Patients’ outcomes with TACE have been recently improved based on the application of micro-catheter technique and doxorubicin-eluting beads technique. The survival benefits of TACE were better in patients with focal liver lesions, hypervascular tumors and without vascular invasion . TACE was usually not performed in the case of multiple lesions, hypovascular tumor, and vascular invasion even extra-hepatic disease. The limitation of TACE was the incomplete target lesion necrosis, which made patients require repeated TACE treatments. In addition, residue tumor proliferation, tumor recurrence and metastasis after TACE influenced long-term outcome [13, 14]. Comprehensive therapy based on combination with systemic therapy played an important role in improving the efficacy of therapy for advanced HCC. The development of molecular targeted agent sorafenib, one of systemic therapies, brought hope for HCC patients.
Sorafenib, an orally active multikinase inhibitor with effects on tumor-cell proliferation and tumor angiogenesis, was initially identified as a Raf kinase inhibitor, by inhibiting the serine-threonine kinase Raf-1 and B-Raf. It also inhibits vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3; platelet-derived growth factor receptor β(PDGFR); and RET receptor tyrosine kinases. Sorafenib inhibits MEK and ERK phosphorylation, down-regulates cyeline D1 level, reduces eIF4E phosphorylation and down-regulates anti-apoptosis protein Mc11 [15, 16]. In SHARP and Oriental trials, monotherapy with sorafenib significantly prolonged overall survivals (44% and 47% respectively) and delayed time to progression (73% and nearly 1 fold respectively) in patients with advanced HCC compared with that in placebo recipients. Moreover, treatment with sorafenib was well tolerated and safe. Based on these data, sorafenib was recommended as the standard treatment for advanced HCC. However, the two trials also showed that the efficacy of monotherapy with sorafenib was limited since the absolute benefit in survival time compared with placebo was not so prominent.
In view of liver primary lesion, portal vein invasion and distant metastasis, there has been a consensus on comprehensive therapy based on combination therapy for intermediate-advanced HCC. The efficacy of the combining use of sorafenib and TACE in patients with advanced HCC including those with BCLC stage C disease was suggested in a recently published phase II clinical trial . Close to 60% of patients achieved objective response and the treatment was well tolerated although 40 sorafenib dose interruptions were observed. However, patients’ survival has not been reported.
The enrolled patients in our study were those of unresectable HCC, BCLC stage B or C. Baseline characteristics were well balanced between the study groups. The median survival time in the group treated with sorafenib plus TACE was 27 (95% Confidence Interval: 21.89–32.10) months, while the median survival time in the group of TACE alone was 17 (95% Confidence Interval: 12.66–29.33) months (Figure 1). Our data indicated that sorafenib could prolong the median survival time of patients with HCC treated with TACE.
We also observed that there was no significant difference in the median survival time between patients with portal vein thrombosis and distant metastasis and those without portal vein thrombosis and distant metastasis in combination therapy group. Although there was probably certain statistics deviation due to the small sample size, it is still suggested that sorafenib could cover the shortage of TACE to improve the outcome of patients with vascular invasion and distant metastasis.
Various adverse events occurred during sorafenib treatment in clinical practice, and significant individual differences were also found. However, no grade 4 adverse events were observed and the most common grade 3 events were hand-foot skin reactions and hypertension. Patients received full guidance during the treatment, thus adverse events were relieved after additional prevention, treatment and dose adjustment of sorafenib. Discontinuation due to adverse events was not observed. Collectively, the combination of sorafenib and TACE do not increase sorafenib related adverse events.
Although patients received sorafenib + TACE were accrued and treated according to our institutional protocol, the comparison between those with or without sorafenib therapy were retrospective in nature. Therefore, during the selection of patients treated with TACE alone, efforts were applied to avoid selection bias and the characteristics of patients and their diseases matched well in our two groups. Furthermore, as the survival data of patients treated with sorafenib in combination with TACE were not available at the time of our study design, sample size calculation for a phase II clinical trial was not possible. We consider retrospective nature of the comparison as well as a small sample size of 45 patients two substantial limitations of the current study.
The results of our current study and the above-mentioned phase II trial provided the only documentation of the efficacy and safety of the combination of sorafenib and local treatment using TACE. Clearly, these results are far from conclusive. The survival advantage of the combination of sorafenib and TACE over sorafenib alone has never been addressed. Furthermore, the optimal use of this combination, especially the optimal timing of TACE during sorafenib use needs to be studied. A number of recently published trials indicated that the use of external beam radiotherapy or I-125 implant might further improve local control of the intrahepatic disease [18, 19]. Whether the combination of sorafenib with TACE and/or radiotherapy can further improve patients’ survival also needs further investigation.