Proton Beam Radiotherapy

Proton Beam Radiotherapy
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A proton beam radiation device used in treatment.
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When treating malignant tumours that are associated with the nervous system, the use of radiation techniques such as photon intensity modulated radiation therapy (IMRT), which includes x-rays and gamma radiation, poses a great challenge. The spreading of the dose of radiation into the healthy structures surrounding the tumour often leads to cognitive deficits and the potential development of secondary brain tumours. Consequently, the use of proton radiotherapy as opposed to the conventional photon IMRT offers a considerably safer treatment approach when dealing with such malignancies. The proton’s properties allow for the specific targeting of the tumour tissue, while at the same time delivering a high enough dose of radiation, leading to the death of tumour cells. Hence, this achieves the optimal goal of eliminating the cancer tissue without causing collateral damage to the critical brain areas that are in close proximity to it. As a result, clinicians have been particularly using proton radiation to treat a wide range of pediatric brain tumours. Clinical research thus far has used proton beam radiation in the treatment of numerous brain malignancies including astrocytomas, medulloblastomas, oligodendrogliomas, optic nerve gliomas, acoustic neuromas, and many others types of tumours [1]. Unfortunately, clinical research appears to be somewhat limited. Moreover, much remains unclear about the precise mechanisms and biophysical properties of proton beams and further investigations in that area are critical. Recent research has been developing methods to further improve the dose distribution of proton radiation, which would pave way for an even higher cell death count in the tumour tissue and further sparing of the healthy tissue [2].

Robert R. Wilson
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The 'Father of Proton Therapy'.
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1. History

The idea behind using protons in radiotherapy was first proposed in 1946 by Robert R. Wilson [3] currently deemed as the ‘Father of Proton Therapy’[4]. In 1958, proton radiation was first used in treating pituitary tumours in a sample of patients at the Lawrence Berkeley National Laboratory in California[5]. Yet, medical institutions did not adopt proton beam radiotherapy until decades later, after intensive research has been performed investigating its use and clinical advantages[6].


2. Rationale Behind Proton Beam Radiotherapy

2.1 Physical Concepts

2.1a Bragg Peak

The high energy, positively charged beam of protons enters the tissue and travels a certain distance while maintaining a constant velocity, before slowing down (see above [6]). During that time, the protons undergo very minimal loss of energy. At the end of proton beam’s path, the protons undergo rapid deceleration, thereby leading to an abrupt deposition of a high peak of energy in the tumour. This high peak of energy is known as the Bragg Peak, named after the British physicist William H. Bragg (see above [6]). No further energy is transferred beyond the Bragg Peak, as protons have no exit dose. The vast majority of the energy is transferred from the radiation beam to the tissue due to the interactions between the protons and the electrons in the tissue[7]. In treating tumours, the use of the Bragg Peak in the irradiation of the cells at various tumour depths is unfeasible, as it will only lead to the irradiation of narrow depths. Hence, the Spread Out Bragg Peak (SOBP) is often used in proton beam radiotherapy in order to ensure the spreading of the dose of radiation to the entire tumour (see above [6]).

2.2 Entering The Tissue

2.2a Linear Energy Transfer (LET)

This measurement describes the number of ionizations caused by a radiation parameter per unit distance (keV/µm) (see above [7]). Different radiations can be categorized into two categories: low LET or high LET. Protons and photons fall under the low LET category. Different factors affect the LET of a radiation particle, including its speed and mass.

2.2b Relative Biological Effect (RBE)

One radiation modality may require a different radiation dose in order to establish the same biological effect as that of another radiation modality. Thus, the RBE is a measurement used to compare the biological effects a radiation modality has to different forms of radiations, having different LETs. Often, the reference radiation source to which a radiation modality is compared to is photons (see above [7]), considering it has been utilized intensively in clinical research in the treatment of tumours. Photons have been established to have an RBE of 1, while protons have an RBE of 1.1[8]. This means protons have a somewhat greater biological effect than photons. However, the RBE of protons is easily affected by factors including the type of tissue, the proton beam’s energy and the dose distribution, making it hard to predict under certain circumstances (see above [8]).

2.3 Cellular Response

Much remains unclear regarding the cellular responses that occur in response to proton radiation[9]. Yet, the cellular effects are thought to be similar to those following photon radiation. Researchers have shown that as protons enter the mammalian cells, the abrupt deposition of high-energy causes molecular and DNA damage[10]. Subsequently, the cellular DNA does not get repaired causing cell death. It has been shown that in comparison to the photon irradiated cells, proton irradiated cells do not delay the expression of apoptotic genes (see above [10]).

Dose Distribution in Proton and X-Ray Radiotherapy
A depiction of how the radiation dose is distributed in proton and x-ray treatments of a tumour.

3. Comparing Proton to Photon radiation

3.1 Physical Differences

3.1a Dose Distribution

As photons enter a tissue, they follow the rule of exponential decay (see above [6]). As opposed to protons, the photons’ velocity decreases exponentially with distance, leading to the deposition of energy at the entrance point of photons along with their exit point.

3.1b Penumbra

A proton beam has a sharper penumbra in comparison to a photon beams. This entails that the radiation caused by the proton decreases at the beam’s edges. This penumbra is also maintained at greater depths of the tumour tissue (see above [6]).

3.1c Tissue Heterogeneity

Photons are more able to travel through the different types of tissue in the body, while protons are more affected by tissue heterogeneities.

3.1d Relative Biological Effect

The RBE of protons is slightly larger, yet overall similar to that of photons (see above [8]), making both protons and photons have similar effects on tumour tissues.

Proton vs. Photon Radiation
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The spreading of radiation into the tissue surrounding tumours following proton
and photon radiotherapy.
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Proton vs. Photon Radiation
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Energy deposition differences between protons and photons.
Retrieved from: Fermi National Accelerator Laboratory

3.2 Clinical Differences

The properties of protons make them more suitable candidate in the treatment of the tumours of the nervous system (see above [6]). Some tumours in specific have been shown to exhibit high resistance to forms of radiation such as those associated with glial cells[11]. Due to the dose distribution properties of a proton beam, the ionizing energy contained in the radiation is confined to the target tumour tissue. This leads to a better energy deposition profile for protons compared to photons. This would ultimately cause the sparing of the healthy, non-target tissue surrounding the malignancy as it lessens the probability of the radiation spreading to nearby structure. In addition, this would enable clinicians to have better local control of the radiation beam. Consequently, this leads to a lower probability of occurrence of secondary malignancies that are associated with the treatment[12]. Moreover, such properties allow for the ‘dose escalation’ of the radiation beam, therefore causing higher tumour cell kill.


4. Associated Toxicities with Proton Beam Radiotherapy

Recent Research investigating the acute toxicities associated with proton beam radiotherapy treatment of pediatric tumours[13] concluded that such effects include fatigue, headache, alopecia, dermatitis, and nausea with less frequent occurrences of vomiting. Very low rates of insomnia were recorded and the subjects’ average weight remained somewhat unchanged. The tumours treated included gliomas, medulloblastomas, ependyomas and several other types. The study also found that the acute side effects were dependent on the tumour’s location, whether it had critical structures surrounding it, the amount of radiation used and whether chemotherapy was used in conjunction with proton radiotherapy.


5. Criticisms

The use of proton radiation in the treatment of nervous system tumours in still limited as only a small number of institutions is utilizing this technology (see above [6]). Thus, clinical data with regards to the use of proton beam radiotherapy remains insufficient (see above [9]). In addition, these treatment institutions are not well distributed. Much remains unknown about the acute and long-term toxicities associated with proton radiation and more data is required in order to observe the proposed clinical advantages of proton therapy over photon radiation therapy (see above [13]). Furthermore, clinical research examining the patients’ quality of life during and following treatment is still required.


6. New Advances and Recent Research

6.1 Proton-minibeam Radiation Therapy

Aimed at investigating the further improvements that could be done to proton radiation therapy, researchers in Italy (see above [2]) are working on a new proof of concept called Proton-minibeam radiation therapy. The demonstration carried by the team of researchers explores the possibility of further sparing the healthy, non-target tissue that surrounds a given tumour during radiation. It was established that the spatial fractionation of the proton beam would indeed yield better advantages than the regular proton beam radiotherapy as it paves way for smaller beams of radiation to be used, which would allow for smaller penumbras, better tumour control, and better protection of the healthy tissue from the radiation.

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2. Prezado, Y. & Fois, G. (2013). Proton-minibeam radiation therapy – A proof of concept. Med. Phys. 40 (3): 1-8.
3. Wilson, R. (1946). Radiological use of fast protons. Radiology. 47: 487-491.
4. Robert R. Wilson: remembered as ‘Father of Proton Therapy’ and achievements in physics and medicine. Retrieved September 1, 2011. The National Association for Proton Therapy.
5. Tobias, C., Lawrence, J., Born, J., McCombs, R., Roberts, J., Anger, H., Low-Beer, B. & Huggins, C. (1958). Pituitary irradiation with high-energy proton beams: a preliminary report. Cancer Res. 18: 21-134.
6. McDonald, M & Fitzek, M. (2010). Proton therapy. Curr Prob Cancer. 34: 257-296.
7. Chen, C., Loeffler, J. & Chapman, P. (2003). Proton beam radiosurgery and radiotherapy. Techniques in Neurosurgery. 9(3): 218-225.
8. Gerweck, L. & Kozin, S. Relative biological effectiveness of proton beams in clinical therapy. Radiol Oncol. 50: 135-142.
9. Merchant, T. (2013). Clinical controversies: proton therapy for pediatric tumors. Semin Radiat Oncol. 23: 97-108.
10. Green, L., Murray, D., Bant, A., Rightnar, S., Todd, S. & Nelson, G. (2002). Response of thyroid follicular cells to gamma irradiation compared to proton irradiation: I. Initial characterization of DNA damage, micronucleus formation, apoptosis, cell survival and cell cycle phase redistribution. Radiat Res. 155: 32-42.
11. Hamza, M. & Gilbert, M. (2014). Targeted therapy in gliomas. Curr Oncol Rep. 16(4): 1-14.
12. Newhauser, W., Fontenot, J., Mahajan, A., Kornguth, D., Stovall, M., Zheng, Y., Taddei, P., Mirkovic, D., Mohan, R., Cox, J. & Woo, S. (2009). The risk of developing a second cancer after receiving craniospinal proton irradiation. Phys Med Biol. 54: 2277-2291.
13. Suneja, G., Poorvu, P., Hill-Kayser, C. & Lustig, R. (2013). Acute toxicity of proton beam radiation for pediatric central nervous system malignancies. Pediatr Blood Cancer. 60: 1431-1436.

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