Radiobiological Effectiveness of Clinical Proton Therapy Applications

Ryan Kisamore

The Ohio State University

RADSCI 4670
1. Lin YF, Chen BP, Li W, et al. The Relative Biological Effect of Spread-Out Bragg Peak

Protons in Sensitive and Resistant Tumor Cells. Int J Part Ther. 2018;4(3):33-39.

Summary:

Lin et al. studied the radiosensitivity between two different types of tumor cells, DNA-

PKcs deficient and functional DNA-PKcs, and the RBE a spread-out Bragg peak proton beam

will have on these cells. The cells were concurrently exposed to 6 MV photons and mid 137

MeV Protons and cultured. After irradiation those cells that still survived were evaluated and

seen to fit the linear-quadratic models. The RBE was shown to be around 6% higher in the

resistant functional DNA-PKcs cells over the deficient and normally radiosensitive counterparts.

This gave evidence that DNA-PKcs dependent cells have less ability to repair following

exposure to mid spread-out Bragg peak protons in comparison to those exposed to photons. This

Cohort Study finds that protons are more efficient than conventional fractionated dose photon

irradiation.

Assessment:

This study took many steps to minimize any deviant results from differential cell type by

using a single original flask from which it was then split and cultured to the desired colony level.

The simple and identical cultures were used throughout the study. A strict observation of colonies

was taken so that each series would be on near equal value and that each level of irradiation

would be to the same number of colonies for both x-rays and proton rays. These steps have

allowed for a valid and reliable study that has a minimalization of potential variables that could

skew results. There were 4-5 flasks irradiated at each dose level where the fifth or final flask was

observed to estimate the number of surviving colonies per flask. Flasks were randomized to x-
ray or proton irradiation and cultured for 7-12 days and evaluated for the ratio of colonies plated

to those that were observed as surviving post irradiation. This time for culture allowed for the

cells that were only damaged to heal themselves, which will indicate how much cell kill the

exposure created. These were necessary steps that allowed for proper identification of radiation

effects on that specific cell type. One possible problem was the proliferation that happens during

this culture period, depending on cell type, they could repair and further proliferate a great deal

in 7 to 12 days. Only testing and irradiating one cell type means that data is only collected for

one cell type. The study was specifically created to test cells with a specific gene, but different

cell types may also contain this gene and react differently. This study can easily be used as a

baseline for future studies on specific cell types and specific cell genes and what effect proton

irradiation has on cell function.

The trays were irradiated at 100 cm from the source and with a 20x20 field size with a

standard dose rate of 600cgy/min through a 5cm solid water buildup. Dosimetric measures with

TLDs were used to ensure that the dose rate throughout the field was within an acceptable

percentage of difference. The study further measured the distance to the cells and the distance to

the TLDs to gain the knowledge about how the dose buildup and exposure would vary. While

TLDS are easy to place and use, are they the best option for use in measuring beam uniformity in

this experiment? They can be time consuming and with more time there is more chance for errors

to arise and results to change. Measuring this many possible variables does a great job on ensure

that all values of as precise as possible and that the results can be properly interpreted and used

to answer and create questions for further study. The researchers found that if there was a slight

over or under estimation of dose regarding the depth would not alter the results desired for study.
 Results from the study indicate that the transfection of DNA PKcs- defective

immunodeficient tumor cell brought an increase in cell resistance to both x-ray and proton

radiation with a greater resistance to the x-rays over the protons. This could be because of the

increase LET at sight of the spread-out Bragg Peak and the cell cycles that irradiation cells were

in at time of irradiation. In short, the results have suggested that the Relative Biological

Effectiveness of Spread-Out Bragg Peak Protons is higher to tumorigenic cells that contain

function DNA double-strand break repair genes over their repair gene counterpart. These results

confirm what many believe, that proton therapy shows a greater effectiveness to local tumor

control when compared to the use of photons. Protons also have the added benefit of reducing

integral dose and removing an exit dose beyond the target. This study takes the steps to ensure

that all data is valid, and a can be used to further research the effects of proton radiation and

shows that the clinical applications have great promise. Proton Beam Therapy is growing rapidly

in popularity and with studies like these, it will allow the Radiation Oncology world to move into

a new era of effective treatments.

2. Guan F, Bronk L, Titt U, et al. Spatial mapping of the biologic effectiveness of scanned

particle beams: towards biologically optimized particle therapy. Sci Rep. 2015;5:9850. Published

2015 May 18. doi:10.1038/srep09850

Summary:

Guan et al. discuss that there is a vast knowledge on the physicality of particles of atoms,

such as protons, and their superior mapping for dose distributions over photons. Protons,

however, have advantages that have not been fully taken advantage of in the clinical use of

radiation beams. The well-defined Braggs Peak and high LET of the proton has an enhanced

biologic effectiveness over others. Past mapping of the of the special variations and isodose
regarding the biological effectiveness has been largely time consuming and given inconsistent

results. Protons are assumed to have a Relative Biological Effectiveness of 1.1, which is close to

that of photons but with the added perks of the Braggs peak. An added understanding of unique

biologic effects of protons could add an important expansion of the therapeutic uses of protons.

This variable biologic effectiveness of the protons needs to be accounted for in treatment

planning of clinical proton treatment. There is a need to develop a precise and accurate model of

proton RBE to enhance the potentials of use in cancer treatment.

Assessment:

The methods of the study include the design and creation of a valid Monte Carlo

Simulation. Biologic Effect was assumed in this report to be a function of dose averaged LET.

They illustrate the importance of using a scanning beam over the previously used passive

scattering. Their highlight of the use of scanning beams over scattering shows the studies clinical

relevance to modern uses as scanning has become the more popular of the two types. It shows

how this study has goals of influence the present and the future. The system was calibrated with

Plane Parallel Ion Chambers and the experiments were set up in as identical of conditions as

possible. These steps allow for the results to be reliable, the identical set up conditions removed

many possible changes in variables that would skew results and remove the validity of the

experiment. The set-up process of an experiment is of vital importance, if there is a miss

alignment or calculation, the results of the experiment lose all validity and the study is essentially

eliminated.

The added film and Lucite jig in addition to the cells irradiated could have introduced an

added energy attenuation component for the Proton Beams, since they have a definitive range.

The Monte Carlo Calculation was used to account for these minor irregularities. There is no real
way to eliminate all variables from an experiment, but the best thing one can do is to keep them

consistent and work to continuously build working knowledge on the subject. The uniform field

and precise accuracy of delivered dose allowed for any irregularities in longitudinal movements

while setting up. A large number of plates were used which gave a varying thickness between the

plates, but it was determined that their gave an uncertainty of +/- 1%. The number of variables

and uncertainties that are mentioned and factored into this experiment show that steps were taken

to minimize outlying data that appears with no reason. I am confident that the data collected and

shown is valid of use for proton beam therapy for years to come.

The combination of both integrated physics and a biology used in this approach allow for

an attempt at absolute minimization of uncertainties while also maximizing the data output.

These steps increase the validity of all results and allow for a differential interpretation of the

data. This is what make this source a quality base for use in future research and the clinic. One

potential problem with the steps taken is that any conclusion that may be made can also be

further disproved by data found to correlate. One shortcoming stated by the authors is that “the

gradual increase in LET along the entrance plateau, followed by the rapid rise proximal to and

just beyond the Bragg peak, the current jig design resulted in oversampling of low-LET points (<

5 keV/µm) and under sampling of LETs in the range of 5–10 keV/µm. Ideally, the design of the

jig could be optimized for uniform LET sampling.” This raises the question of how this was not

accounted for in the experiment, since the Bragg Peak of Proton beams has been well defined

before the time of this study. This could be due to the access to equipment, maybe technology

just was not fully able to handle the job wanted by the researchers. This problem may seem to be

moderately significant, but the data provided still proved amply beneficial. This is not the first

time a study has been made to study the mapping of LET-dose effects, it is difficult to compare
studies of the same goal due to difference is study set up. This difference creates questions as to

the validity of all results found in these studies. There are still countless potential benefits for all

of the potential negative effects, it is studies like this one that spark further investigation into the

use of heavy ions for cancer treatment.

3. Mizumoto M, Murayama S, Akimoto T, et al. Proton beam therapy for pediatric malignancies:

a retrospective observational multicenter study in Japan. Cancer Med. 2016;5(7):1519-25.

Summary:

While proton therapy has shown a lot of promise in cancer treatments for many

histologies, its applications to pediatrics have shown a great potential to reduce secondary

malignancies. Mizumoto et al. talk about how recent progress in standard surgery, chemotherapy,

and radiation therapy have created great survival, there are still a high number of secondary

effects. The study evaluates the safety and efficacy of proton beam therapy for pediatric patients

in Japan. This was a retrospective observational study of pediatric patients. Data that could affect

any potential outcomes was collected such as; birth date, reason for Proton Therapy, tumor size,

dose, and many more. A total of 343 patients were admitted into the study and there was a

median age of 7 years. Patients were further broken down into subcategories based on their past

treatments and other factors that may affect therapy effectiveness. While there were many

toxicities present in patients following irradiation, there was a noticeable reduction in these

numbers due to the favorable dose distributions. The severity of toxicities was high due to the

relatively short follow-up period giving this firm conclusion. The study states that the efficacy

needs to be further established along with the overall safety of the procedure and an increase in

data from longer term follow-ups. Pediatrics have a different set of difficulties that arise in
treatment using radiation and special procedures must be taken to both patient safety and

comfort.

Assessment:

This retrospective study is a good way of seeing how clinically effective the use of proton

beam therapy has been as it continues to advance and become more popular. Advancements have

allowed for better treatment planning and more effect treatments. The data taken in by this study

is lengthy but allows for any person to effectively compare the data collect to see correlations

between them and ask more questions to gain greater knowledge. Data taken includes “date of

birth, sex, height, weight, disease, reason for PBT, potential for other treatment (photon

radiotherapy, surgery), clinical target volume, tumor size, irradiation port number, dose

fractionation and treatment period, reference point, combination treatment, sedation,

performance status (PS) at the start of treatment, dose to organ at risk, start and end day of PBT,

early toxicity, late toxicity, last survival date or date of death, secondary cancer, discontinuation

of PBT, and possible comparison of dose distribution to IMRT.” This shows that there was no

detail spared, it is this precision that will make interpretations of the data more reliable. When

treatment information and data was recorded, every variable in the treatments of the individual

patients were considered, this shows how combinations of therapies have affected pediatrics in

terms of both late and acute toxicities. The doses to the patients under study varied greatly,

ranging from 10.8 GyE to 100 GyE, this could be beneficial to see how different doses have

created tumor control and other side effects. It would have also been beneficial to see similar

doses to many patients and the effects the treatment has on this population. Another downfall of a

retrospective study is that the observer does not get to see the patient’s tolerance and reactions to
treatment as it happens. Taking facts, data, and numbers will get a lot of valuable information but

the lack of quality patient values could create pitsfalls.

In discussion it is said that Proton Beam Therapy has a reduced toxicity and a decreased

risk of secondary cancer. It is noted that while this data shows these many results based on

patient’s histology, age, and combined treatment, the period of study is still relatively short when

considering pediatrics due to their long-life expectancy after malignancy. As proton therapy

becomes more clinically relevant and popular it is studies like this that will allow physicians to

make accurate plans for treatment while also being able to give patients a better description of

how the treatments may affect the child over that of photon radiation. As technologies improve

the downfalls seen in this study may be minimized or even removed, further increasing the long-

term survival rates in both pediatrics and adults. The study takes the time to discuss possible

implications that could follow, such as using that data to further investigate other measures of

biologic response as a function of LET. The mentioning of possibilities like these give the reader

the comfort knowing that the results of this study are not final and that there is much more to

study and learn. Accurate mapping of not just the physical but the radiative effects that particle

will have inside a medium could help to create treatment techniques that allow for maximum

tumor control with minimal adverse effects. The positives may seem great, but it is important to

consider the negative implications that this knowledge could bring, one may find that there are

severe adverse effects that have not been observed yet. While the possibilities are endless it is

imperative that one keeps an open mind on both sides of the spectrum.
Links to sources:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6167011/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4650781/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4867672/