A comparison of proton therapy and external beam photon radiotherapy
1. Introduction
Since the late 1800s it has been known that exposure to x-rays can cause discomfort, skin markings and tissue damage. In 1903, radiation was first used to treat skin cancer. This took the form of a radium source (discovered by Marie Curie five years earlier) being secured close to the tumours, a technique called brachytherapy which is still used today [1]. Throughout the early 20th century, radiation was successfully used to cure Hodgkin’s lymphoma although the detrimental effects of radiation exposure were observed and techniques to reduce exposure of healthy tissue were investigated.
The idea of using protons for radiation therapy was proposed in 1946 by Robert R Wilson, although accelerators at the time did not have enough energy to treat tumours deep in the body. [2]
Now, radiation therapy is a growing field in the medical world with many applications, mostly in cancer treatment. More than 50% of patients with cancerous tumours which haven’t spread are treated with radiotherapy. [3] This therapy can be used to destroy cancer cells with an aim to either cure the patient or shrink the tumour enough to allow surgery or prevent it causing uncomfortable symptoms. Radiotherapy can also be used to prevent the spread of cancer. For example if a type of cancer often spreads to the lungs, it may be assumed that some cancer cells are there even if they do not appear on a scan. This area can be treated with radiation to kill the cancerous cells and prevent secondary tumours forming. Radiotherapy can also be used to treat other conditions such as thyroid disease, blood disorders and benign or non-cancerous growths, but this is less common.
This article investigates the physics of two types of external beam radiotherapy, both traditional photon radiotherapy and the more recently implemented proton therapy and compares how each method achieves the aims of radiation treatment.
2. Principles of radiotherapy
The aim of radiotherapy in cancer treatment is to damage the DNA of tumours in order to kill the tumour or prevent it from growing any further. This is achieved by ionizing radiation, or by the production of free radicals from high energy photons. At the same time, it is vital to a good treatment that the exposure of healthy tissue to radiation is as limited as possible. Treatment is planned using computer software which allows monitoring of the dose to different areas. This enables the maximum dose to be delivered to the tumour whilst minimizing the exposure to the surrounding area.
When external beam radiotherapy is being planned, it uses images gathered from CT and MRI scans to ensure the treatment area is as accurate as possible. In order to have a fixed point to work from, the scanner rooms will have a laser grid which corresponds to an identical grid in the treatment rooms. Patients are positioned comfortably, this position is reecorded, and then they are given small tattoos where the lasers meet their body to ensure they are always in the same position relative to the machines.
For treatments in the head and neck area, where tissue is highly susceptible to radiation, it is even more imperative that healthy tissue is not over-exposed. A mask can be molded to each individual patient and made out of plastic mesh or Perspex. This then clips into the scanner and treatment beds to physically hold the treatment area still. For treatments which require even more precision, such as radiosurgery which uses higher doses than traditional radiotherapy, a metal cage can be screwed to the patient’s head to hold it still to a higher accuracy when attached to the treatment bed.
3. Physics of radiation therapy
3.1 Particle accelerators
Particle accelerators are an integral part of any type of radiation therapy.
3.1.1 LINAC
A linear accelerator (LINAC) accelerates charged particles in a straight line by one of two methods. The first method is acceleration by a constant electric field along the length of the LINAC, but this would require a potential difference of several kilovolts, which would have consequences for insulation and safety. [4, p.19]
A more common method is to use a series of tubes with gaps in between. An alternating potential difference is applied over each gap such that the electric field is at a maximum whenever a charged particle reaches the gap. The particles are accelerated over the gap and then allowed to drift through the tubes at a constant velocity. [4, p.31] The drift tubes are made of conducting material in order to prevent the existence of an electric field within the tube. The drift tubes increase in length to compensate for the increased velocity and keep the time the particles are in each tube consistent so that the periodic field can act on each cycle.
3.1.2 Cyclotrons and synchrotrons
A cyclotron, seen in figure 1, is made of two semi-circular regions with a gap across which an alternating potential difference can be applied. A magnetic field acts throughout the system perpendicularly to the plane in which the charged particles move. The charged particles enter the cyclotron and are acted upon by the electric field.
Figure 1: A schematic diagram of a cyclotron. [5]
As the particle begins to move, the magnetic field causes it to take a circular path through the first semicircular region. The frequency of the alternating potential difference is such that as the particle exits the first region, it is then attracted to the other region and accelerates across the gap. As the velocity is now higher, the radius of the path in the second region is larger, but the time taken to trace the semi-circle doesn’t change. This process repeats, with the protons spiraling outwards until they have reached the target energy.
Figure 2: A schematic diagram of a synchrotron. [6]
Particles are injected into the synchrotron via a linear accelerator, as seen in figure 2. The beam travels in a circle or loop contained by a series of magnets, passing through the accelerator with every circuit. As the radius of the path is fixed, the strength of the magnetic field must be increased with every orbit in order to keep the particles on the correct path. This contrasts with the cyclotron where the magnetic field is kept constant but the radius of the path increases. The particles are extracted once they reach the desired energy.
Both cyclotrons and synchrotrons are used as accelerators in proton therapy, but cyclotrons have an energy limit of around 70 MeV, making them only appropriate for ocular treatments. Synchrotrons have the benefit of being able to extract the protons at varying energies unlike the cyclotron which has a fixed extraction energy. However, synchrotrons are less compact and require more room where they are installed. Both accelerators also require shielding due to the emission of synchrotron radiation when particles are accelerated. [7]
3.2 Photon radiotherapy
External beam radiotherapy uses x-rays with energies from 4 MeV to 25 MeV. A linear accelerator accelerates electrons across a potential difference into a target metal, usually a tungsten alloy. This causes Bremsstrahlung radiation in the x-ray region of the electromagnetic spectrum which can then be collimated by lead or another radiation-opaque material, such as depleted uranium, to form a rectangular aperture. The beam can then be further collimated by a multi-leaf collimator which consists of 40 to 120 strips of lead or tungsten, in pairs, to form a more complex shape and further decrease the amount of healthy tissue exposed to the damaging radiation. [8] Alternatively, a cobalt-60 source can be used to produce gamma radiation.
At the energies used in photon radiotherapy, the predominant effects are the photoelectric effect, the Compton effect and pair production, but photons can also undergo coherent scattering or photodisintegration. [9]
The most powerful effect is the Compton effect, as its strength is proportional to electron density and therefore the radiation is absorbed by all tissue similarly.
The cross-section of pair production, is approximated by
(1)
where Z is the atomic number of the target material, re is the radius of an electron, is the fine structure constant and P(E,Z) is a complex function where E is the energy of the photon. Therefore, the probability of pair production occurring is approximately proportional to Z. The strength of the photoelectric effect is proportional to Z3 and therefore the different interactions have different strengths depending on the tissue type. [9]
Beams of photons ionize the material they come into contact with but pass all the way through the body, exposing a lot of healthy tissue to ionizing radiation which may damage their DNA and cause mutations. Photons deposit most of their energy in the first 0.5-3 cm of the body they encounter, and lose energy from that point as shown in figure 3, so less of the radiation reaches the treatment site. [10] Treatment can be planned to minimize the exposure to healthy tissue and keep radiation away from vital structures such as the spinal cord which has a low tolerance to ionizing radiation.
Two main techniques for limiting the radiation dose are image guided radiotherapy (IGRT) and intensity modulated radiotherapy (IMRT). IGRT uses frequent scans by the radiotherapy machine or an external sensor to ensure that the target area is always being treated efficiently as, for example, a lung tumour may move as the patient breathes. IMRT changes the shape of the beam via the multi-leaf collimator and also adjusts the intensity of the beam at different positions around the body to conform the shape of the treatment area as closely as possible to the shape of the target.
3.3 Proton therapy
Proton therapy uses a beam of protons with energies between 60 MeV and 250 MeV [3] to treat tumours. The beam is created by applying a potential difference over hydrogen gas. The protons are then accelerated using a cyclotron or synchrotron and delivered to the patient. The treatment beam can be in a fixed position for lower energy ocular treatments, or can rotate 360 around the treatment bed to apply the radiation from multiple directions and treat more complex areas.
Protons lose their energy mostly through Coulomb interactions with outer-shell electrons in the target matter and the mass stopping power, , can be approximated by the Bragg-Kleeman rule, given by
(2)
where is the mass density of the target material, is a constant which depends on the material, x is the distance travelled in the material, p is a constant which depends on the proton’s energy and E is the energy of the proton beam. [2] This causes excitations and ionization within the target atoms, leading to the cell damage required in radiation therapy.
As the protons slow down, they cause more ionisations and therefore deposit more dose. Therefore the dose as the proton enters the body gradually rises as the proton slows, but then sharply rises as the proton finally stops. This stopping point gives rise to the Bragg peak, the point to which most of the radiation dose is delivered, as shown in figure 3.
In order to treat an entire tumour, several thousand proton beams of various energies are summed to create a spread-out Bragg peak (SOBP), seen in figure 3. [3] This means that the entire depth of tumour can be treated. The width of the peak can be adjusted to treat tumours of different sizes and shapes.
Figure 3: Graph showing the dose deposit per centimeter depth in tissue for a photon beam, a single proton beam (showing the Bragg peak) and a modified proton beam (showing the SOBP. [11]
Due to the Bragg peak, although some energy is deposited as the beam enters the body, there is no irradiation beyond the peak. This limits the amount of healthy tissue exposed to radiation, which is desirable in radiotherapy as there is no exit beam.
4. Discussion
Figure 4: An image of treatment planning. The orientation of the image is looking from the head to the feet, with the patient lying on their front so the spinal cord is at the top of the image. The image on the left was planned using x-ray treatments, and the image on the right was planned using proton therapy. The amount of dose delivered to an area is shown, with purple being the highest dose and green the lowest. [12]
Figure 4 shows treatment planning for a paediatric spinal cord tumour. It can clearly be seen that the proton therapy plan will deliver much less radiation outside the treatment area than the photon treatment which is vital for reducing side-effects such as pain and movement issues.
There are less than 60 proton therapy centres worldwide, [13] and the UK currently has only one proton therapy facility which only works with energies high enough to treat ocular tumours, although two more will be operational in the UK by 2019. Due to this lack in institutions which perform proton therapy, it is normally only used in the cases of rare cancers and there have not been trials performed which directly compare the effectiveness of proton therapy and photon radiotherapy. [11] Also, proton therapy is a relatively recent invention, so no studies of long-term effects have yet been completed.
However, there are some clear benefits to proton therapy over other forms of radiotherapy. These are mostly due to the Bragg peak reducing exposure of healthy tissue to radiation. This reduces the side-effects of the treatment which is better for the patient’s health and helps save the costs of treating the side-effects. On the other hand, there are still some side-effects of proton therapy which can’t be reduced, such as skin irritation, hair loss and fatigue. [9]
Sparing healthy tissue is particularly important in treating areas close to radiation-sensitive organs such as the spinal cord or optic nerve and in paediatric cases as children are more sensitive to radiation than adults.
Proton therapy has been shown to be capable of delivering 2-7 times less radiation than the equivalent treatment with photons.[14] There is also evidence [15] [16] that proton therapy has a lower risk of causing the patient to develop a secondary cancer in later life when compared to other forms of radiotherapy.
Proton therapy is not always a recommended treatment option. It is best used on those who have small tumours which have not spread to other locations in the body. For large tumours or cancers which have spread, other forms of radiation therapy or chemotherapy may be a preferable option. Also, proton therapy costs more per patient than traditional radiotherapy, so traditional radiotherapy may be preferred when both methods are equally as effective. [17]
5. Conclusion
Radiotherapy is an area of medicine which has been undergoing a lot of expansion and refinement in the last 100 years. New techniques are developed with the main aim of treating the target area with a high dose of radiation without exposing healthy tissue to dangerous levels due to damage by ionization.
Proton therapy achieves these aims well, due to the Bragg peak which causes the heavy particles to deposit most of their energy at a precise point before stopping. This means there is no radiation deposited further than the tumour, and therefore decreases the side-effects and risks of the treatment. This is particularly important when treating areas close to radiation-sensitive parts of the body or when treating children.
This also means that more dose can be given to the target area without greatly increasing the dose to the surrounding healthy tissue. There is evidence that this improves the effectiveness of the treatment.
However, there are currently limited resources for proton therapy. The UK currently only has one proton therapy treatment centre, which works with energies only high enough to treat certain rare eye tumours. Two more centres are being built which will work at higher energies. Even then, there are some cases where traditional radiotherapy may be just as, or more, effective than proton therapy, and more cost-effective.
Overall, proton therapy is a highly effective way of delivering radiation to a defined target area whilst minimising damage to surrounding tissue, and increased resources in the UK will soon mean that more patients can be treated in the most effective way.