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Page 8 of 10 Bieu et al. Hepatoma Res 2020;6:49 I http://dx.doi.org/10.20517/2394-5079.2020.39

alone in HCC patients with tumor size ≥ 3 cm and a prospective randomized clinical trial is required to
[33]
[34]
confirm the result . In another pilot phase II trial, Buckstein et al. combined drug-eluting bead (DEB)
TACE followed by SBRT in 25 HCC patients with single tumor size 4-7 cm. 92% of target lesions showed
objective response including 64% CR (n = 16) and 28% PR (n = 7). 2-year OS and PFS were 67% and
52%, respectively. Cause-specific survival (CSS) was 91% at 1 year and 83% at 2 years. He suggested that
the results show very promising response rates when combining TACE and SBRT in large, unresectable
[34]
HCC with the excellent OS, PFS, and CSS . However, up to date, we do not found any paper address the
combination of TACE and SBRT as a bridge therapy to LT for patients with HCC.

In our case, the patient had a big tumor size > 5 cm with very high serum PIVKA II and AFP levels so we
combined both TACE and SBRT to increase the chance of local control as well as downstage the lesion
to LT criteria. TACE was performed first and adjuvant SBRT was followed to exploit the advantage of
combination therapies. It took 6 months for both therapies to downstage the tumor and 10 months on WL
for the patient to find a suitable donor. After two TACE treatments, the tumor showed partial response but
the serum AFP was still higher than 200 ng/mL. The patient had a high risk of drop out from the WL for
LT post TACE because there was still no suitable donor for him. Adding SBRT had kept the patient in the
WL and finally, his LT was successfully done.

However, SBRT for HCC is a highly specialized procedure requiring both clinical and technical
expertise. Considerations such as accurate target localization, rigid patient immobilisation, strict motion
management, and proximity to adjacent viscera such as bowel and biliary structures must be considered
prior to, and throughout treatment. As such, this technique can only be delivered safely and effectively
in experienced centers with synchronized equipment, coupled with a well-oiled multi-disciplinary team
comprising radiation oncologists, medical physicists and radiation therapy technologists.

At our center, we use 4D CT, gating, breath-hold techniques, or abdominal compression to manage the
respiratory movement of the tumor, so that we can treat the tumor precisely with a 3-5 mm margin from
ITV to PTV. Moreover, when combining SBRT with TACE as a bridge therapy to LT, it is necessary to have
close teamwork between surgeons, gastroenterologists, and radiation oncologists. Additionally, adjuvant
SBRT to TACE can do more harm to liver function and cause gastrointestinal toxicities such as bleeding
or ulcer. So patient selection is very important to safely combine TACE and SBRT. Our patient had a good
liver function with CP A5 and normal liver volume > 700 mL. His tumor was close to the chest wall and
liver dome so it is difficult for RFA and more suitable for adjuvant SBRT post-TACE. That is why he had
only grade hepatic toxicity and no gastrointestinal toxicities post-TACE and SBRT. It is also important that
after bridge therapy with TACE and SBRT, patients must continue the treatment of chronic liver disease, in
our case was HBV, to prevent tumors from progression.

Finally, we should be cautious when evaluating treament response after TACE combined with SBRT for
HCC. With this patient, we found that the tumor size did not change one month after SBRT and only
decreased slightly 3-month post-SBRT with central necrosis. Interestingly, contrast enhancement was seen
in normal liver tissue surrounding the primary tumor one month post SBRT and it seemed increased with
time [Figure 2B and C]. It was a normal liver reaction after SBRT and can be misinterpreted with tumor
[35]
progression. In a series of 26 HCC patients treated with SBRT, Price et al. found that this phenomenon can
even last 6 months post-SBRT. He suggested that nonenhancement on imaging, a surrogate for ablation, maybe
[36]
a more useful indicator than size reduction in evaluating HCC response to SBRT in the first 6 to 12 months .
Sanuki-Fujimoto et al. also noted in their study that the CT appearances of the normal liver seen in
[36]
reaction to the treatment of an HCC by SBRT were therefore related to background liver function and
should not be misread as recurrence of HCC.