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2 8 19 Paper
2 8 19 Paper
Mrs.Sasser
8 February 2019
Introduction
The overall topic of this paper, cancer, is the second leading cause of death globally with
1 in 6 deaths resulting from any form of cancer. In the United States, 1 in 3 men and women will
develop cancer at some point in their lifetime, while the mortality rate of cancer is 1 in 5 people
in the United States (Lifetime Risk of Developing or Dying From Cancer, 2018). Continuous
developments in cancer treatment have worked to reduce this unfortunate statistic, however a
majority of treatments such as radiotherapy (RT), chemotherapy (CT), and immunotherapy (IT)
can lead to long lasting impairments and extraneous damage to the human body. The focus of
this paper, proton therapy (PT), is a recent development that was discovered in 1946 by Robert
R.Wilson (History of Proton Therapy, n.d.). It functions by accelerating a proton to a high energy
state, where it is administered in the body and releases the radiation over time. It is unique due to
a phenomenon known as the Bragg’s peak, where the proton gradually releases energy as it
travels and then releases all of its energy in one dose at the end of its travel (Mohan et.al,2016).
This limits the damage to normal healthy tissue in the body, while maximizing the destruction of
tumoral cells. Over time, this type of therapy has been enhanced by gradual advancement in
technology and precision in the mechanical aspects of treatment. However, it is not perfect.
While PT has a reputation for its accuracy, safety, and effectiveness, it also has its drawbacks. It
is very sensitive to natural errors in treatment, resulting in great uncertainty in treatment that
result from many factors. These factors that influence proton therapy accuracy are range
uncertainty and setup variation which can significantly delay and reduce the effectiveness of
treatment planning. However, they can be significantly nullified through applicable methods
Many modern cancer treatments have difficulty adapting to modern developments and
mutations in cancer cells. These cells have become more radioresistant, metastatic, and even
malignant. Relapse of cancer is at an all-time high, however, one new method of cancer
treatment has shown to work to combat these issues: proton therapy. Proton therapy is known for
its accuracy and effectiveness at eliminating cancer cells, especially with its unique property, the
Bragg peak. However, no cancer monotherapy is perfect, and proton treatment is no exception to
this. Proton particles are very sensitive to external forces and collisions with localized tissues,
therefore leading to uncertainty in proton treatment. These uncertainties can derive from various
factors; some are uncontrollable, while some are easily neutralized. However, the two main
drivers of uncertainty in proton treatment are each individual's unique anatomical structure, and
First, it is necessary to discuss the various types of uncertainty in proton treatment: range
uncertainty and set-up variation. Range uncertainty is defined as the deviation of a proton
particle from its target point in the distal tumor volume. This can be attributed to various
phenomena, such as the natural properties of a proton particle including sensitivity and energy
release, and tissue density which results in protons releasing different energies at different points
in the body. Protons are very different in comparison to conventional photon (radio) therapy
through various contrasting properties such as the Bragg peak, exit dose, speed of travel, and
sensitivity. However, the most critical of these contrasting properties is the speed of travel. Since
protons travel at a very slow pace in comparison with photons, not all of the protons accelerated
to the same energy will travel the same distance (Paganetti, 2012). This results in protons
executing different Bragg peaks at different depths over time, which could potentiate risk to
close proximity organs, make uncertainty harder to calculate for proton physicians and increase
uncertainty in treatment. On the other hand, tissue densities can result in increased range of
uncertainty in therapy. This is because much of the organ tissues in the human body vary based
on density (Figure 1 shows the density values of tissues in various organ systems). These tissue
structures serve as “linear stopping powers” (LSPs) which cause the proton particles to lose
energy as they travel and approach the Bragg peak which initiates the stopping of the proton
(Palta, n.d). As protons travel through these tissues, they release energy during their movement
through the tissue. However, the proton releases different amounts of energy based on the
density of the tissue, and this density determines how much energy a proton loses over the
duration of its travel. The denser a tissue, the more energy a proton releases, and therefore the
shorter the distance it will travel. On the contrary, a less dense issue will induce less energy
emission from a proton, and therefore its course will not be hindered to the same degree. Human
body anatomy naturally does not have the same tissue over a certain distance in the body, as
various organs are in close proximity to one another and various tissue structures are utilized in
an organ structure. A clear indication of this is in the small intestine, which has epithelial tissue,
skeletal muscle tissue, and smooth muscle tissue. Moreover, the amount of each respective tissue
in each individual varies from person to person, thus leading to increased uncertainty during
treatment. Overall, it has been shown that these tissue densities and variation can cause
uncertainty between 1-3 mm away from the target tumoral volume, which can result in critical
Figure 1: This table develop by Uri.M at Harvard University lists the organ identification
(ID) number, medium, density, and mass of each organ/tissue.
Set-up variation, on the other hand, is also another factor that induces range uncertainty
during treatment due to anatomical variation. This variation is caused by the daily repositioning
of organs, muscles, bones, and other structures possibly due to epigenetics, adaptations that serve
as a stimulus response to the direct environment. This means that a patient that obtains a tumoral
CT scan one day, will not produce that same CT scan another. Therefore, these daily
repositionings increase uncertainty in proton treatment, and it remains imperative that repeated
CT scans of the tumoral area be conducted to compensate for the daily reposition of anatomical
structures (Zhang, 2007). However, these CT scans cannot be repeated within a short time
interval, otherwise, the photon radiation would induce an increased growth of cancer within the
patient's body. Due to this, it is highly unlikely that a patient will be placed in the same position
during the previous treatment fraction as the muscles and bones will not rest in the same manner
(Trofimov, 2001). This, in turn, increases range uncertainty in treatment, and ultimately makes it
Overall, the range uncertainties induced by set-up variation and tissue density variation
have a drastic effect on the accuracy, safety, and effectiveness of treatment. As many organs and
bodily systems are in close proximity to one another, tumors often prove difficult to treat due to
their adjacency to critical organs. This is why proton therapy physicians express persisting
concern about treatment uncertainties in the proton beams as these uncertainties may inflict
damage or unnecessary radiation dosage on other critical organs (Trofimov, 2001). This is
especially concerning, considering how the body is 75% water-based, and proton uncertainty in
an aquatic environment is inevitable. The range of margin of error for this uncertainty is ±3.5%
on the distance traveled in a water environment in addition to naturally being 1 mm off course of
the target due to natural uncertainty (Schuemann, 2014). As somatic and tumoral cells are 10-100
um in diameter, this means that uncertainty in treatment can be off by over 1,000,000 cells,
thereby killing normal body cells and allow the remaining tumoral cells to develop resistance and
reducing its effectiveness and lengthening the treatment period. However, they can be reduced
through various optimization methods. One such method that is very prominent in the radiation
Robust Optimization
In any form of radiation treatment, it is very difficult to confine beamlets to a certain area
of space due to the inconsistency of proton properties. For many years, proton physicians have
struggled in finding the answer to this problem. However, the answer may not lie in the scientific
calculation that deals with reducing uncertainty of trajectory and beam-like compounds by
confining it to a small area in space. What makes this method unique, is that when applied to
proton therapy, it influences the objective and constraint functions that proton physicians
optimization expert, robust optimization assumes that the objective and constraint functions only
belong to certain areas in a given volume, and this function area is defined as the tumoral volume
between the distal and proximal ends of the tumor (Ahmadi 2016). The proximal and distal ends
of a tumor refer to the positions of which the tumor is closest to the radiation beam and furthest
from the radiation beam respectively. This means that the proton beams in treatment are
manipulated to be confined to the normal tumoral volume, ensuring that the proton particles
engage in direct contact with the tumoral cells, ultimately killing them. However, robust
optimization is a very difficult method to apply, especially to proton therapy. As proton particles
are all positively charged, the subatomic particles tend to repel one another and ultimately split
into microbeams. This tendency makes it very difficult for proton physicians to make accurate
calculations, as thousands of beamlets in each individual dose voxel (tumoral volume) must be
computed to minimize radiation delivered to critical organs (Liu et al., 2011). Despite robust
degree.
When robust optimization is applied to the microbeams of protons, it confines the space
of the beam to reduce range uncertainty. As mentioned before, the calculation confines the beam
space into a beam that emulates the nominal dose volume, the optimal where the protons are
unaffected by uncertainties, thus resulting in a more accurate delivery and more effective
treatment (Liu et al., 2012). Ironically, robust optimization can reduce range uncertainty by using
range uncertainty as a primary source of treatment improvement. Through the use of repeated CT
scanning and recurring uncertainty calculations, range uncertainty can be preempted due to
obtained information about patient anatomy, tissue density, and many other factors which help
proton physicians create a hypothetical defined space where the beam should land on the tumor
through worst and best case optimization, ultimately reducing range uncertainty during the
treatment course (Pflugfelder et al., 2008). Robust optimization seems like the ideal solution to
reducing range uncertainty, and its overall effect on treatment is very positive.
robustness or strength of proton treatment increases along with the increased sparing of normal
tissues and critical organs from radiation in comparison to conventional methods (Liu et al.,
2011). Finally, the restriction and confinement of beamlets through robust optimization results in
each proton beamlet covering the tumoral target uniformly over the nominal dose volume,
leading to a balanced and localized single-field uniform dose distribution (LSFUD) (Liu et al.,
2012). This uniform dose distribution allows for proton particles to enter the tumor from all
angles, allowing for a stronger delivery of treatment and increased killing of malignant tumor
cells. Figure 2 illustrates the difference between conventional method PTV optimization and the
uprising robust optimization. It can easily be identified that robust optimization provides a much
Figure 2: This image shows the difference in accuracy between robust optimization and
PTV optimization.
smaller and confined space to the proton beam, even when a 3.5% uncertainty control was
applied to both plans. Moreover, robust optimization increased regularity in the shape of beam
confinement, allowing for a uniform dose distribution, which increases the effectiveness of
https://bionumbers.hms.harvard.edu/files/Density%20and%20mass%20of%20each%20
organ-tissue.pdf
Paganetti, H. (2012). Range uncertainties in proton therapy and the role of Monte Carlo
https://doi.org/10.1088/0031-9155/57/11/R99
Schuemann, J., Dowdell, S., Grassberger, C., Min, C. H., & Paganetti, H. (2014). Site-
specific range uncertainties caused by dose calculation algorithms for proton therapy.
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Trofimov, A., Nguyen, P. L., Efstathiou, J. A., Wang, Y., Lu, H.-M., Engelsman, M., …
and soft tissue, and their implications on the delivery of proton therapy for localized
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