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Reyngold et al. Hepatoma Res 2018;4:49 I http://dx.doi.org/10.20517/2394-5079.2018.84 Page 5 of 10

motion is primarily due to respiration (and/or patient movement), while interfraction motion is primarily
impacted by the change in location/shape of the liver and luminal organs day-to-day.

The amplitude of liver movement with respiration varies significantly from patient to patient and depends
on the location of the tumor within the liver. The range of motion generally is greatest in the cranio-caudal
[19]
direction, with amplitude exceeding 2 cm in some patients . Further, although breathing amplitudes can
be different during four-dimensional computed tomography (4D CT)-based treatment planning versus
[20]
during radiation delivery, the direction of variability seems to be predictable . With regard to the effect of
tumor location within the liver, the closer a tumor is to the center of the hemidiaphragm, the greater the mo-
tion. The liver also deforms throughout the respiratory cycle, especially in elderly patients with diminished
abdominal wall muscle tone. Chest versus abdominal breathing also affects liver shape, and must remain
consistent from the simulation to the treatment delivery. It is important to note that organ motion of the
diaphragm is perhaps even more important for proton therapy than for photon therapy because the dose de-
livery is significantly more affected by tissue density of the surrounding organs in the case of proton therapy.

Intrafraction organ motion due to breathing can either be addressed with respiratory motion control coupled
with image guidance or by accounting for the range of motion of the tumor with an internal target volume
(ITV). It is often not advisable to use the latter option for liver tumors because of the proximity of organs at
risk and the larger normal liver volume that needs to be included. The addition of abdominal compression
is an effective way to reduce the ITV. Several commercial devices are available for this application. The most
common technique uses an abdominal compression plate that is placed 3 to 4 cm below the costal margin.
The plate is connected to a load cell that can measure how much force is being applied to the abdomen. This
device is usually used when the superior-inferior movement of the tumor exceeds 1 cm, but it may also be
[26]
needed for tumors within 1 cm of the GI tract . Because compression plates can cause variable deformation
of the liver, an alternative solution for liver tumors is the use of a pneumatic compression belt. This option
[27]
has been reported to reduce respiratory motion to less than 5 mm . Notably, compression only minimizes
rather than eliminates motion, and does necessitate the use of an ITV approach.

Motion management can very efficiently be accomplished with respiratory gating. Options include inspira-
tory or expiratory breath hold including the Varian RPM system or the Active Breathing Control system.
Interfractional variations in breath hold position can exceed 4 mm [28,29] , and so a breath hold technique is
usually coupled with image guidance to verify the target position with each fraction. Image guidance can be
achieved by using 2D image sets or with 3D images obtained in the breath hold position.

Day-to-day differences in bowel position and shape are other uncertainties that must be accounted for and
monitored to ensure safe treatment. The extent to which the luminal GI organs affect accurate proton de-
livery has not been well described and may not be predictable. Filling of the stomach can vary substantially
from day to day, depending on the amount of air, liquid, and solid present within it. This variation can lead to
an increase in the range of the proton beam, but not the photon beam. This is a relatively minor problem to
deal with if during the planning process beams are designed such that they don’t traverse the gastrointestinal
tract. The left lobe of the liver is susceptible to deformation caused by stomach filing, whereas the right lobe
is less affected by the surrounding organs. Generally, we instruct our patients to ingest nothing for at least 3 h
before radiation sessions in an attempt to reduce the variability of stomach filling and enhance the tendency
of the stomach to pull away from the left lobe of the liver. The amount of solid, liquid and gas in the ascend-
ing, transverse, and descending colon can vary from day to day. This variability should be monitored and
assessed for position changes near the tumor. We use simethicone for patients who have significant amounts
of gas in the large bowel. Reduction in bowel gas can often increase the separation between the tumor and
colon.