Targeting Tumours with Proton Beam Therapy

Proton Beam Therapy – A Radiotherapy Revolution

In Memory of Bozidar Erakovic (1928-2012)

In July 2018, Simon Hardacre was the first person in the UK to receive high energy proton beam therapy for the treatment of an aggressive form of prostate cancer at the Rutherford Cancer Centre in Newport, South Wales.  This is currently the only clinic in the UK where high energy proton beam therapy is available.

Proton beam therapy in the UK has joined the radiotherapy revolution to fight cancer.  This new approach is an advanced form of external radiation therapy which uses high-energy protons rather than photons.  In the UK, the Rutherford Cancer Centre operates proton beam therapy delivered by the IBA Proteus®ONE machine.

The Proteus®ONE is IBA’s (Ion Beam Applications S.A.) compact single room proton therapy solution which can be integrated into the healthcare setting. It is smaller and more affordable than conventional multi-room proton systems which makes it more accessible to clinical institutions worldwide for the treatment of cancer patients.  It uses Pencil Beam Scanning technology to minimise radiation exposure to healthy tissue.

Pencil Beam Scanning Proton Therapy is capable of enhancing accuracy by using an ultra-narrow proton radiation beam.

Therefore, it reduces radiation exposure to the organs and healthy surrounding tissue and lowers the associated risk of side effects.

Also, it increases the types of tumours which can be treated with proton therapy to include irregularly shaped tumours which are intertwined with critical tissue and organs.

These cancer destroying machines are capable of providing proton beam therapy via pencil beam scanning.  Consequently, these advances in technology allow the radiation dose to be given to the exact shape of the tumour target volume.  During the targeting of the tumour, the patient is positioned on a couch with the most up to date imaging capability which includes cone beam computed tomography allowing the delivery of precise proton beam treatments.

Proton beam therapy is changing the way we manage tumours without causing damage to organs through the technological revolution in radiotherapy, guided imaging systems and treatment planning.

The patient in receipt of proton beam therapy will have a personalised treatment plan according to their own particular needs.

How does Proton Therapy work?

Conventional radiotherapy works by using high energy X-rays which damage DNA within the cancer cells.  This process causes the cancer cells to undergo apoptosis leading to cell death.  The proton beam therapy can also be used following surgery or after chemotherapy, hormone therapy and targeted drug therapy. The advantage of proton beam therapy is that the proton beams can be targeted to the tumour site and therefore, limit damage to healthy surrounding tissues: this compares more favourable than conventional radiotherapy.  The proton beams can be used to treat complex tumours; which are difficult to remove by surgery due to their close proximity to sensitive healthy tissues.

The protons are accelerated to 60% of the speed of light – with a kinetic energy of 250 MeV using cyclotrons and synchrotrons – to be able to penetrate approximately 38 cm into the body.  During their journey towards the cancer site, small amounts of energy are transferred to the molecular electron clouds causing a low degree of ionisation.

This process slows the mono-energetic ions down generating a greater linear energy transfer which results in the braking effect of the proton.  At this point, there forms an energy burst known as the Bragg peak towards the end of the proton path.  In contrast to X-rays, the proton radiation is deposited at a lower dose in front of the tumour.  Consequently, the tissue mass behind the tumour is not exposed to any radiation.  Therefore, this physical phenomenon makes it possible to determine the depth of the Bragg peak which takes into account the modulation of the particle velocity and is able to focus the radiation within the tumour volume.  This process is conducted with absolute precision and therefore improves the ratio of therapeutic radiation to the effects of harmful radiation.

The spreading and shaping are achieved electro-mechanically to treat patients with passively-scattered proton therapy.  However, a technique which uses magnetic scanning with thin beamlets of protons contains a sequence of energies. Furthermore, magnetic scanning technique to treat patients with optimised intensity modulated proton therapy (IMPT) is the most powerful proton modality.

The application of proton beams instead of X-rays, allows medical physicists to increase the therapeutic dose while controlling the dose deposited in healthy tissue. This approach has reduced the radiation deposited in healthy tissue from 43% to 78%, depending on the shape of the tumour.

It is planned for the next three years that the UK will have at least six proton beam centres.  However, two of the proton centres will be operated by the UK National Health Service and the remainder controlled by Proton Partners International.  This proton beam therapy revolution will enable for the first-time cancer patients to be treated in the UK.  Before this significant revolution, these same patients would have had to travel to clinics in the US and Europe.

It has been predicted that Proton Partners International will reach approximately 6% of cancer patients who receive radiotherapy every year in the UK.

It is also planned to open more proton therapy centres in Northumberland, Reading, Liverpool and London.  The aim is to build eight centres in the UK, to be branded as ‘Rutherford Cancer Centres’.

By the end of 2020, the NHS will operate higher capacity proton beam centres at the Christie Hospital in Manchester and University College London Hospital.

Proton Beam Therapy Systems used in the Clinical Setting

Brief History of Proton Beam Therapy

Proton beam therapy has been driven by cyclotron technology since it first used in 1932 by Ernest Lawrence at the University of California, Berkeley.  This was followed in 1937 by the European cyclotron located at the Radium Institute, Leningrad and developed by George Gamow and Lev Mysovskii.  However, the largest cyclotron is located at the RIKEN laboratory in Japan and is known as the Superconducting Ring Cyclotron (SRC).  The SRC weighs about 8,300 tonnes and accelerates uranium ions to 345 MeV per atomic mass unit.  The TRIUMF cyclotron based in Canada is capable of producing a field of 0.46 T while a 23 MHz 94 kV electric field is used to accelerate the 300 μA beam.

Proton beam therapy can trace its progress back to the cyclotron physicist Robert Wilson who in 1946 predicted the use of energetic protons to be used in radiotherapy.  In the past two decades, proton therapy has become an emerging treatment option for patients with certain types of cancer as there are advantages over conventional x-ray therapy.

In 1985, at the Fermilab conference, James Slater, Leon Lederman, and Philip Livdahl presented the viability of building a hospital-based proton cyclotron.  This was endorsed by the interest of Robert Wilson in the medical use of protons for the treatment of cancer.

Proton beam therapy uses a beam of energetic protons while x-rays use a photon to irradiate diseased tissue.  To reach the tumour volume both the protons and photons have to travel through the patient’s skin and surrounding tissues.  Photons have no associated mass or charge and are capable of delivering a dose of radiation by penetrating the tissue. This radiation is delivered to a depth of 0.5 cm to 3 cm from the patient’s skin and is dependent on the initial energy. The energy of the photons diminishes at the tumour target because the radiation ionises the surrounding healthy tissues as well as the tumour site.  Also, the photons leave the patient’s body and continue to emit radiation: this is known as the exit dose.

However, the proton is heavy (equivalent to ~2000 electrons), and as a charged particle it gradually loses its speed as it interacts with human tissue.  This property gives an element of control and delivers a maximum dose at a precise depth: this is associated with the amount of energy obtained from the cyclotron and is capable of a penetration depth of 38 cm. The advantage of using protons over photons is that protons are very fast at the point of entry into the body and therefore deposit only a small dose on the surrounding tissues.

The beam of protons allows the absorbed dose to increase gradually with greater depth and lower speed.  This then produces a peak at the point where the proton comes to rest and is known as the Bragg peak.  Proton therapy aims to control the proton beam by directing the Bragg peak inside the tumour volume which is followed by a burst of energy when the proton comes to a sudden rest during irradiation.  The advantage of proton therapy is that it is possible to target tumours within the body and precisely localise the radiation dose with limited damage to the surrounding healthy tissue.

In 1954, the first proton therapy clinic opened at Berkeley treating 30 patients: since 1990, over 17500 patients have been treated. During the development of proton therapy, new guided imaging systems and treatment planning approaches had to be discovered and implemented.

Since the 1970s, proton therapy has been part of the clinical setting in the USA receiving U.S. Food and Drug Administration approval in 1988. To date, about 100,000 people have received proton therapy at centres throughout Europe, Asia, and the USA.

https://www.texascenterforprotontherapy.com/proton-therapy/proton-beam-radiation-therapy

A breakthrough in the diagnosis of cancer was the development of X-ray computed tomography (CT) in 1970.  These imaging machines were able to generate 3-D scans to provide tumour volume location and also the assignment of CT Hounsfield numbers.  This information was beneficial for calculating electron-density distribution which is required to perform 3-D dose calculations.  The development of CT scanning provides the way forward to CT-based radiation technologies in the treatment planning of cancer patients.  Subsequently, in the 1980s the diagnostic tool magnetic resonance imaging (MRI) arrived which was central to the evaluation of the disease states in patients.

The primary emphasis on the development of diagnostic imaging tools is to find a relationship between a tumour and surrounding healthy tissue.  The advantage of MRI over CT is that there is a generation of images with higher spatial resolution and contrast.

During the 1990s, positron emission tomography (PET) imaging joined the diagnostic toolbox in the treatment planning of cancer patients.  Then further advancements led to hybrids scanning machines such as PET-CT which were able to visualise tumours and provide more detailed images.  The focus of PET imaging was to distinguish between tumours and normal tissue sites due to their different rates of metabolism.

These modern imaging modalities – in conjunction with proton beam therapy – are used to detect the geometric contours of tumours and to ensure that the correct radiation dose is delivered accurately to the tumour site. Also, further advancements in imaging-guided therapy have produced 4-D computed tomography imaging as the basis for respiratory-gated proton beam therapy to limit motion artefacts.

Today, the apex of medical imaging has combined X-ray radiation techniques with proton beam therapy to treat a broad range of cancers and eradicate them.  The treatment of cancer depends on the ability of the physicist to conform the irradiation outline to the tumour volume.

The problem arises when conventional radiotherapy techniques are used which introduce a high risk of damaging surrounding healthy tissues.  Therefore, treatment planning in important to reduce radiation dosage and limit damage to the surrounding healthy tissues as well as limiting other side-effects.

Prostate Cancer

According to Cancer Research UK, there about 14.1 million new cases of cancer globally. The top four cancers include lung, breast, bowel, and prostate respectively. Prostate cancer is caused by the uncontrollable growth of cells in the prostate gland. In men, the prostate neoplasm is the most common form of non-skin cancer and nearly 3% of individuals affected die from this disease due to many medical interventions offered to treat prostate cancer.

The application of proton therapy to treat patients with prostate cancer has increased more than 2-fold from 2004 to 2012.  Various studies have shown the rate of proton beam therapy use has risen from 2.3% in 2004 to 5.2% in 2011 and to 4.8% in 2012.

The overall advantage of proton beam therapy over conventional radiotherapy is the ability to use protons at a higher radiation dosage.

The emerging concept of theranostics (therapy + diagnostics) is used by medical physicists to control and manage cancer with the aim to reduce damage to healthy tissue and surrounding organs. Proton beam therapy offers a personalised approach to using radiotherapy for the treatment of cancer.

Advantages of PBT

·         Proton beam therapy has the ability to targets tumours with precision and therefore reduce the exit dose.

·         The overall radiation dose in the patient can be lowered.

·         The proton beam reduces the side effects of radiation on the surrounding healthy tissues and organs.

·         Proton beam therapy is able to deliver an optimal radiation dose to the tumour volume.

·         Also, proton beam therapy can be used to treat recurring tumours.

·         The quality of life after treatment is significant.

·         The long-term and survival rates of using proton beam therapy are beneficial to a wide range of tumours.

Other PBT Centres

Proton beam therapy systems are available in at least 24 sites across the United States; this includes a new proton therapy centre at the Miami Cancer Institute.  These facilities can cost over $225 million each and have been called the single most expensive medical devices ever built.  Consequently, treatment costs do exceed those of traditional photon external-beam radiotherapy (EBRT) modalities.

The conventional linear accelerator (LINAC) produces radiation by accelerating electrons down a long, straight tube.  However, protons require much more energy to cause them to move: this can only be achieved using a cyclotron.  Cyclotrons can cost up to £100m and since the advancement of cyclotron technology can be purchased for £25m compared to a conventional radiotherapy machine which costs about £2.5m.

Nevertheless, proton beam therapy is more expensive than conventional LINAC-based radiotherapy and is currently mostly channelled towards paediatric cancers of the brain and spinal cord.  In addition, proton beam therapy treatment for the lung and prostate reduces long term side effects.  Also, in patients where the anatomy of a tumour contains critical normal tissues a dose distribution with protons is the favourable option.

Presently, two proton beam therapy machines are being installed at University College Hospital in London and Christie Hospital, Manchester.  These will be equipped with large machines which can cost about £80m and require up to 80 staff to manage each machine.

However, the compact models being installed by private sector providers for NHS use cost less than £25m and require only 20 staff.  That means the cost per single treatment will be far more expensive in the NHS installations.

Therefore, the UCLH/Christie true cost per treatment will approach £5,000 whereas the cost of the compact model will be less than £1,500.

Radiotherapy in the UK urgently requires upgrades since routine radiation machines are more than 10 years old.  Replacing these machines with modern versions involves an injection of capital and by 2020 the NHS may produce a £20bn deficit.

Due to an ever-ageing population, there is a requirement for more effective means of delivering the radiation dose to destroy cancer. Therefore, partnerships with the private sector can help the NHS in the area of proton beam therapy.  This is by creating advanced radiotherapy networks throughout the UK which use high energy beams of protons rather than high energy X-rays to deliver radiotherapy.

The national proton beam therapy service was an integral part of the Government’s Cancer Strategy Improving Outcomes: A Strategy for Cancer (2011).

Particle beam therapy facilities in clinical operation (Since February 2019)

Particle beam therapy facilities under construction (January 2019)