Page 557 - Read Online

Bieu et al. Hepatoma Res 2020;6:49 I http://dx.doi.org/10.20517/2394-5079.2020.39 Page 7 of 10

conformal radiation therapy is a safe and efficacious local bridging therapy for patients with HCC on the
[12]
[24]
WL for LT . In another article, Sapisochin et al. reported an intention to treat analysis about SBRT used
as bridge therapy in HCC patients not eligible for other locoregional treatments and observed similar drop-
out rate with SBRT and TACE or RFA. SBRT is proven to be safe and effective for tumors with a diameter
[25]
< 6 cm, even in lesions near the central biliary system, where surgery or RFA is impossible . In a recent
study by Moore et al. , 23 early-stage HCC patients who were not candidates for resection or local therapy
[26]
treated with SBRT as bridge therapy to LT. The median prescribed doses to the tumor and the normal livers
were 54 Gy (range 30-54 Gy) and 6.0 Gy (range 1.6-12.6 Gy), respectively. 22 patients had no significant
changes in lab tests in 12 weeks follow-up but one patient developed RILD. 16 patients were on WL post
SBRT and 11 were successfully transplanted. The median overall survival (OS) and progression-free survival
(PFS) for the transplanted patients were not reached (range, 2.0-53.7 months, and 54 months, respectively)
and were 23 and 14 months, respectively for the non-transplanted patients. Pathology report of liver
explant post LT revealed 3 tumors (27.3%) with complete response (CR), 6 tumors (54.5%) with partial
response (PR), and stable disease in 2 tumors (18.2%). The authors concluded that SBRT was effective and
[26]
safe to be used as a bridge therapy to LT without compromising the surgical procedure . Furthermore, in
[27]
a retrospective study, Gresswell et al. found that SBRT with functional treatment planning can be used
safely as a bridge to LT in select patients with CP ≥ 8 cirrhosis.

Until now, there are no guidelines available to define which bridging therapy is the preferred treatment
for specific patients. The choice of suitable bridging therapies has to be tailored to the the patient’s status,
the tumor characteristics, and more important the center experience. RFA is the treatment of choice in
patients with a single tumor size < 5 cm. The benefit of RFA as bridging therapy is best seen in patients
[28]
with small tumors < 3 cm and < 1-year waiting time . TACE should be considered for patients with HCC
between 3-5 cm, because nodules with 3 cm of diameter or more are better vascularized, with a large
feeding artery, therefore the effectiveness of TACE appears to be better; whereas smaller HCC has not yet
a completely developed arterial neoangiogenesis [29,30] . SBRT has the advantage to treat the tumors adjacent
to the central biliary system, in the liver dome or subcapsular HCC, these lesions are not suitable for
RFA. However, SBRT is not suitable for tumors close to the duodenum, stomach, or bowel, for high risk
[25]
of ulcer, hemorrhage, and perforation . Up to now, there are several ongoing prospective phases 2 and 3
randomized trials to compare the safety and effectiveness of SBRT and TACE as a bridge therapy to LT [31,32] .

Experiences with combined therapies such as SBRT and TACE have been published in recent years, mostly
in the scenario of unresectable HCC with diameter > 3 cm [33,34] . The rationale for treatment combination
is to achieve a higher local control rate due to higher rates of complete tumor necrosis. The potential
advantages when combining TACE followed by SBRT are: (1) TACE is most effective at the center of the
HCC and failures are most commonly seen at the periphery of the tumor, where the ischaemic effects of
TACE are least potent because the surrounding normal liver parenchyma is well oxygenated; (2) on the
contrary, SBRT is most effective in the well-oxygenated periphery of the HCC and failures often occur in
the more hypoxic zone at the tumor center; (3) large tumors that are not suitable for SBRT alone become
more amenable to this therapy following TACE due to the effect of TACE in the hypoxic area at the tumor
center; and (4) a theoretical radio-sensitization by the cytotoxic agents used in TACE may result in the
improvement of tumor response .
[34]
The approach of SBRT and TACE combination may be applied even as bridging therapy to LT. A
[33]
retrospective study combined TACE followed by SBRT in patients with HCC size ≥ 3 cm by Jacob et al.
showed that local recurrence was significantly decreased in the TACE plus SBRT group (10.8%) when
compared with the TACE-only group (25.8%) (P = 0.04). The TACE plus SBRT group also had significantly
longer OS than the TACE-only one (33 months and 20 months, respectively; P = 0.02). The author
supposed that combined TACE and SBRT resulted in a survival advantage over treatment with TACE