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Page 2 of 23 Thonglert et al. Hepatoma Res 2023;9:40 https://dx.doi.org/10.20517/2394-5079.2023.47

[1,2]
term survival rate and a high incidence of tumor recurrence . To maximize treatment outcomes, a
comprehensive, multidisciplinary treatment approach has become essential. Within this approach,
radiotherapy (RT) is a component that holds the potential to improve clinical outcomes in select patients.

Conventional RT with photons or x-ray is standard for various types of cancers, including iCCA. However,
due to the physical property of photons that result in dose deposition along their trajectory, coupled with
the typical anatomic location of iCCA tumors in or near radiosensitive organs such as the liver and luminal
GI structures, advanced RT techniques are often necessary for the safe and effective RT treatment delivery.

Over the past decades, radiation techniques have evolved significantly. These advancements aim to optimize
the precision of radiation delivery to tumors while minimizing exposure of the surrounding normal tissue.
Photon-based radiation techniques have evolved from two-dimensional (2D) techniques to three-
dimensional conformal radiotherapy (3D-CRT), to intensity-modulated radiation therapy (IMRT), and
most recently, to stereotactic body radiation therapy (SBRT). Each stage of evolution has its advantages. For
instance, 3D-CRT, which uses 3D mapping of tumors in place of 2D imaging, enables more dose
conformality. However, it lacks the ability to modulate beam intensity - a limitation that IMRT helps
overcome. IMRT employs inverse treatment planning, which incorporates defined planning goals to
iteratively generate plans that modulate the intensity of radiation beams. SBRT, an even more precise
approach, can deliver high radiation doses in five or fewer fractions, enhancing tumor control and reducing
toxicity to surrounding tissues.

Concurrently, image-guided radiotherapy (IGRT), an in-room imaging guiding the radiation delivery, has
evolved from portable x-ray to orthogonal kilovolt x-ray images, and to cone-beam computed tomography
(CBCT). This development enhances the clarity of tumor visualization before each fraction of treatment,
enabling more precise radiation delivery with smaller margins.

Despite these advancements, current standard techniques still have limitations in certain situations.
Emerging technologies such as proton beam therapy (PBT) and magnetic resonance imaging-guided
radiotherapy (MRgRT) have been developed to overcome these limitations. This review examines and
summarizes advanced and emerging RT technologies focusing on PBT and MRgRT. Additionally, with
advancements in molecular research, targeted therapy and immunotherapy have become the standard of
care; we will explore novel RT approaches when combined with these systemic therapies.

ROLE OF RT FOR ICCA
Adjuvant RT for resectable iCCA
Surgical resection is the cornerstone treatment for iCCA. Following surgical resection, adjuvant
[3]
chemotherapy is considered the standard of care, as it can potentially improve OS . To date, no phase III
study has evaluated the efficacy of adjuvant RT or chemoRT (CRT). However, retrospective studies have
shown that adjuvant RT may benefit select patients with iCCA . The potential benefit of adjuvant CRT is
[4-9]
its ability to improve locoregional control or survival, particularly in patients with positive margins or
lymph nodes. Kim et al. found that in R0 resection, lymph node-positive iCCA patients, adjuvant CRT was
associated with a trend towards longer OS compared with no adjuvant treatment (median OS: 72.1 vs. 27.2
months, P = 0.059), while adjuvant chemotherapy alone did not improve OS . Lin et al. found that in iCCA
[9]
patients with positive margins, postoperative CRT improved OS compared to adjuvant chemotherapy alone
for early (HR 0.65; 95%CI: 0.56-0.92; P = 0.01) and advanced stages (HR 0.51; 95%CI: 0.36-0.75; P < 0.001)
patients . Despite studies indicating the potential benefit, the role of adjuvant RT remains controversial as
[7]
[10]
conflicting findings have been reported .