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Comparison Between Photon and Proton Radiation Therapy for

Pediatric Patients with Medulloblastoma

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Abstract

Background: Pediatric patients with medulloblastoma typically undergo post-operative radiation

treatment. There are multiple radiation therapy techniques used to treat medulloblastoma, such as

photon therapy and proton therapy. Both methods run the risk of developing secondary cancers

later in life.

Objective: To compare and contrast the risks and benefits of late side effects between proton

and photon radiation therapy for pediatric patients with medulloblastoma.

Methods: A literature review was performed to further gain information about both treatment

techniques. All sources used were screened to access reliable information. All publications used

related to neurocognitive effects and secondary cancers that can occur after a pediatric patient

with medulloblastoma is treated with radiation therapy.

Results: Proton therapy is becoming a popular form of treatment due to the decrease in late side

effects in pediatric patients. Three-dimensional conformal radiation therapy has an exit dose that

irradiates healthy tissue. This tends to cause a lot of toxicities later in life such as: heart

problems, hearing loss, recurrence of the primary cancer, and neurocognitive deficits. The cost of

proton versus photon radiation treatment can also be a huge factor in which modality is chosen

for each patient.

Conclusion: Proton radiation therapy has better outcomes clinically than photon radiation.

Neurocognitive deficits decrease due to the absence of exit dose with protons. The risk of

multiple late toxicities also decreases. Proton therapy is overall more cost effective than photon

radiation.

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Introduction

Medulloblastoma is the second leading cancer diagnosed in pediatric patients, with close

to 600 new cases diagnosed each year in the United States.1,5 Most of these patients are under 21

years of age, with the average age around five years old.3,9 The main form of treatment for

patients with medulloblastoma is surgery to remove the tumor with radiation therapy post-

operatively.3,4 Chemotherapy can be an adjuvant form of treatment in combination with radiation

therapy, but is not always used.4 Although there are many treatment techniques and regimens to

help treat this horrible disease, over half of these patients will develop late side effects such as

secondary cancers, infertility, or possible heart failure.2 When considering which treatment

technique would be best suited for a pediatric patient, it is important to look at the possible risks

and benefits of each. Within the radiation therapy field there are many different machines and

imaging techniques that can be utilized to help treat patients such as image guided radiation

therapy (IGRT), intensity modulated radiation therapy (IMRT), and proton therapy. Using

protons for radiation therapy treatment is becoming increasingly popular, especially among

pediatric patients, due to the decrease in late side effects.1,5,6

Irradiating the brain can cause many long term neurocognitive side effects including

difficulty paying attention, learning deficits, information processing speed, and memory.3

Although cognitive function is a main concern during treatment, there are other late side effects

to be concerned about. Those that tend to occur in pediatric patients with medulloblastoma after

photon radiation therapy treatment include: pneumonitis, heart failure, xerostomia and

hypothyroidism.8 The total dose used, type of machine, age of the patient during treatment, as

well as cost can all play a factor in the outcomes of survivors of medulloblastoma as a pediatric

patient. The primary purpose of proton therapy is to help improve the overall quality of life for

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these survivors. Since new treatment modalities, such as proton therapy, allow patients to live

longer, the goal is to find a technique that decreases the risk of developing a late side effect. It is

important as radiation therapists to understand the differences in treatment techniques and how

photon and proton radiation therapy can affect pediatric patients diagnosed with

medulloblastoma.

Methods

In order to gain knowledge in the differences between photon therapy and proton therapy,

a literature review was performed. Articles were searched via Murphy Library at the University

of Wisconsin-La Crosse, PubMed, as well as Ebscohost. The terms used to help search these

databases include “medulloblastoma,” “proton therapy,” “radiation therapy,” “pediatric cancers,”

and “side effects.” These terms were used in various combinations to help find the best results.

Of the articles that were found, each were screened for reliability and statistical evidence. The

search was also limited to articles written in English, studies performed on humans, as well as

were published in the past five years. The articles determined to be the most applicable discussed

the use of proton therapy and photon therapy for pediatric cancers, how these treatment

techniques affected the patients during treatments and after treatment, the cost of the different

procedures, as well as the risk of developing late side effects cause by radiation therapy

treatment.

Review of Literature

The most common treatment planning method for radiotherapy in medulloblastoma

patients is to treat the whole brain and the spinal cord with a potential boost to the tumor bed.4

Although this treatment course is used throughout many hospitals across the nation, there is

always the potential risk of pediatric patients developing a late toxicity due to the radiation

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treatment.1,5,6,9 Secondary cancers are one of the main reasons for mortality among survivors of

medulloblastoma.5 According to the Childhood Cancer Survivor Study,5 death due to the primary

cancer is decreasing, while the secondary cancer mortalities are increasing. This decline can be

related to new treatment modalities in radiation therapy.

With advancements in technology and research studies, the next step is to analyze the

difference between photon radiation therapy and proton therapy, as these are two of the most

common modalities used for radiation treatment among pediatric patients with medulloblastoma.

The survival rate among these patients is improving tremendously, roughly around 60 percent.10

This focuses the attention of future studies towards reducing the late toxicities that arise from

radiation treatment.10 Multiple studies1,5,6,9 have been conducted to compare the risk of

developing a secondary cancer due to radiation therapy treatment between proton and photon

radiation. These late toxicities include, but are not limited to: pneumonitis, heart failure,

xerostomia, blindness, hypothyroidism, ototoxicity, endocrine dysfunction, neurocognitive

problems, and recurrence of medulloblastoma.6,7 Cerebrospinal fluid metastases account for 30

percent of recurring tumors for these patients.10 Due to the exit dose from photon therapy, these

complications are more likely to occur later in life.4 Although it is important to compare the two

types of modalities, medulloblastoma patients are already at an increased risk for secondary

cancers due to the nature of the disease itself.6

In a study completed by Christopherson et al,3 all of the potential late toxicities that can

occur in patients receiving craniospinal radiation were examined. The researchers in this study3

treated 53 children from the ages of one year to 18.5 years at the age of diagnosis. Once these

patients were treated with radiation, Christopherson et al3 performed follow-up surveys on the

survivors. It was found that the most common late toxicities were growth impairment and

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neurocognitive deficits, with 61.5 percent and 49 percent of survivors reporting these issues

respectively.3 While these were the main complications following photon radiation, this study3

was able to break down other toxicities based on different organ systems, endocrine defects,

radionecrosis, and secondary malignancies.

After surveying the patients, Christopherson et al3 found that every organ system tends to

react a little differently to photon radiation; for example, radiation to the endocrine system

causes growth deficits among patients.3 Because this study3 is focused on photon radiation, the

exit dose plays a large role in what types of after effects will occur. The exit dose during cerebral

spinal radiation has the potential of damaging the thyroid, resulting in hypothyroidism.3 Hearing

loss can also be another potential issue that pediatric medulloblastoma patients can develop.3

This can occur from having whole brain radiation, as well as having adjuvant Cisplatin

chemotherapy.8

It is hard to determine the source of ototoxicity because patients do receive both

chemotherapy and radiation therapy.8 Schrieber et al2 found that patients who lost their ability to

hear are at a higher risk for a decline intellectually. Patients of all ages can be greatly affected by

radiation, but the age group that was affected the most were patients that were under the age of

seven, either at diagnosis or while under treatment.8 The age at diagnosis can be one of the

biggest factors in predicting the decline of a patient’s learning ability.8 Typically, the younger the

age at treatment and diagnosis, the more likely the child will have a greater decline, not only in

cognitive function but in other late side effects as well.8

The chance for cancer to return is an intimidating thought, but is always a possibility for

every cancer patient. With medulloblastoma being so common in younger patients, the

possibility of it recurring due to a longer survival period, increases.10 In a study by Ibrahim et al10,

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medulloblastoma patients were classified into two different groups, average risk and high risk,

for recurring tumors. Both groups were also based on age, staging of the cancer, and how much

of the tumor was originally resurrected during surgery.10 Children who were three years or older

with no signs of metastatic disease were classified as average risk, and every other patient in the

study10 was considered high risk. These two groups can help physicians in predicting the

prognosis of patients as they go through treatment.10 Since many pediatric patients with

medulloblastoma are treated with craniospinal radiation, it is essential to have consistent updates

on their status throughout treatment.

Treating the whole brain with a boost to the tumor bed is a key component of

craniospinal treatment. However, the effects of photon radiation on cognitive function can be

severe.9 Pediatric patients are at an increased risk of developing a deficit in cognitive functioning

due to radiation.7,9 Cognitive function can be categorized by attention, concentration,

information processing speed, language, learning, and memory.7 Of those who have researched

how radiation affects the functionality of the patient post-treatment, it has been hypothesized that

radiation to certain parts of the brain has different effects.7 This is hypothesized because most

pediatric patients who need radiation therapy tend to have whole brain radiation treatment, rather

than to the tumor bed/tumor location.7 Since this tends to cause difficulty in determining the

different deficits a patient may have in the future, most studies1,3-10 focus on more of the overall

aspect of the effects of radiation as a whole.

Based on a study completed by Ida et al7, many children who are treated with whole brain

irradiation using photons, are more likely to have academic skills below the standard level for

their age group.7 Typically, this decrease in academic level is delayed about five years after

treatment is completed.7,8 It has been found that pediatric patients can lose up to 17 intelligence

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quotient (IQ) points after radiation treatment.9 Not only does photon radiation have an effect on

intellectual skills, but it has also been shown to decrease processing speed, attention, and

memory functions.7 Reduction in these categories typically occurs before a decrease in

intellectual level.7 The decline in academic ability can cause children to require special attention

in school, which can inhibit their overall quality of life.7

All of these neurocognitive toxicities can be associated with how much overall dose the

patient receives, as well as the age at diagnosis.7,8 Typically, younger age at diagnosis and a

higher cumulative dose during treatment tend to have more deficits later in life.6-9 In a study

conducted by Ida et al7, a difference in the academic performance between pediatric patients that

were treated with a cumulative dose of 18 Gray (Gy) compared to a total dose of 24 Gy was

found. It was also noted that girls are more likely to have neurocognitive dysfunctions than boys

when given the same treatment and dose.7 Patients in this study7 were treated with photon

radiation for the entirety of their treatment.

Pediatric patients who receive three dimensional conformal radiation therapy (3D CRT)

are more likely to have adverse side effects, as well as run a higher risk of developing secondary

cancers such leukemia, urinary and digestive tract tumors, thyroid cancer, or a recurrence in the

central nervous system (CNS).3,6 When comparing 3D CRT and proton radiation, the risk of

developing a secondary malignancy is higher among patients who received 3D CRT.6 These

patients run a 55 percent chance of developing a secondary cancer with 3D CRT and only a four

percent chance with proton treatments.6 The decrease in lifetime risks can be attributed to the

little to no exit dose in proton therapy.4 By not having an exit dose, doctors are able to treat the

area of interest using protons without harming any healthy tissue around that area.11 Figure 111

shows the dose from photon radiation penetrating deeper into the tissue compared to proton

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radiation. Although the area of interest, the spine, is being covered accurately in both images, the

amount of exit dose in photon therapy is much larger than proton therapy.11 The fact that the

treatment area encompasses a large portion of the patient’s body may have the potential to cause

these secondary cancers.6 Treating a substantial volume on a small body for pediatric patients

can cause them to experience a lot of problems.6 This is where proton therapy comes into play

because the locations of treatment are very exact.

While proton therapy can treat very precisely and leave no exit dose, conformal 3D

radiation tends to have a few complications due to the different field set-ups and techniques used

to treat the patients. Three dimensional conformal radiation therapy has a couple different factors

that should be considered when deciding to treat a pediatric patient for medulloblastoma. One

factor is the amount of time since the patient was treated.6 This will help to determine when the

late effects will occur, especially for anything involving the spinal cord.6 Another factor that can

be an inhibitor for 3D CRT is the risk of treatment fields not lining up properly between the

different fields used for treatment.6 This can potentially create cold or hot spots, neither of which

are an ideal outcome, as it can create either overdosing or under dosing in a critical area.6 Not

only should the area of interest be a concern when treating pediatric patients with

medulloblastoma, but the healthy tissue around the target volume should be closely monitored

throughout treatment.

Proton therapy is a great tool to avoid for not radiating normal tissue, which helps reduce

the recurrence of many late toxicities.1,4-6 Ibrahim et al10 conducted a study that compared doing a

boost to the posterior fossa (PF) versus to the gross target volume (GTV). The GTV was defined

as the area that contained “all gross residual tumors and/or the tumor beds at the primary site”

throughout the study.10 Each patient received the same dose of radiation to the whole brain, 23.4

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Gy, and were then divided into two different groups.10 Through this study10 it was found that

treating the whole brain with only the tumor bed boost can be just as effective as treating the

entire PF after the whole brain treatment. This helps to decrease the total volume of the brain that

is being irradiated at such a high dose during the boost.10 This study10 hopes to follow up with

patients on how this specific technique affects various late toxicities.

Although there are many medical factors that show why proton therapy is typically

prescribed as a treatment for pediatric patients with medulloblastoma, a factor that plays an

immense role in the decision making process is the cost of treatment.11 According to a study

completed by Mailhot-Vega et al11, the cost for construction of a proton center can cost up to

$140 million.11 While this treatment center is extremely expensive to build, the cost of treatment

per patient for proton therapy is around $400,000, compared to $10,000-$50,000 for photon

radiation treatment.11,12 There are many clinical reasons for selecting proton therapy versus 3D

CRT, but the cost of treatment for this new technique can be a determining factor on which

treatment modality to use. Mailhot-Vega et al11 compared the cost effectiveness of proton

therapy to photon radiation therapy.

In order to obtain the information needed for this study11, researchers applied a Monte

Carlo simulation using health records of multiple pediatric patients who were treated for

medulloblastoma. Patients’ data was tracked from 11 years old through adulthood in order to

look at different health complications.11 After looking at risks, benefits, and costs of both types

of treatment techniques, it was found that proton therapy was indeed more cost-effective than

photon radiation therapy.11 This was primarily due to the costs of managing care for late side

effects that occur because of photon radiation.11 Although the initial cost of proton therapy is

higher, it ends up costing less in the long run because there are not as many life threatening side

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effects from this treatment.9,11 The cost to care for future heart problems, neurocognitive deficits,

and a secondary cancer will exceed the cost of only treating with proton therapy.11 Since

pediatric patients with medulloblastoma are treated at such a young age, around three to five

years old on average, they are expected to have a long life ahead of them.11 The concern of many

parents is whether to pay the upfront cost of proton therapy, or take the chances that their child

will not have severe late side effects from 3D CRT.

Conclusion

Medulloblastoma is a very common cancer in pediatric patients, with the typical

treatment regimen including surgery, radiation therapy, and potential chemotherapy. Proton

therapy is becoming an increasingly popular form of treatment for medulloblastoma because it

leaves no exit dose during treatment, which helps reduce the amount of healthy tissue receiving

radiation. Due to the decrease in exposure to normal tissue, side effects are reduced later in life

and the risk of a recurrence of the primary cancer has also diminished. Although

medulloblastoma patients are already at a higher risk of developing a secondary cancer, proton

therapy can help to decrease the potential risk of developing a late side effect. Some late effects

from photon radiation therapy include heart problems, hearing loss, deficiencies in growth

hormones, the cancer returning, and neurocognitive deficits. These mainly arise in the areas

being treated, the brain and spinal cord, with exit dose hitting healthy organs and tissue in the

process. Problems that arise from neurocognitive deficits typically result in difficulties in school,

the ability to retain information, as well as information processing speed. All of these late

deficiencies can have a huge impact on a child’s quality of life, no matter the age of treatment.

It has been shown that the younger the child is when receiving treatment, as well as being

treated to a higher cumulative dose of radiation, results in greater deficiencies among these

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patients. While many studies1,5,6,9 have shown how proton therapy can reduce late side effects in

pediatric patients, the next step is comparing the cost between the two modalities. Proton therapy

can be quite expensive upfront. This daunting amount of money can potentially turn patients and

families away from getting treated with protons. Even though the cost can be intimidating, it has

been shown that proton therapy is more cost effective because patients are not having to pay for

future medical bills that arise from secondary cancers that photon therapy can cause.11 Future

studies should look into the long-term effects that proton therapy may have on pediatric patients

with medulloblastoma. Overall risk when comparing cancer versus non cancer side effects is

significantly lower for proton beam radiation compared to 3D conformal radiation and IMRT.

With a decrease in late side effects, better cost efficiency, and better overall clinical outcomes,

pediatric patients diagnosed with medulloblastoma are great candidates for proton therapy.

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Figure 1.

This figure is a representation of the dose distribution to the spinal cord and rest of the body

between photon radiation and proton radiation. The dose is represented in centigrays for these

two images.11

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Figure 1.

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References

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2. Cure Search. Childhood cancer statistics- graphs and infographics. Cure Search Web site. http://curesearch.org/Childhood-Cancer-Statistics. 2016. Accessed February 7, 2016.

3. Christopherson K, Rotondo R, Bradley J, et al. Late toxicity following craniospinal radiation for early-stage medulloblastoma. Acta Oncologica. 2014; 53(4): 471-480. doi:10.3109/0284186X.2013.862596.

4. Jones B, Wilson P, Nagano A, Fenwick J, and McKenna G. Dilemma concerning dose ditribution and the influence of relative biological effect in proton beam therapy of medulloblastoma. The British Journal of Radiology. 2012; 85(1018): 912-918. doi:10.1259/bjr/24498486.

5. Zhang R, Howell R, Taddei PJ, et al. A comparative study on the risks of radiogenic second cancers and cardiac mortality in a set of pediatric medulloblastoma patients treated with photon or proton craniospinal irradiation. Radiotherapy and Oncology. 2014; 113(1): 84-88. doi:10.1016/j.radonc.2014.07.003.

6. Brodin P, Rosenschööld P, Aznar M, et al. Radiobiological risk estimates of adverse events and secondary cancer for proton and photon radiation therapy of pediatric medulloblastoma. Acta Oncologica. 2011; 50(6): 806-816. doi:10.3109/0284186X.2011.582514.

7. Ida, M, Moore I, Hockenberry M, Krull K. Cancer-related cognitive changes in children, adolescents and adult survivors of childhood cancers. Seminars in Oncology of Nursing. 2013; 29(4): 248-259. doi:http://dx.doi.org/10.1016/j.soncn.2013.08.005.

8. Schrieber JE, Gurney J, Palmer S, et al. Examination of risk factors for intellectual and academic outcomes following treatment for pediatric medulloblastoma. Neuro-Oncology. 2014; 16(8): 1129-1136. doi:10.3978/j.issn.2304-3865.2014.01.03.

9. Blomstrand M, Brodin P, Rosenschöld P, et al. Estimated clinical benefit of protecting neurogenesis in the developing brain during radiation therapy for pediatric medulloblastoma. Neuro-Oncology. 2012; 14(7): 882-889. doi:10.1093/neeonc/nos120.

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10. Ibrahim N, Abdel A, Abdel K, Makaar W, Shaaban A. Reducing late effects of radiotherapy in average risk medulloblastoma. Chinese Clinical Oncology. 2014; 3(1):

4. doi:10.3978/j.issn.2304-3865.2014.01.03. 11. Mailhot V, Bussière M, Hattangadi J, et al. Cost effectiveness of proton therapy

compared with photon therapy in the management of pediatric medulloblastoma. Cancer. 2013; 119(24): 4299-4307. doi:10.1002/cncr.28322.

12. Cost Helper. How much does radiation therapy cost? Cost Helper Web Site.

http://health.costhelper.com/radiation-therapy.html. 2015. Accessed February 7, 2016.