Page 106 - Read Online

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

Based on these studies, PBT presents benefits in terms of providing favorable outcomes with acceptable
toxicity rates. However, a lingering query pertains to identifying the specific patient cohort that would
benefit from proton therapy instead of photon therapy. No randomized data are available to address this
inquiry. Nevertheless, since ablative dose radiation can potentially result in improved outcomes, the benefit
of PBT may be more significant for patients who cannot achieve ablative doses with photon-based RT due
to the high dose or volume of RT to organs at risk. Even though cirrhosis may not be present in many
patients with iCCA, minimizing the RT dose to the normal liver remains crucial to reducing the risk of
RILD. This is particularly important in situations where liver dose cannot meet constraints due to various
reasons, such as large tumors, multiple intrahepatic tumors, small liver volume, and/or circumstances that
increase the risk of RILD development even with low doses of radiation, such as poor liver function
[31]
[Figure 1] .
Challenges and limitations of PBT in iCCA
The characteristic high-dose deposition in the exact range of PBT presents advantages and disadvantages.
Because the proton beam range is highly sensitive to variations in tissue electron density within the beam
path, tumor underdosing and overdosing of organs at risk are potential concerns. Sources of uncertainty
include inaccuracies in Hounsfield unit (HU) values obtained from CT simulation, tumor target
[40]
uncertainty, organ filling or variation, and breathing motion . However, these uncertainties can be
addressed through various methods used during the simulation, treatment planning, and treatment delivery
processes.

During CT simulation, uncertainty reduction can be achieved by employing dual-energy CT to enhance HU
value accuracy , utilizing Monte Carlo dose calculation algorithms to improve dose calculation
[41]
precision , establishing reproducible positions with proper immobilization to minimize setup
[40]
uncertainty , and implementing effective respiratory motion management to mitigate the interplay
[42]
[43]
effects . In the treatment planning phase, uncertainties can be reduced by selecting robust beam angles to
circumvent highly variable soft tissue regions and using 3D or 4D robust plan optimization and
[44]
evaluation . During PBT delivery, plan robustness can be monitored throughout the entire treatment
course by using CT-based IGRT or CT-on-rail to detect anatomical changes that could impact the proton
range or by utilizing interval quality assurance scans .
[45]

In addition to these technical limitations of PBT, the availability and cost of PBT are also significant factors
to consider. The cost of PBT is higher than that of photon treatment, and PBT machines are not as widely
available as photon-based RT. However, the development of compact proton accelerators and single-room
gantries may lead to the more widespread availability of proton centers in the future.

Future directions of PBT for iCCA
It is important to note that all clinical results of PBT in iCCA to date have utilized passive scattering
techniques [20,22,23,35-39] . In this approach, a narrow proton beam is spread over a larger area to cover the tumor.
Although passive scattering provides excellent dose conformity at the distal edge of the tumor, it lacks the
ability to conform to the proximal shape of the tumor. PBS proton therapy, particularly intensity-modulated
proton therapy (IMPT), represents an advanced technology of PBT. It employs a narrow beam and
modulates the intensity of each proton sport to scan across the tumor layer by layer. PBT-IMPT has more
potential in its ability to better target conformal regions while sparing critical structures, which may reduce
treatment-related toxicities. This technique may be vulnerable to variations in tissue electron density and,
consequently, may be less robust than passive scattering proton therapy [46,47] . In addition, it poses more
technical challenges for moving targets . However, these issues can be addressed by using proper motion
[48]