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Thonglert et al. Hepatoma Res 2023;9:40 https://dx.doi.org/10.20517/2394-5079.2023.47 Page 3 of 23

The American Society for Radiation Oncology (ASTRO) also conditionally recommends adjuvant CRT,
alone or in sequence, after systemic chemotherapy in iCCA patients who underwent curative surgical
[11]
resection and had high-risk features, including positive lymph nodes and/or R1 resection .

RT for localized unresectable iCCA
Although surgery is the main treatment for localized iCCA, only a small percentage of patients are
candidates for this treatment option because tumors are often asymptomatic in their early stages. The
combination of gemcitabine and cisplatin is considered the standard of care, according to the ABC-02
[12]
trial . Recently, the TOPAZ-1 study reported that the addition of durvalumab to this combined
chemotherapy may also provide a survival benefit [13,14] . However, most of the patients in both studies had
distant metastases [12,13] . For patients with unresectable iCCA without distant organ metastases, locoregional
failure remains a problem. Approximately 70% of patients who receive chemotherapy alone die from
progressive liver disease and subsequent liver failure rather than distant metastases. Patients who received
local therapy showed a lower incidence of liver failure at the time of death, implying that consolidative local
[15]
therapy may benefit this group of patients .

There are several options for locally directed therapy, including catheter-based therapies (chemo- or
radioembolization), hepatic arterial infusion of chemotherapy, ablation, and RT, but no randomized
controlled trials have compared these modalities. The choice of treatment depends on patient and tumor
characteristics and treatment availability and expertise .
[16]

As chemotherapy has become the standard of care, the question is: "Does additional RT provide benefits in
this scenario?" Although there are no randomized studies to answer this question, RT could improve
[15]
intrahepatic control and reduce the risk of death from liver failure due to intrahepatic tumor progression .
Some studies have shown that CRT appears to improve survival outcomes compared with chemotherapy
alone . Verma et al. retrospectively reviewed 2,842 patients in the National Cancer Database (NCDB) of
[17]
newly diagnosed iCCA without distant metastasis: 2,176 (77%) received chemotherapy alone,
while 666 (23%) received CRT . The study found that the median OS of the CRT group was superior to the
[17]
chemotherapy-only group (13.6 vs. 10.5 months; P < 0.001). CRT was also an independent prognostic factor
that predicted improved OS (P < 0.001).

Several studies have shown that RT is an effective treatment for localized unresectable iCCA, with 1- and 2-
year OS rates ranging from 51%-87% and 31%-62%, respectively [17-25] . LC at 2 years was reported to be
between 45%-94% [18,20-23] . Data also suggests a benefit of radiation dose escalation for iCCA tumors. As
shown in a retrospective study of inoperable tumors treated with curative intent by Tao et al., a biological
equivalent dose (BED ) > 80.5 Gy was associated with improved LC and OS . The 3-year LC for patients
[23]
10
who received BED > 80.5 Gy was 78%, compared to 45% for those with BED10 ≤ 80.5 Gy (P = 0.04).
10
Additionally, patients with BED > 80.5 had superior 3-year OS than those who received BED ≤ 80.5 Gy
10
10
(73% vs. 38%; P = 0.017). De et al. also retrospectively reviewed the data of unresectable iCCA patients in the
NCDB and found that patients who received ablative RT with BED ≥ 80.5 Gy had significantly better OS
10
[19]
than those who received conventional RT with BED < 80.5 Gy . The median OS was 23.7 months in the
10
ablative RT group compared to 12.8 months in the conventional RT group (P < 0.001). Ablative RT was an
independent prognostic factor for OS (HR 0.6; 95%CI: 0.48-0.76; P < 0.001).
In the context of unresectable iCCA with regional lymph node involvement, systemic treatment is also seen
as the standard treatment approach [12,13] . There is limited data available for the use of additional RT or CRT
in these cases; however, in theory, these methods might offer improvements in locoregional control.