RADIOBIOLOGICAL EFFECTS

DUE TO SECONDARY
NEUTRON PRODUCTION
Josie Walter
The Ohio State University
Radiation Biology
December 6th, 2017
 There are three main interactions that occur in therapeutic radiation medicine that are

dependent on energy and particle used. Characteristic x-rays used in diagnostic imaging is

produced in a lower energy range. Compton scatter is utilized in therapeutic energy ranges to

treat with photon energies. The third is pair-production which occurs most often in higher energy

spectrums. While this can occur in photon therapy ranges, it is of particular concern in proton

therapy where these interacts are more likely to happen. Pair production interactions cause the

creation of neutrons—large non-charged particles that can cause secondary ionizations—which

are not currently being equated to absorbed dose to patients getting treated for cancer. While

extra dose to the planned treatment volume is considered beneficial in treating the tumor, having

excess dose to surrounding structures is correlated with the development of secondary cancers.

A term relative biological effectiveness (RBE) is a unit that describes a relative

relationship to the damage caused by an ionization wave compared to a specific energy x-ray.

This measure is widely used in this area of research to term secondary neutron dose results.

Hall, E. Intesity-modulated radiation therapy, protons, and the risk of second cancers.

International Journal Radiation Oncology Biological Physics. 2006; 65 (1): 1-7.

Due to the known disadvantage of increased monitor units used to treat intensity

modulated radiation treatments (IMRT), Hall in 2006, designed an experiment to determine if the

use of proton therapy is a viable treatment option to avoid secondary malignancy outcome. They

used retrospective analysis to compare the history and influences of different techniques of

radiation therapy on the secondary malignancy population of patients. Using previously gathered

information from atomic bomb survivors a standard of radiation induced solid tumors in a linear
relationship was used to compare throughout the study. Another control group they used were

prostate and cervix cancer patients in which surgery alone was a cure.

When analyzing IMRT treatments it was stated that; the increase in monitor units as well

as increased treated volume—due to a greater amount of treatment fields—were the greatest

factors in possibly causing a secondary malignancy. They used previous research conclusions to

support a thesis that IMRT raises a person’s probability of radiation induced secondary cancers.

Pediatric patients were specially noted as their greater life expectancy makes these outcomes

more significant. Proton therapy is often utilized as a treatment option for pediatrics due to the

higher integral dose of IMRT. Although, a scattering proton beam, will have to travel through a

large scattering foil and as a byproduct create neutrons. These neutrons, not considered in

prescription dose, will add to the total dose and do not follow the same physics as proton

radiation. They created two propositions to help with these issues. One, to increase the shielding

of the treatment head and reduce radiation leakage. And two, advance the jaws simultaneously to

again reduce leakage this time by the MLCs.

As a retrospective analysis, strong references and implemented gold standards provide a

foundation to support their hypothesis. Using large scale studies provided the study with

reliability. However, more data need to be brought in and evaluated to further enhance their

conclusions. A well-defined meta-analysis on a specific topic would have greater traction

clinically. This would also offer more validity to the claims they are making.

Paganetti, H; Nuclear interactions in proton therapy: dose and relative biological effect

distributions originating from primary and secondary particles. Physics in Medicine and Biology.

2002; 47: 747-764

 Paganetti et al., in 2002, was published for their work in determining three factors of

secondary neutrons: proton penetration depth, RBE changes, and contribution to total dose. The

Monte Carlo system was used to apply different variables, such as bone densities and ability to

track secondary protons, to create a more realistic scenario than the ideal model that has only

calculated primary photon paths used for treatment planning. For calculations of RBE the used a

previously determined accurate track model to compare end point survival levels on 3 different

cell types, including human skin fibroblasts. They found that an average of .68 secondary

neutron particle will result from one primary proton interaction. Due the additional interactions it

was determined that the total absorbed dose received is most notably seen in the therapeutic

spread out Bragg peak (SOBP) when adding secondary particles into calculations. Secondary

neutrons more specifically will see a greater effect in the distal region of this SOBP. This area is

of high importance for scaling RBE as the distal edge has a higher effectiveness and has a greater

contribution from secondary interactions. However, it was concluded that dose 2 cm from the

end of the peak was less an .04% and was heavily dependent on the amount of protons as well as

field size. There was a change in biological effectiveness but was deemed negligible to the

significance to secondary induced cancers. More prominent was the difference in the plateau

region absorbed dose due to other secondary reactions.

This study by Paganetti was very robust and used strong analytical techniques to

demonstrate their results. By cross referencing previous works as well as current protocols it

created a strongly validated experiment. The reliability of their findings were supported by use of

internationally recognized calculations and models. An important factor of this study were the

comparative models and modifications made to include secondary particle interaction, while this
may seem to impede on reproducibility, citing similar modifications in other studies helps to

verify their model. Not having tested their results on living tissue the significance clinical is still

under question and further testing is imperative.

Jarlskog, C; Risk of developing second cancer from neutron dose in proton therapy as

function of field characteristics, organ, and patient age. International Journal Radiation

Oncology Biological Physics. 2008; 72 (1): 228-235.

In 2008, Jarlskog and Paganetti expanded Paganetti’s previous work and considered more

specific factors in neutron dose contamination and secondary cancers. They focused this study to

pediatric patients due to their long life expectancy after treatment, organs in developmental

stage, and greater organ volume percentage treated compared to adult treatments. Because of

previous trials, the RBE of protons is better known and computer models can be used to

determine probability of late effects to organs. They used Monte Carlo simulations with several

specially created phantoms based on age and gender. Both male and female phantoms were used

at the ages of adult,14 years old, 11 years old, 8 years old, 4 years old and 9 months old. The

simulation was completed with eight different brain treatments, two of which were clinically

preformed. They used protocol determined by the Biological Effects of Ionizing Radiation

(BEIR) report to model their statistically findings. Organs that were considered: stomach, colon,

liver, lung, breast, bladder, thyroid, esophagus, pancreas, and kidneys. They also calculated a

risk for a secondary malignancy of leukemia.

Using a Lifetime Attribution Risk (LAR) they reported a greater LAR for females at

about a factor of 2.5 at the age of 4 and a decrease in LAR significantly as a treatment age
increases. It was also concluded that a larger filed size could increase the LAR up to a factor of

two. The field index also contributed to the contribution of secondary neutrons in the treatment.

To improve validity of the study they included uncertainties in their risk estimates.

Statistical ranges for each organ were calculated with the highest in breast estimates up to 20%.

They also considered planning factors such as radiation weighting which can be significant in

neutron dose predictions. However, in order to gain reliability, they followed a more

conservative recommendation set by International Commission on Radiological Protection

(ICRP) Report 92. They concluded that there is an increased risk of developing a secondary

cancer with a scattering proton treatment and all variables—age, gender, and treatment fields—

resulted in significantly different risks. A cross-sectional study could be used to later support

their findings. This may become easier with a greater population of pediatrics treatment moving

to proton techniques.

All of the information gathered from the three sources build upon themselves to show a

clinical value. It is important to understand what is occurring during the treatments and to help

minimize any uncertainties within it. While it is the job of the physician to provide the risks to

the patient, implementing the current plan with the best of the ability falls large part on the

therapist. Setting up the patient is critical to maintain the correct PTV coverage and minimize

over irradiation of normal tissue. In a field where innovation happens rapidly it is also important

to stay up to date on current issues or findings. Knowing that changes might be up head better

prepares you to be knowledgeable in new treatment techniques.

 Works Cited

Hall, E. Intesity-modulated radiation therapy, protons, and the risk of second cancers.
International Journal Radiation Oncology Biological Physics. 2006; 65 (1): 1-7.

Paganetti, H; Nuclear interactions in proton therapy: dose and relative biological effect
distributions originating from primary and secondary particles. Physics in Medicine and Biology.
2002; 47: 747-764

Jarlskog, C; Risk of developing second cancer from neutron dose in proton therapy as
function of field characteristics, organ, and patient age. International Journal Radiation
Oncology Biological Physics. 2008; 72 (1): 228-235.