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Page 8 of 10 Shimizuguchi et al. Hepatoma Res 2020;6:66 I http://dx.doi.org/10.20517/2394-5079.2020.51

Studies involving patients with more advanced liver tumors, or in those with impaired liver function,
reported a greater risk of treatment-related toxicity. In the largest prospective Phase I/II study in patients
with multiple HCC, 68% of patients had two or more lesions, resulting in a mean liver dose > 20 Gy in
a fraction of patients. Seven patients experienced Grade 5 adverse events (liver failure for five patients).
[6]
Additionally, 29% of the patients experienced deterioration in the CP class 3 months after SBRT . A study
involving patients with poor liver function (CP B or C) reported that the OS rate at 1 year was 32% and 63%
[13]
of patients experienced a decline in CP score by 2 or more points at 3 months . For challenging cases, the
indication for patient-oriented SBRT should be decided based on HCC prognosis, liver function, patients
request, and other options.

The originally defined adverse factors, both physical and tumor factors, in this study did not seem to be
a crucial issue in the liver SBRT. Of the total included patients, 88% had at least one and 46% had two or
more adverse factors, although a high local control rate and acceptable toxicity were achieved. Thus, our
approach appears reasonable in terms of patient selection and toxicity management.

In the future, novel technologies might change the borderline of the indication of liver SBRT. Magnetic
resonance imaging linac provides real-time high contrast image-guided radiation therapy, which enables
highly accurate dose delivery with a minimal PTV margin . Moreover, proton beam RT has an advantage
[14]
on dose distribution over standard proton-based radiation in terms of its physical profile, and some
[15]
prospective trials have reported the clinical outcome . However, as there is no direct comparison to date,
its clinical advantage over photon-SBRT remains unclear. To clarify this point, a Phase III randomized trial
NRG-GI003 (NCT03186898) is open for accruing patients.

Advances in other local liver treatments, including, surgery and radiofrequency ablation, have also
provided the opportunity for less invasive local treatment for HCC. Indeed, laparoscopic resection is a
recently established method of hepatic resection that is supported by several studies [16,17] . Furthermore,
robotic surgery is a promising modality in the field of surgical resection of malignant disease. With regards
to liver tumor resection, due to lack of evidence, robotic surgery is not the standard of care at this time,
[18]
while oncological efficacy and the perioperative outcome is under evaluation . In the future, as less
invasive treatment options become available, the current indication of local treatment can be overwritten.
Discussion in a multi-disciplinary team, consisting of a surgeon, hepatologist, medical oncologist, and
radiation oncologist, may lead to better decision making, especially in cases with adverse factors.

This study has several limitations due to the small retrospective study basis. The number of patients and
events are not sufficient to perform a reliable statistical test to detect the critical adverse factors related to
SBRT. Additionally, there were no highly challenging cases in the current study population; for example,
poorer liver function, poorer performance status, or multiple lesions. Thus, the boundary of feasible
patients on liver SBRT was not shown in this study.

In conclusion, SBRT was safely and effectively administered to a group of patients harboring both physical
and tumor adverse factors as long as conducted following patient selection and dose constraints that were
used in this study. Therefore, SBRT seems to be a good treatment option for patients with primary liver
tumors.

DECLARATIONS
Authors’ contributions
Made contributions to conception and design of the study, performed data analysis and interpretation and
manuscript writing: Shimizuguchi T
Performed data acquisition, technical and material support and manuscript editing: Imamura J, Hashimoto
S, Karasawa K