib, given the confounding role of underlying cirrhosis, it was critical to select patients with well-preserved liver function (Child-Pugh class A), with an ECOG performance status score of 0–1, and without neoplastic invasion of intrahepatic vascular structures or extrahepatic spread.
The design of the present study included a double-blind randomization phase to minimize the likelihood of erroneous conclusions regarding the efficacy of sorafenib, and results were compared with the outcome in a homogeneous control group that met the same inclusion criteria. Early evidence of HCC progression is a critical point in the assessment of sorafenib efficacy. Indeed, short surveillance intervals and CEUS provided unequivocal advantages in that HCC nodules were detected when they were <20 mm in diameter (15.3 mm ± 2.1 mm).
Sorafenib is likely to delay disease progression in patients with resected or ablated HCC by inhibiting both tumor growth and neoangiogenesis as a result of blocking the molecular components of Raf–mitogen-activated protein kinase/extracellular signal–related kinase (ERK) kinase–ERK signaling, VEGFR-1, VEGFR-2, VEGFR-3, and PDGFR-β [14
], which are the key pathways in the pathogenesis of HCC [29
]. We found that the rate of metachronous, multicentric progression of HCC was substantially lower in sorafenib-treated patients, whereas the proportion of local progression was comparable with that found in the control group. The clinical importance of these findings is further emphasized by the knowledge that HCC progression distant from the primary site appeared late in time. It is likely that metachronous, multicentric HCC nodules originate from de novo hepatocarcinogenesis and are effectively influenced by sorafenib treatment, which has a smaller effect on local HCC progression. Indeed, long-term follow-up studies in patients with HCV-related HCC showed a higher frequency of metachronous, multicentric progression than in patients with HCC arising from different etiologies [30
This likely reflects the high carcinogenic risk of nontumoral areas in HCV-related HCC. It is known that the pathophysiology of hepatocarcinogenesis is tightly linked to the evolution of underlying cirrhosis, which accelerates cancer formation through different pathways, such as chromosomal instability and alterations in the microenvironment that stimulate cell proliferation in HCV-related damage [31
]. In addition, HCV-related hepatocyte necrosis and chronic inflammation may be closely involved in the pathophysiology of HCC progression in chronically HCV-infected patients who have had complete HCC resection or ablation [32
]. Hence, it was postulated that HCV elimination would help prevent HCC progression by clearing the carcinogenic field and eliminating the chances of novel tumorigenesis [33
The question of why certain molecularly defined HCC subgroups show a poor or no response to sorafenib is difficult to answer. No predominant or pathognomonic molecular mechanisms have been described to explain why a single targeted agent does not achieve clinical CR in HCC patients. Molecular alterations may differ depending on the etiology, activity, and duration of the underlying liver injury, thus influencing the response to therapy [34
]. No independent predictor of HCC progression was detected among several clinical and laboratory parameters, including tumor burden, number of HCC nodules, and α-FP level. Indeed, these conventional indicators of HCC progression do not seem to be appropriate. Promising innovations, which delineate gene signatures pertaining to premalignant conditions [35
], are coming from molecular biology. Serum or tissue-based molecular biomarkers are eagerly awaited to predict HCC progression.
Common side effects, including hand–foot syndrome, erythema, hyperbilirubinemia, hematological toxicity, and diarrhea, were noted in 22% of sorafenib-treated patients. Though recognized as common side effects of antikinases molecules, they are a leading problem in the clinical management of these patients. Dose reductions and pauses in the administration of sorafenib may prevent the attainment of therapeutic benefit in the adjuvant setting. Different treatment strategies should be recommended for this subgroup of patients, who deserve further consideration in terms of tailored dose and treatment schedules.
In conclusion, our data indicate that sorafenib administered as a sequential modality holds promise to become a useful adjuvant treatment to support the current TACE procedure for patients with HCV-related, intermediate-stage HCC. Obviously, our results need confirmation in a larger, well-designed, phase III clinical trial, which should include a follow-up period long enough to demonstrate an overall survival advantage.
Additional administration modalities can also be envisaged and should be thoroughly examined. Recent reports indicate that improvements in the control of HCC growth and in the prevention of HCC progression can be achieved using concurrent sorafenib and transarterial therapy in patients receiving sorafenib 2–4 weeks before transarterial therapy [19
], using continuous administration of sorafenib starting 7 days prior to TACE with doxorubicin [36
], and using sorafenib combined with concurrent TACE with doxorubicin-eluting beads [37