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Page 4 of 23 Thonglert et al. Hepatoma Res 2023;9:40 https://dx.doi.org/10.20517/2394-5079.2023.47

Historical studies conducted prior to the establishment of chemotherapy as a standard treatment indicated
that EBRT had a 60% response rate (complete response [CR] and partial response [PR]) in patients with
[26]
lymph node metastasis and could improve OS in patients with unresectable iCCA (P = 0.003) . These early
findings suggest a possible benefit of RT in this patient population, but further research is warranted to
evaluate the potential benefits of additional RT.

RT as a neoadjuvant treatment for iCCA
Given that margin-negative resection remains a primary approach in the curative-intent treatment of iCCA,
neoadjuvant treatment for patients with localized, unresectable disease can be used to downsize tumors,
with the aim of converting these patients to resectable status. This approach shifts the treatment goal from
palliative to curative intent. Although neoadjuvant therapy is widely used in other malignancies, it is less
commonly applied in patients with iCCA. Currently, there is no high-level evidence supporting the use of
neoadjuvant treatment, and comparison data between treatment modalities are absent [27,28] . Our current
understanding of radiation in this setting is based primarily on small retrospective studies. One study
showed 85.7% of unresectable iCCA patients experiencing tumor shrinkage post CRT, with 71.4%
undergoing resection (80% achieving R0 resection), improving OS compared to those who did not undergo
surgery (37 months vs. 10 months; P = 0.027) . Another observed 25% PR rate with 12.5% reaching
[29]
[30]
curative resection, leading to better locoregional recurrence-free survival (LRFFS) and OS . These findings
suggest that CRT may have a role in downsizing tumors and converting them to a resectable status, which
can improve OS [29,30] . Despite these findings, the effectiveness and resectability rates after neoadjuvant
treatment can vary significantly, and many questions regarding optimal initial and local treatments, and
appropriate radiation doses remain unanswered due to limited data. Further investigations are necessary to
understand the role of neoadjuvant EBRT in this setting.

ADVANCED AND EMERGING RADIATION THERAPY TECHNIQUES
Proton beam therapy (PBT) for iCCA
Current standard radiotherapy techniques and limitations
Until recently, the standard RT approach for treating iCCA has involved photon therapy or high-energy
X-ray, with advanced techniques including IMRT and SBRT. These advanced treatments have been
developed to enable a more conformal delivery of RT to the tumor, minimizing unnecessary radiation
exposure to the surrounding healthy tissue. IMRT, an advanced form of 3DCRT, allows for variable
radiation intensity across each beam, which results in improved target conformity and sparing of normal
tissue. SBRT, more technologically intensive, can deliver high doses of radiation per treatment fraction, with
the entire course of treatment typically consisting of fewer than five fractions. However, due to the physical
properties of photons, which cause radiation deposition along the beam path, advanced RT is not without
its limitations. In certain patient conditions, such as the presence of large or multiple tumors and poor liver
function, it may not be feasible to treat tumors without delivering high doses of radiation to healthy
[31]
tissue . As a result, ablative doses may not be achievable with photon treatment, potentially leading to
suboptimal outcomes.

The rationale for PBT
PBT offers a dosimetric advantage over photon RT, providing a promising approach for liver tumor
treatment [32,33] . Photon RT deposits doses along the beam path and extends beyond the tumor, leading to
undesired exposure from the exit radiation to adjacent normal tissues, especially the healthy liver. On the
other hand, proton has a limited range in tissues. The proton energy loss remains minimal until the end of
the beam range, with the residual energy lost over a very short distance. This results in a distinct sharp rise
in absorbed dose, followed by a rapid dose fall-off, known as the "Bragg peak" distal to the tumor and
subsequent sparing of normal tissue exposure to radiation beyond the tumor . Consequently, PBT offers a
[34]