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Page 2 of 7 Li et al. Hepatoma Res 2020;6:39 I http://dx.doi.org/10.20517/2394-5079.2020.13

for small liver tumors. Some patients with unresectable tumor thrombus can be converted to surgical
resection after radiotherapy, and external radiotherapy can also be applied for bridging treatment before
liver transplantation. A narrow margin with a distance of less than 1 cm from tumor resection edge is
possible with radiotherapy after liver resection, to reduce local recurrence or distant metastasis of HCC and
to prolong disease-free survival (DFS) of patients. The mechanism of killing tumor cell by SBRT may be
different from conventional fractionated radiotherapy. With the increase of fractionated dose, double-strand
DNA breaks increase, and the repair of sublethal damage decreases. Moreover, when the single fractionated
dose is more than 8-10 Gy, the tumor vascular endothelial cells rapidly wither after 1-6 h of irradiation,
and blood vessels are occluded, leading to a secondary tumor killing effect, which is mainly through the
acid sphingomyelinase pathway-mediated apoptosis of vascular endothelial cells [1-3] , but conventional
radiotherapy does not have the above effect. After conventional fractionated radiotherapy, tumor cell death is
mainly achieved by cell apoptosis, while after high dose irradiation, tumor cell death is mainly in the form of
[4]
“swelling death” , and tumor cell membrane is destroyed, releasing tumor specific antigen, becoming “in situ
[5]
tumor vaccine”, which can stimulate the immune system to kill residual tumor .
EFFECT OF SBRT ON LIVER FUNCTION
[6]
Cárdenes et al. conducted a phase I clinical study of dose escalation in patients with liver cancer: patients
with a tumor diameter less than 6 cm and Child-Pugh (CP) Class A could tolerate 48 Gy in three fractions,
and the patients with CP class B could not tolerate 42 Gy in three fractions, while no adverse effects occurred
after adjustment to 40 Gy in 5 fractions. The CP score was the only risk factor related to hepatotoxicity or
death within six months of SBRT treatment (P = 0.03). Three patients had classic radiation-induced liver
disease, all of which were above CP class B7. We believe that good liver function was needed for SBRT
treatment of liver cancer. Furthermore, CP score must be ≤ 7, and patients with CP score > 8 have high risk
of liver failure after SBRT treatment.

SBRT FOR PRIMARY LIVER CANCER
Many studies in the literature have focused on the study of liver cancer lesions with the diameter of less than
6 cm. The 1- and 2-year local control (LC) rates after SBRT were 72%-100% and 54.4%-100%, respectively,
and the 1-year survival rates were 72.7%-100% and 45.3%-87.9%, respectively [6-17] , but the dose fractionation
of radiotherapy used in various clinical studies was not the same. Patients with CP class A or tumor diameter
less than 3 cm usually undergo irradiation more than 10 Gy each time, total for 3-5 times. Because of the
good LC rates and tolerability, SBRT is recognized as an alternative for small liver tumors unsuitable for
[7]
surgery. Yoon et al. applied SBRT to treat 93 cases of inoperable liver cancer with median diameter of 2 cm
(1-6 cm), given 30-60 Gy or 10-20 Gy in 3-4 fractions, and the 1- and 3-year overall survival (OS) rates were
86 and 53.8%, respectively. LC failure was mainly seen in patients with liver cancer ≥ 3 cm, and the 3-year
LC rates of liver cancer with diameter ≥ 3.0, 2.1-3.0 and ≤ 2.0 cm were 76.3, 93.3 and 100%, respectively,
the intrahepatic 3-year recurrence-free survival (RFS) rate was 32.4%. Six patients (6.5%) had ≥ grade 3
[8]
hepatotoxicity. Similarly, Kwon et al. reported that 42 cases of liver cancer were treated with CyberKnife
at a dose of 30-39 Gy in 3 fractions; the complete response (CR) rate was 59.6% and the partial response
[9]
(PR) rate was 26.2%, while the 1- and 3-year OS rates were 92.9 and 58.6%, respectively. Kimura et al. used
48 Gy in 4 fractions to treat 65 patients with CP class A/B and median tumor diameter of 1.6 cm; 2-year OS,
RFS and LC were 76, 40 and 100%. Fifteen patients (23%) had ≥ grade 3 adverse reactions 6-12 months after
[9]
SBRT, and the level ≥ 3 adverse reactions in CP class B were higher than those in CP class A (P = 0.0127) .

There is no prospective study comparing SBRT with surgery or TACE in the treatment of primary liver
[15]
cancer. Honda et al. applied sequential SBRT and TACE compared with TACE alone in the treatment of
primary liver cancer with diameter less than 3 cm; of the 30 cases in the SBRT group, 29 cases (96.3%) had
a CR, but only 1 in 38 cases in the TACE group had a CR (3.3%). There was no radiation-related injury in