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Page 8 of 10 Zhao et al. Hepatoma Res 2019;5:17 I http://dx.doi.org/10.20517/2394-5079.2018.116

option for patients with HCC (≤ 5 cm) without increased liver toxicity compared with TACE. Chung and
Hwang suggested that SBRT combined with TACE can be a therapeutic option for HCC at the caudate lobe
[26]
with marginal resectability. In the study by Kang et al. stereotactic body radiation therapy combined with
[27]
TACE in the treatment of primary HCC with portal vein cancer thrombus can significantly improve the
local control rate, survival rate, the effective rate of portal vein cancer thrombus, and AFP improvement rate.
Besides, SBRT before TACE may have superiority in protecting liver function. Furthermore, SBRT combined
with TACE may be a useful complementary treatment approach for HCC > 5 cm in diameter .
[28]
The application of SBRT combined with TACE in the treatment of intermediate-to advanced-HCC patients
produced a synergistic therapeutic effect which may be related to the following factors: (1) TACE can shrink
tumor volume and reduce normal liver tissue damage; (2) Chemotherapeutics have the effect of enhanced
sensitivity for radiotherapy; (3) SBRT can denature vascular endothelial cells and block blood capillaries,
prolong the storage time of iodide oil and drugs in the body, and avoid repeated TACE treatment; (4) TACE
and SBRT have different therapeutic effects on cancer cells at various growth stages; (5) TACE can promote
the transformation of the remaining cells from non-proliferative stage cells to the proliferative phase which
can improve the sensitivity and the therapeutic effect of SBRT.

Six studies revealed that the side effects in the combined therapy group were slightly more substantial
than those in the monotherapy group, such as decrease of hemoglobin, leukocyte, thrombocytopenia,
gastrointestinal reactions, and liver function damage, but there was no significant difference between the
experimental group and control group (P > 0.05). The prognosis of the patients generally did not be affected
through the active symptomatic treatment [29,30,32,33,36,39] .

The results of our meta-analysis are subject to several limitations. Firstly, although a total of 13 studies
including 1210 patients were enrolled and the whole studies selected were high-quality RCTs, the sample sizes
of most studies were relatively small [29-41] . As a result, the studies selected maybe not capable of finding out
the details of all aspects and performing more subgroup analyses to evaluate the effect of the patients treated
by SBRT plus TACE compared with SBRT or TACE monotherapy. To verify and extend the observations,
a more randomized controlled, multi-center, large sample of trials are necessary. Secondly, for the sake of
clinical practice guidelines and ethical issues, there might be produced potential selection bias which may
derive from the characteristics of the patients such as the age, the liver function, tumor size. The above
limitations may influence the final results. Thirdly, due to lack of sufficient data, the sequence of the two
therapies and the interval of them, the frequency of TACE and the dose of radiotherapy were not performed
in this meta-analysis which was expected to be answered by further clinical studies. Fourthly, the included
studies were all conducted in China, which may bring the regional bias.

In conclusion, compared to the treatment of TACE or SBRT alone, SBRT combined with TACE is a mild, safe
and effective treatment which can extend the survival time and be beneficial to the prognosis of intermediate-
to advanced-stage HCC patients without any significant increase in severe untoward effects. Further studies
should be performed to confirm the impact of the combined therapy.

DECLARATIONS
Authors’ contributions
Discussed, agreed upon the content, contributed to the development and revision of the draft manuscripts,
read and approved the final manuscript: all authors
Drafted the initial version: Zhao SJ, Dai BS
Contributed to constructive suggestions and modification: Shao ZJ
Developed the idea for the study and contributed useful criticism and suggestions: Du XL, Zhang WL, Long Y