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Page 10 of 12 Zeng et al. Hepatoma Res2020;6:43 I http://dx.doi.org/10.20517/2394-5079.2020.29

CONTRAINDICATIONS FOR SBRT IN SMALL HCC
If tumors and luminal structures (esophagus, stomach, duodenum, or intestine) are closely situated at < 1 cm,
SBRT is relatively contraindicated for this patient. However, hypofraction imaging-guided radiation therapy
could be recommended when HCC is inoperable or unsuitable for RFA.

At least 700 mL of normal liver (Child-Pugh Class A) must receive < 15 Gy. If this condition is not met, we
must be careful in choosing such patients.

The safety of liver radiation for HCC in patients with Child-Pugh Class C cirrhosis has not been established,
but SBRT could be used as bridging therapy for patients with HCC awaiting liver transplantation.

RESPONSE TO SBRT
HCC
[15]
Tumor response rates increase over time after SBRT. Sanuki et al. reported that HCC complete response
increased from 24% at three months after SBRT to 67%, 71%, and 93% at 6, 12, and 24 months, respectively,
[15]
after SBRT . Using modified Response Evaluation Criteria In Solid Tumor (mRECIST) criteria, complete
response occurred within three months after completing SBRT in Cases 9 and 11 and > 9 months after SBRT
in Cases 1, 5, and 7. Of note, we prefer to evaluate tumor response to SBRT using European Association
[16]
for the Study of the Liver (EASL) or mRECIST criteria rather than RECIST criteria . Case 7, for example,
exhibited a complete response according to EASL or mRECIST criteria in the fourth year after completion of
SBRT, but only a stable disease and partial response using RECIST criteria, at six months and one year after
completing SBRT, respectively. Similarly, Case 5 had a partial response using EASL or mRECIST criteria, but
stable disease using RECIST criteria, at six months after completing SBRT.

Liver parenchymal reactions
Early focal liver reaction refers to a surrounding low-intensity area observed on both computed tomography
(CT) and magnetic resonance imaging (MRI) scans within six months after completing SBRT. This focal
reaction is more visible in patients who undergo initial therapy with SBRT, as shown in Cases 1, 2, and 5.

Delayed focal liver reactions are classified as areas of hyperdensity, isodensity, and hypodensity in all
enhanced phases on follow-up MRI or CT > 6 months after SBRT completion [17,18] . Features of hyperdensity
were found in Cases 6 [Figure 6F and G] and 11 [Figure 11D]; features of isodensity were found in Cases 3
[Figure 3E], 7 [Figure 7C and D], and 11 [Figure 11E]; and features of hypodensity were found in Cases 1
[Figure 1E], 2 [Figure 2D], and 5 [Figure 5E].

The incidence of hyperdensity reactions in irradiated hepatic parenchyma may gradually increase after
6 months post-SBRT completion, potentially interfering with accurate assessment of treatment response and
being misinterpreted as recurrent tumor. Lack of washout in the delayed phase in hypervascular areas helps
[19]
distinguish SBRT-related changes from residual or recurrent HCC . Hyperdensity will typically disappear
2-3 years after treatment, as shown in Case 6 [Figure 6H]. Hypodensity represents the presence of regional
liver atrophy within 1-2 years, as shown in Cases 1 [Figure 1F], and 5 [Figure 5H].

The types of focal reaction did not appear to be related to liver function in our cases. The focal liver reaction
threshold dose following SBRT for HCC is 30 Gy for livers with Child-Pugh Class A function and 25 Gy for
livers with Child-Pugh Class B function, when delivered in five fractions [20,21] . The doses used in our cases
[Figures 1C, 2C, and 5D] were consistent with these thresholds.

TOXICITY
Hepatic damage
A consensus article summarizing the results of 15 previously published studies, including 1063 patients with
HCC undergoing SBRT, reported that only eight patients (0.8%) developed Grade 5 liver failure, and most