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Page 10 of 23 Thonglert et al. Hepatoma Res 2023;9:40 https://dx.doi.org/10.20517/2394-5079.2023.47

Figure 1. Case example of a patient with recurrent multifocal iCCA treated with PBT. A 67-yr-old woman initially diagnosed with iCCA
was treated with neoadjuvant chemotherapy followed by right hepatic lobectomy, postoperative SBRT to 45 Gy in 5 fractions for close
margins (A); and adjuvant chemotherapy. She developed oligometastatic disease and was treated with multiple lines of systemic
treatment, with the most recent being ivosidenib. She eventually developed solitary progression in the liver with multifocal intrahepatic
recurrence and was treated with salvage PBT with PBS (B); Due to the close proximity of the tumors to nearby GI organs, a
simultaneous-integrated boost technique was utilized to safely treat the tumors to 37.5-60 GyE in 15 fractions. She remains disease-
progression-free two years after completion of PBT (C).

management, 4D robust optimization to improve intrafractional motion robustness, employing rescanning
to reduce interplay effects, and performing verification CT more frequently to determine whether adaptive
planning is needed [49,50] . Studies using PBS are needed to evaluate the value of this PBT technology for
iCCAs.

Proton-FLASH therapy is the latest advancement in RT, garnering attention for its potential to minimize
radiation injury to normal tissues while maintaining effective tumor control. In comparison with the
conventional dose rate of proton therapy, which is approximately 0.03-0.1Gy/s, FLASH therapy is 400 times
more rapid, with a dose rate of > 40 Gy/s . Proton-FLASH has shown promise in superior normal tissue
[51]
protection and effective tumor control in numerous in vivo studies [52-55] . Consequently, the benefits of
Proton-FLASH in terms of normal tissue sparing may be further enhanced. Mascia et al. reported the first-
in-human trial of proton-FLASH therapy for the clinical treatment of painful bone metastases in
extremities, with results showing clinical feasibility, pain relief similar to conventional dose-rate photon
therapy, and minimal toxic effects . In theory, proton-FLASH therapy is an exciting new treatment
[56]
strategy that can potentially improve cancer treatment using radiation. However, translating this approach
into clinical practice remains challenging, and further investigation is necessary.

Magnetic resonance-guided radiation therapy (MRgRT) for iCCA
Current standard radiotherapy techniques and limitations
Delivering an ablative dose to unresectable iCCA using SBRT or hypofractionation is challenging, as it
requires accurate tumor targeting to maximize the probability of tumor control while minimizing toxicity.
iCCA can be located adjacent to radiosensitive GI organs, such as the stomach, small intestine and
duodenum, which have interfractional anatomical changes due to organ filling and peristalsis-induced
tumor motion. In addition, the tumor is located in the liver, which moves with respiration. Respiratory
motion management should be used, with the need to verify tumor location before treatment delivery.
However, high-fidelity visualization is difficult to achieve, as iCCA tumors are often in areas where the
tumor cannot be adequately verified with daily imaging using conventional CT-based IGRT due to poor soft
tissue resolution and lack of IV contrast. The utilization of fiducial markers is often employed to assist in
image guidance. In addition to the drawback of requiring invasive implantation, this approach also has
other significant uncertainties, including fiducial marker migration and challenges of imaging and
visualizing OAR changes. All these uncertainties may be compensated for by increasing the irradiated target
volume, which trades off the potential gain benefit of OAR sparing. Consequently, dose-escalated RT while