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Thonglert et al. Hepatoma Res 2023;9:40 https://dx.doi.org/10.20517/2394-5079.2023.47 Page 15 of 23

Figure 2. Case example of a patient with unresectable iCCA treated with MRgRT. An 81-year-old woman with a pacemaker and
cochlear implant, who was diagnosed with a 4 cm iCCA, was initially treated with 3 cycles of gemcitabine and cisplatin followed by
MRgRT after stabilization of disease. Due to the proximity of the tumor to the stomach and duodenum, she was treated on a 0.35T MR-
Linac and prescribed 50 Gy in 5 consecutive fractions. Since the predicted duodenum and/or stomach dose constraints would have
been violated if original plan was used on each fraction due to interfraction anatomic changes, online adaptive replanning was utilized to
ensure that all organ at risk constraints were met while optimizing target coverage by the ablative prescription dose. She did not
experience acute or late grade 2+ higher toxicity and achieved a complete metabolic response.

delivering photon radiation, which has low to moderate dose spillage in the uninvolved liver tissue.

Future directions of MRgRT for iCCA
Fast and accurate auto-segmentation is essential for online adaptive MRgRT. Further development of
artificial intelligence could potentially facilitate faster and more accurate auto-segmentation, resulting in
enhanced contour quality . When combined with faster automated treatment planning and delivery
[74]
systems, these may contribute to a shorter MRgRT treatment time, making therapy better tolerated,
improving patient compliance, and increasing patient endurance in treatment position . Shortening
[75]
treatment times could allow more patients to access this advanced technology.

Obtaining a variety of MRI imaging data, which includes both pre-treatment and during-treatment imaging,
allows for the investigation of early functional imaging biomarkers and may enable the personalization of
RT for individual patients . This approach can potentially lead to administering higher radiation doses to
[76]
regions of biological resistance while reducing doses in areas with good response, which may result in
improved LC while minimizing toxicities.

IMPACT OF MOLECULAR CHARACTERISTICS ON RADIOTHERAPY IN ICCA
Radiation and targeted therapies in iCCA
With the development of gene technologies, the role of gene mutations and abnormal signaling pathways in
the pathogenesis of iCCA has been discovered, and several molecular targets have been identified, leading to
more treatment opportunities and better treatment outcomes. Fibroblast growth factor receptor 2 (FGFR2)
fusion/rearrangement and isocitrate dehydrogenase (IDH) 1 mutation play a significant role in
tumorigenesis in iCCA and have become promising targets for treatment. Although FGFR fusion or
rearrangement and IDH inhibitors have shown promising efficacy in treating patients with advanced CCA,
the impact of these genetic alterations on radiotherapy response remains unclear. In addition to the
mutations discussed in this article, there are several other rare mutations in iCCA, including NTRK fusion,
BRAF V600E mutation, HER2 overexpression and/or amplification, and RET fusion.