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					I M AG I N G R E S E A R C H A N D CA N C E R D I AG N O S I S

Viewing the body’s function
A novel camera for imaging tumours
Bob Ott
BSc PhD
Professor of Radiation Physics

Taking photographs inside the body

However, there is a major limitation to the use of this very important technique, and that is the high cost of the imaging device – the positron camera. The Radioisotope Physics Team in the Joint Department of Physics at The Institute and The Royal Marsden have developed a novel positron camera called PETRRA that is not only low cost, but is also ideally suited to whole-body imaging of patients with cancer.

P

ositron emission tomography (PET)

is a non-invasive scanning technology used to image cancer. In the last few years, the use of PET has led to a substantial improvement in the diagnosis and treatment of cancer patients. The reasons for this are twofold: • PET imaging determines the spread of cancer to the body as a whole better than is possible using conventional computed tomography (CT) scanning. Therefore, clinicians are able to determine the stage of the disease more precisely, which will influence the treatment a patient is given; • Images from PET show improved differentiation between benign and malignant disease in residual masses after cancer therapy compared with other scanning technologies. Hence, clinicians are better informed to decide whether or not a patient needs further treatment.

PET imaging follows a radioactive tracer around the body
PET uses specially designed radioactive tracers to image molecular events in the body. A tracer comprises a biological molecule, often similar to those found normally in the body, to which a radioactive component known as a radionuclide is attached. After a tracer is introduced into a patient, PET imaging is used to follow its distribution and concentration in the body. Radionuclides used in PET emit positively charged electrons called positrons when they decay. After this decay, the positron will travel a short distance of less than 1 mm before it collides with a nearby electron (which is negatively charged) in the tissue and they annihilate each other. During this annihilation, energy is produced in the form of a pair of back-

nucleus Conventional positron camera e+ νe γ-ray Annihilation (enlarged view)

γ-ray

to-back gamma rays (Figure 1). Some of these back-to-back gamma

e–

rays exit the body and can be detected simultaneously by the positron camera. The most commonly used positron emitting radionuclides include: • oxygen (15O), carbon (11C) and nitrogen (13N) – which are important isotopes of biological elements (isotopes are elements that can exist in more than one form, each having a different atomic mass); • fluorine (18F) – an isotope which can be used as a surrogate for hydrogen.

Block detector (enlarged view) LEC PMT PMT

Figure 1. Schematic diagram showing the basic principles of PET scanning. A nucleus of the radionuclide decays producing a positron and a neutrino. The positron meets an electron, in the surrounding tissue, and they are both annihilated, producing two back-to-back gamma rays which are detected by the positron camera. Conventional positron cameras are made up of several block detectors, usually consisting of many light-emitting crystals (LEC) coupled to light detectors, photomultipliers (PMTs).

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These radionuclides all have short half-lives (ie the time taken for the radioactivity to fall to half its original value) of less than two hours, and can only be produced by a special device known as a cyclotron.

electric field around each wire, and the amplified signal is recorded as an image showing the location of the radioactive tracer in the body. The large chambers of PETRRA have a sensitive area of

Importantly, it is our ability to incorporate these isotopes into many biological molecules, such as amino acids, proteins and DNA precursors, which makes it possible to follow the tracers around the body. At present most PET imaging is performed with the compound
18F-labelled

60 cm x 40 cm with wire separations of only a few millimetres, providing a good spatial resolution over a large volume of the body. Because the light is emitted in a very short time (about 10-9 second) the PETRRA detector is very fast. In addition, the large area detectors, which have a similar spatial resolution to conventional positron cameras of 5–6 mm, can also be constructed relatively cheaply. The PETRRA system has two large-area detectors mounted on a rotating gantry, enabling 3D imaging by rotating the detectors continuously around the patient (Figure 2).

fluorodeoxyglucose (FDG), which is similar to glucose in how it is used by the body and, notably, is avidly taken up and accumulated in most growing tumours. An interesting area of recent research has been to radiolabel compounds that can be used to image specific molecular processes, such as how fast cells divide, the rate of cell death, the blood supply to tissues and, perhaps most excitingly, the existence of cancer genes.

Expensive equipment is required to view PET images
To visualise the biodistribution of the tracer we need a device known as a positron camera to produce PET images. Conventionally, a positron camera consists of a large number of scintillation counters arranged in a ring around the patient. Each of the counters consists of a glass-like crystal that emits light when irradiated with gamma rays (Figure 1). These crystals are connected to a set of light detectors called photomultipliers, which in turn are connected to amplifiers that convert the light into an electrical pulse.

PETRRA images are high quality
We have imaged radioactive phantoms so that we can evaluate the performance of the PETRRA camera. Phantoms are life-like models made of tissue-equivalent material and filled with radioactivity to realistically simulate the uptake of tracers in the body. Our results have been encouraging, and confirm that: • PETRRA has intrinsically high spatial resolution and can produce high quality images in an experimental environment (Figure 3); • the camera will be useful in a clinical environment where

Only when two gamma rays are detected simultaneously will the electrical pulses record the event. During a PET scan of a patient, many millions of events are acquired, and an image is subsequently reconstructed from the recorded events using special mathematical algorithms. Whilst existing commercial positron cameras produce excellent quality images with a spatial resolution of about 5 mm, they are unfortunately expensive to purchase (a camera costs more than £1 million), which means that access to PET is usually limited to only the richest clinical centres.

background from activity inside the patient but outside the camera’s field of view is substantial (Figure 4).

PETRRA — a novel and innovative positron camera
The Radioisotope Physics Team in collaboration with the Rutherford Appleton Laboratories near Oxford have developed a novel positron camera based on a lightemitting crystal which is coupled to what we call multiwire proportional chamber (MWPC) technology. How does this technology differ from the conventional positron camera? An MWPC comprises a set of picture frames which support finely spaced wires within a gas-filled enclosure. Light produced by crystals placed in front of the MWPC is converted into charged particles (electrons) in the gas. These electrons are subsequently amplified by a high
Figure 2. PETRRA positron camera. Two large area detectors are mounted on a gantry that rotates them around the patient couch.

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Figure 3. Cross-sectional PETRRA image through a radioactive phantom brain. This image simulates the normal uptake of tracer in grey (white arrow) and white matter (blue arrow) and the basal ganglia (yellow arrow) of the brain, illustrating the excellent spatial resolution which can be achieved with PETRRA in the ideal imaging situation.

The PETRRA camera is now installed at The Royal Marsden and is being used, in collaboration with the Breast Unit and the Nuclear Medicine Department, in a clinical trial to assess the status of lymph nodes in patients with breast cancer.

Figure 4. PETRRA images, viewed in three different planes, of a brain injected with the radionuclide 18F-FDG. High uptake (represented by the whiter areas) of 18F-FDG occurs in the parts of the brain that normally have enhanced glucose metabolism, ie the grey matter (white arrow) and basal ganglia (blue arrow).

to die. This approach will use new tracers currently under development which act as markers of biological processes associated with tumour growth, such as apoptosis (cell death), hypoxia (lack of oxygen), angiogenesis (growth of blood supplies) and cellular proliferation. Studies here will be carried out in collaboration with the Cancer Research UK Centre for Cancer Therapeutics and the Clinical Pharmacology Unit.

An exciting future for PET
As well as the clinical use of PET described above, there are major applications for using the technology in both the clinical assessment of anticancer drugs and the planning of radiotherapy.

Radiotherapy planning
For instance, there is evidence that in some patients PET imaging shows up tumours that have not been picked up by the conventional X-ray or CT scans used to plan the patient’s radiotherapy treatment. Therefore, it should be possible in the future to include PET scans of the patient as part of the radiotherapy plan. Having more accurate imaging of tumours should enable better local control of the disease. We will be performing studies in this area in collaboration with the Academic Department of Radiotherapy and the Radiotherapy Physics Team at The Institute and The Royal Marsden.

Gene imaging
In the last few years there has been some exciting laboratory work with PET tracers that can be used for gene imaging. In this technique, the PET tracer interacts with cellular enzymes that are produced by a marker gene, which recognises and connects to cancer genes. The PET tracer enters and is subsequently trapped inside a cell only if the enzyme is present. If there is no enzyme, the PET tracer is excreted from the cell. Hence, the PET image obtained will show the level of the enzyme in cells – a measure that is directly related to the existence of the cancer gene. We hope to initiate further studies in gene imaging in collaboration with the Cancer Research UK Centre for Cell and Molecular Biology.

Drug dosing and drug monitoring
In the past, the amount of a drug given to a patient has been determined by measuring the concentration of the drug in blood and urine combined with a knowledge of how the drug is distributed in tissues in animals. However, using PET we can correlate these measurements with tissue uptake of a drug in the patient, making it possible to determine accurately the amount of drug that can be given to individual patients. This method involves radiolabelling anticancer drugs to allow their biodistribution to be measured. Furthermore, it is possible to create PET images that tell us exactly how drugs are working – for example, whether a drug is inhibiting tumour cell division or is causing the cells

It is clear that PET has an exciting role in future cancer research, and our PETRRA camera should enable PET to become more widely available than it currently is. The Royal Marsden and The Institute form part of a consortium that is actively seeking to determine whether it is possible to commercialise the camera in order to make it available to more centres.

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