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Page 6 of 10 Reyngold et al. Hepatoma Res 2018;4:49 I http://dx.doi.org/10.20517/2394-5079.2018.84

IMAGE GUIDANCE
As described in the previous paragraphs, image guidance is a critical component of treatment with ablative
doses. Some options for image guidance include fiducial-based kilovoltage X-ray solutions that can be used
for tumor tracking, deep inspiration breath hold, end inspiration breath hold, and free-breathing gating tech-
niques such as end-expiratory gating and abdominal compression. Another option, soft tissue imaging via
CT-on-rails or cone beam CT (CBCT) have the advantage of being able to visualize the interface of the liver
with the GI tract, and, most of the time, the tumor within the liver.

Because cone beam CT images are acquired over 40 to 60 s, motion artifact is significant. This can be sub-
stantially reduced with a deep inspiration breath hold image acquisition. Most patients can hold their breath
for that duration if the image is acquired during deep inspiration. This technique produces images that are
clear enough to assess the interface between the stomach and the liver, which can vary from day to day. A
gated cone-beam CT is another option but is currently still an emerging technology. For photon therapy,
magnetic resonance imaging equipped linear accelerators may offer the best soft tissue definition. This capa-
bility will become more widely available in the future.

Most small liver tumors can be treated with a free-breathing ITV that accounts for respiratory motion and
setting up to bony landmarks. For larger tumors, or tumors near the GI tract, we recommend a deep inspira-
tion breath-hold technique. Metallic fiducials or surgical clips that have been placed from prior surgery can
be used for initial set up. Alternatively, it is possible to use a soft tissue set-up to the liver shape obtained with
a breath-hold cone-beam CT.

ROLE OF PROTON BEAM THERAPY
Proton therapy is a form of external beam radiation therapy that utilizes accelerated protons as particles to
deliver therapeutic radiation. The benefit of protons derives from the lack of exit dose, resulting in lower in-
tegral doses to normal tissues compared to intensity modulated radiation therapy. Theoretically, when using
a dosing schema based on meeting a particular mean liver dose threshold, the lack of exit dose may allow for
a potentially greater dose of radiation delivered to the tumor. However, the use of protons is also associated
with unique challenges that must be taken into account when planning and delivering a treatment.

Proton beam range is highly dependent on the electron density of tissues it transverses. This is one of the
reasons for range uncertainty that must be accounted for when creating PTV margins in addition to margins
needed for setup uncertainties, and target motion. For liver treatments specifically, the presence of different
amounts of air in the luminal organs day to day and diaphragm motion that moves the interphase between
lung and soft tissue can significantly impact delivered doses to target and surrounding structures, and must
be accounted for when treating with protons. Another important disadvantage of protons is their wider pen-
umbra due to lateral scatter, which results in less conformality. Therefore, PTV coverage for tumors close to
the sensitive GI structures is best achieved with IMRT. Dosimetrically the greatest advantage for PBT over
photons may in treatment of very large liver tumors with small healthy liver remnants located far from lumi-
nal GI tract. NRG-GI003 is a recently opened US multi-institutional phase III trial that randomizes patients
with unresectable HCC to photon vs. proton based hypofractionated SBRT will determine whether PBT may
confer an OS advantage compared to photons. Both a 5 and 15-fraction regimens are allowed at the discre-
tion of the treating physician.

CLINICAL OUTCOME DATA OVERVIEW
Historically, the majority of the ablative radiation therapy experience has come from Japan, where HCC is
endemic and quite common. Protons have been largely used as they allowed larger treatment volumes to
be treated to larger doses per fraction. Results from hypofractionated regimens (16-25 fractions) to ablative