Med Phy 779Radiation Health Risks and Benefits

TEAM MEMBERS:FERNANDES, TomROY, SudipVU, Thao DucWANG, Guiping

Positron Emission Tomography - An Overview

November 01, 2004

Table of Contents

1 INTRODUCTION.................................................................................................................................1

1.1 PREAMBLE........................................................................................................................................11.2 EVOLUTION OF PET.........................................................................................................................1

2 PRINCIPLES OF PET..........................................................................................................................2

2.1 BASIC NUCLEAR PHYSICS ON PET..................................................................................................22.2 MAIN COMPONENTS AND SCAN PROCESS.......................................................................................22.3 METABOLIC AND LABELED COMPOUNDS........................................................................................22.4 CYCLOTRON.....................................................................................................................................32.5 PET RECONSTRUCTION TECHNIQUES..............................................................................................32.6 INTEGRATED APPLICATIONS OF PET AND CT.................................................................................4

3 CLINICAL APPLICATIONS OF PET...............................................................................................5

3.1 CARDIOLOGY...................................................................................................................................53.2 NEUROLOGY.....................................................................................................................................53.3 ONCOLOGY.......................................................................................................................................63.4 CASE STUDY....................................................................................................................................63.5 PET ACCURACY IN CANCER DIAGNOSTICS.....................................................................................73.6 RISKS OF PET SCAN........................................................................................................................7

4 CANADIAN GOVERNMENT POLICY AND STATUS..................................................................8

4.1 POLICY.............................................................................................................................................84.2 STATUS.............................................................................................................................................9

5 CONCLUSION....................................................................................................................................10

6 References.............................................................................................................................................11

1 Introduction

1.1 Preamble

Earnest O. Lawrence in 1930 invented the cyclotron producing short lived isotopes such as Carbon-11, Nitrogen-13, Oxygen-15 and Flouorine-18 which are still in use today for radio-pharmaceutical. During the Second World War, development in production of short-lived isotopes was delayed due to the shift in the research work towards the development of nuclear weapons. However, some spin-off benefits from the wartime efforts were realized with the development of the rectilinear scanner and the gamma camera that later helped to boost the ongoing work in PET technology.

At the same time, other diagnostic methods were being researched such as X-ray, Computed Tomography (CT), Magnetic Resonance Imaging (MRI), Ultrasonic Tomography (UT). This report provides an overview of the PET scanner as a non-evasive medical diagnostic tool that provides a tomographic image of a body based on its metabolic activity.

1.2 Evolution of PET

In 1951 a feasibility study on the use of positrons for patient imaging was conducted by F.R. Wrenn. Subsequently, in 1953, G. Brownell constructed a device to record the annihilation that occurred when positrons from positron-emitting pharmaceuticals collided with electrons in the human body.

Throughout the 1960s and 1970s, series of research work continued on developing coincidence based detector configuration. Finally in 1974, the development of the PET III the first scanner was spear headed by M.E. Phelps and his colleagues (J. Cox and E. Hoffman). It was a crude scanner and was limited in use for the brain scan only. In 1976, Sokoloff developed the radiopharmaceutical fluorodeoxyglucose with Fluorine-18 (FDG) that provided the groundwork for expanding the scope of PET scanner capabilities.

The main drawback of the PET III was the cost. Cyclotron and the production of short-lived radiopharmaceutical required experienced Physicists and Chemists. During the 1980’s, the cyclotron and its shielding was miniaturized and the production of the positron emitting radiopharmaceutical was automated and block detectors were developed. The advancement in the cyclotron technology allowed trained technicians to operate the equipment. At the same time, two companies namely General Electric and Computer Technology Images were particularly interested in the PET technology and provided the necessary resources to transfer the technology from research application to commercial application. By 1990, the first commercial PET scanner for whole body scan was developed. (Ref. 3)

In late 1990, a shift was made to using a new detector material Lutetium Oxyorthosilicate (LSO) in place of bismuth germinate (BGO). LSO gives a superior image quality in less time, thereby increases the availability of the PET scanner to service more patients. (Ref. 5)

A marked break through occurred in 2000 when D. Townsend, a physicist, and R. Nut, an electrical engineer, combined the CT anatomic information with the functional image of PET in one scanner. This scanner was aptly dubbed the SMART scanner because it can help to identify the location, size and shape of the cancerous region(s) in the body.

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2 Principles of PET

2.1 Basic Nuclear Physics on PET

Positron Emission Tomography (PET) is an imaging methodology for obtaining in vivo cross-sectional images of positron-emitting isotopes that demonstrate biological function, physiology (study of the functions and vital processes of living organisms or their parts and organs), or pathology (conditions, processes, or results of a particular disease).

Positrons (+) are positively charged electrons. They are emitted from the nucleus of some radioisotopes that are unstable because they have an excessive number of protons and a positive charge. To stabilize the nucleus, the excess proton on a radioisotope is converted into a neutron and emits a positron in the process. The positron emitted from a decaying nucleus travels a short distance before colliding with an electron (-) of a nearby atom and the masses are transmuted to two 511-keV -rays that are emitted at 180 ± 0.25° to one another. (Ref. 6)

2.2 Main Components and Scan Process

The PET machine consists of rings of discrete detectors that include scintillation crystals such as bismuth germanate (BGO) or Lutetium Oxyorthosilicate (LSO) coupled to miniature photo-multiplier tubes (Figure 1). When -rays interact with the scintillation crystals, they are converted into light photons. Each detector in a ring is in electronic coincidence with an opposing detector in the same ring. Prior to conducting a PET

scan, the patient is administered an organic compound containing positron-emitting radioisotope by injection, ingestion, or inhalation. Once entered the body, the radioactive organic compound is transported by the bloodstream to areas of high organic compound metabolic rates such as brain tissues, cancerous tissues or cardiac muscles. During the scan, the patient lies flat on a movable table that incrementally passes the patient through the gantry within which the detectors and photo-multiplier tubes are located (Figure 2). As positrons emitted from the radioisotope and the surrounding electrons transmuted to two coincident 511-keV -rays, the detectors record the coincident -rays and send the raw count data to the processing unit for three-dimensional tomographic image reconstruction.

2.3 Metabolic and Labeled Compounds

Table 1 identifies some of the metabolic and labeled compounds used in PET. The principal positron-emitting isotopes that are used in labeled compounds are C-11, N-13, O-15, and F-18. These isotopes typically have short half-lives, which result in low dose to the patient. If the compound of interest is labeled in a known position and it maintains this position or assumes a consistent chemical form, a PET scan can measure trace concentration (uCi/mL) in a volume as small as 0.2 cm³.

Figure 1 PET’s detectors and photo-multiplier tubes

Figure 2 Typical PET scan

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Table 1 Typical Metabolic and Labeled Compounds used in PET Scan

Metabolic Factor Labeled Compound Half-life

Blood volume [11C]carbon monoxide 11C: 20.39 min.

Perfusion [13N]ammonia 13N: 9.96 min.

A-type amino acid transport -[11C]Aminoisobutyric acid 11C: 20.39 min.

L-type amino acid transport L-[11C]Aminocyclopentane-carboxylic acid

11C: 20.39 min.

Glucose metabolism 2-D-[18F]Deoxyglucose 18F: 109.77 min.

Oxygen utilization 15O215O: 2.07 min.

2.4 Cyclotron

From Table 1, it can be seen that the positron-emitting isotopes typically have half-lives ranging from several minutes to less than 2 hours. To ensure adequate supplies of positron labeled compounds for PET imaging, a cyclotron within acceptable travel distance to the PET scanner is required.

A cyclotron is an accelerator for atomic and sub-atomic charged particles. Once injected into the cyclotron from a source, the charged particles are accelerated in a spiral motion caused by powerful magnets. The acceleration of these particles occurs under vacuum to minimize collisions with air and other gases. As they accelerated, the charged particles gradually gain energy and once sufficient energy has been obtained, the electrons are stripped from the charged particles to reveal protons (or in some cases deuterons) that are then fired into a target of special atomic composition. Those nuclei of the target that absorb a proton become radioactive and are known as “radioisotopes”. The choice of target determines the type of radioisotope produced.

2.5 PET Reconstruction Techniques

During the PET scan, data are obtained at multiple positions and angles consistent with the sampling required to achieve a specific resolution. Subsequently, the PET’s reconstruction software takes the coincidence events measured at all angular and linear positions to reconstruct an image that depicts the localization and concentration of the positron-emitting radioisotope within a plane of the organ that was scanned. Raw count data are corrected for:

1) physical decay of the positron-emitting radioisotope,

2) attenuation by water molecules present in the patient,

3) random signals from nearly simultaneous occurrence of two separate decays,

4) scatter signals (a 511 keV photon that undergoes a Compton scatter interaction with the patient or detector shielding before being detected in coincidence with its corresponding back-to-back 511 keV photon),

5) detector inhomogeneities, and

6) dead-time count rate losses due to injected activity producing count rates below the count rate limitations of the scanner.

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After the correction, the raw count data profiles undergo a Fourier transformation to convert these profiles into frequency space where a standard filter is applied to enhance/emphasize a particular frequency range while suppressing others.

The final step in the processing chain of the PET data is to generate graphical images for the diagnosing physician either on the computer display or on the X-ray film.

2.6 Integrated Applications of PET and CT

In the treatment of cancer, Positron Emission Tomography (PET) and Computerized Tomography (CT) complement each other in detecting and pinpointing the location, size and shape of cancer within the body.

Because cancerous cells have significantly higher metabolic rates than normal living cells, the glucose (sugar) that has been “tagged” with a radioactive chemical isotope (generally F-18, or FDG) that was administered to the patient will localize mainly in regions of high metabolic rates (i.e., cancerous regions). Therefore, the PET scan will detect the metabolic signal of actively growing cancerous cells in the body.

Once the cancerous region(s) in the body has been detected by PET, the patient can undergo a CT scan with emphasis on the cancerous regions previously identified by the PET scan. During a CT scan, the scanners send x-rays through the body, which are then measured by detectors in the CT scanner. The signals measured by the CT detectors are processed by a computer algorithm to produce anatomical details of the size and shape of abnormal cancerous growths.

Alone, each imaging technique has particular strengths and limitations, but when the results of PET and CT scans are combined, they provide exceptional image quality and accuracy of diagnostic information with complete information on cancer location, size, shape and metabolism.

Figure 3 and 4 illustrate the power of

combining PET and CT. In Figure 3, the PET image on the right indicates regions in a patient’s spleen where there is high metabolism, and the CT image on the left provides a detailed view of the patient’s spleen. Figure 4 is a fusion of the PET and the CAT images. From Figure 4, the localized tumor location in the spleen (arrow) is apparent in this patient with lymphoma. The green-arrowheads shown in Figure 3 indicate normal physiologic activity in the bowel and kidney.

Figure 1 Separate views of CT (left) and PET (right) of a patient’s spleen with lymphoma

Figure 2 Combined view of CT and PET4

3 Clinical Applications of PET

Positron Emission Tomography Scan is a powerful non-invasive tool that can helps doctors to diagnose and monitor the development of cancers in patients. Because of its ability to provide tomographic imaging of metabolic rates, PET is also used in Cardiology such as coronary artery disease detection, and in Neurology for the detection of Alzheimer's disease, Parkinson's disease, and epilepsy.

3.1 Cardiology

Cardiological uses of PET scans consist of (1) Cardiac Scan Evaluation, (2) Dietary Effects on FDG Metabolism, (3) Parametric Imaging, (4) Polar Maps, (5) Single & Double Vessel Diseases, (6) Myocardial Viability- Match & Mismatch and (7) Ischemic & Idiopathic Dilated Cardiomyopathy or coronary artery disease.

Fig 3 shows the anatomy of the heart that has been obtained as a set of transverse

cross-sectional images. This is a cross-sectional image of a normal heart obtained after the injection of FDG.

Fig 4 shows the re-sliced image that has been obtained from the data set of Fig 3. This image is useful for obtaining short-axis views, so that all portions of the myocardium can be seen distinctly.

3.2 Neurology

PET plays a vital non-invasive role in (1) Pre-surgical assessment of patients with refractory epilepsy (see Fig 5). PET has greatly diminished the need for deep electrode monitoring of the brain, with all its attendant morbidity. (2) PET is the only clear non-persistent method to differentiate between tumor

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Figure 3 PET Image of Heart

Figure 4 Resliced Image of Heart

Figure 5 PET Details showing abnormal activity in right temporal lobe (arrow) of an epileptic patient

reappearance and radiation necrosis in the brain of post-surgical patients. (3) PET provides the earliest positive diagnosis of Alzheimer's Dementia and in differentiating Alzheimer's Dementia from other forms of dementia. All present treatments of Alzheimer's and probably all future ones will require early detection to be effective. PET also contributes to scanning of (4) Neurological Scan Evaluation, (5) Metabolic development of the brain, (6) Development errors, (7) Infantile Spasms, and (8) Parkinson’s disease

Figure 6 shows PET scans of a normal person and on the right hand side a patient with Parkinson’s disease after they were injected with [18F]6-fluoro-L-m-tyrosine. In the figure, the person's nose is towards the top and their left is on the right. The pink color represents the maximum accumulation of 18F, followed by the red, yellow, green and blue.

3.3 Oncology

Cancer is a complex form of disease, however with PET scan, the possibilities include (i) detection of dangerous cancerous tumors (ii) tumor perfusion quantified (iii) evaluate tumor metabolism These enable PET scan to detect cancer at an early stage and evaluate an effective of cancer treatment for the patient. PET scan is beneficial to patients with brain or lung or colorectal cancer, lymphoma and melanoma to name a few. PET can also evaluate oncological function of head and neck, Musculoskeletal System and thorax.

3.4 Case Study

The patient is a 58-year old female with a palpable growth in the base of her tongue. A pre-treatment MRI image (Figure 7) of the patient could not detect the growth in the base of her tongue.

A pretreatment FDG-PET image of the same patient is shown on Figure 8 that revealed increased metabolic activity on the left side of

the tongue (red arrow). Biopsy of the mass disclosed squamous cell carcinoma.

10 weeks after completion of radiotherapy, FDG-PET images (Figure 9) showed symmetrical FDG uptake with no abnormality in the affected area. The patient has remained clinically free of the disease and the mass is not palpable during a physical exam. This situation reveals the sensitivity of FDG-PET in the discovery of small, metabolically active lumps and the utility of PET in determining resolution of lump following treatment

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Figure 6 PET scan of normal brain (Left) and that with Parkinson Disease (Right)

Figure 7 MRI of base of tongue

Figure 8 PET Image of base of tongue (Pre-treatment)

Figure 9 PET Image of base of tongue (Post-treatment)

3.5 PET Accuracy in Cancer Diagnostics

Based on the study conducted in 2001 by University of California, Los Angeles (Table 2), it appears that PET has a higher accuracy in detecting various types of cancer than other conventional imaging techniques.

Table 2 Comparison of Imaging Technique Accuracy in Cancer Diagnostics

Cancer Type Conventional Imaging PET

Breast 67% 89%Colorectal 80% 94%

Gastro-Esophageal 68% 83%

Head and Neck 65% 87%

Liver 81% 93%

Lung 68% 82%Lymphoma 64% 88%Melanoma 80% 91%Pancreatic 65% 81%Testicular 68% 92%Uterine/Cervical 43% 87%

Source: The Journal of Nuclear Medicine Supplement, Volume 42, Number 5, May 2001 and UCLA.

3.6 Limitations and Risks

Infants may require sedation during the imaging procedure till improvements are made to tackle respiratory motion blur.

FDG-PET has a poor spatial resolution which sometimes may lead to false negative results. On going research and advancement in technology will overcome this issue.

Neural activity indication from blood flow PET measurement does not give the precise location of “miswiring” in the brain. PET shows the total connectivity and not the disjointed synaptic connections. Surgery cannot be performed to rectify the “miswiring” if its exact location is unknown. This problem could be overcome by employing, with PET scan, chemical tracers to high light the regions of interest.

The perceived risk of PET is the injection of radioactively labeled drugs. The radiation dose is very low and dissipates in 2 to 24 hours causing no damage to cells or tissue and having no effect on the normal process of the body. Allergic reactions to the drugs are very rare.

The main fear is the psychological effect of ingesting radiation. The amount of radiation dose received from the radionuclide is minimal as compared to the background radiation received from Radon or from a CT scans. Although the dose of the tracer is so small, the choice of PET scans during pregnancy is to be considered in the same manner as any danger associated with radiation treatment.

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In the chemical used for the radio pharmaceutical, the amount of glucose is minimal (about a few licks of a candy). Diabetic are provided with special treatment in the scanning process.

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4 Canadian Government Policy and Status

4.1 Policy

Federal Government:

After several years of debate, on June 10, 2004, Health Canada, issued a policy named “Regulatory Requirements for Positron-Emitting Radiopharmaceuticals”. As its definition, Positron Emitting radio- pharmaceuticals (PERs) are essential components of PET, an in vivo nuclear medicine imaging technology. The manufacture, sale, labeling, or advertising and sale of PERs including that for clinical investigation/drug development is governed by the Food and Drugs Act and its associated Regulations. Therefore, a regulatory framework already exists that applies to PERs. A drugs that is a “radiopharmaceutical” is further defined in section C03.201 of the Food and Drugs Regulations as “a drug that exhibits spontaneous disintegration of unstable nuclei with the emission of nuclear particles or photons”. PERs are those radiopharmaceuticals that emit nuclear particles call positrons. (Ref. 9)

According to this policy, hospitals or academic centres that produce and/or distribute PERs for clinical trial application, must in all cases comply with Division 5 of the Food and Drugs Regulation. In order to comply with Division 5, a clinical trial utilizing a PER must be authorized by Health Canada under the auspices of a Clinical Trial Application. The accessibility of PET technology to Canadians is a task that falls heavily under other jurisdiction, and therefore, beyond the scope of this policy. (Ref. 9)

Quebec:

In March 2001, a report, Positron Emission Tomography in Quebec, was submitted to the Quebec Minister of Research, Science and Technology. This report concluded:

1) Since the clinical efficacy of PET is recognized in many oncological, cardiological, and neurological applications, it would be advised to promote and sustain the deployment of PET for clinical purpose in Quebec’s public health-care system. (Ref. 10)

2) PET scans should be available on a priority basis for the clinical applications with recognized clinical efficacy. These applications should be reviewed periodically as new hard data reflecting the rapid development of relevant information become available. (Ref. 10)

In its report, the Quebec government concluded that PET has proven to be useful in a variety of medical fields, helping to detect certain types of cancer, cardiac disease and neurological disease. The list of recognized clinical applications of PET continues to grow as the research advances.

As a result, Quebec became the first and the only province in Canada that pays for positron emission tomography or PET scans for certain types of cancer at the end of year 2003.

Ontario:

The Ontario Ministry of Health presently classifies the PET technology as experimental. Started in 2002, Ontario launched a series of tests at four hospitals in the province to evaluate the feasibility of PET in the detection and staging of lung, breast, head, and neck cancer and

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several types of lymphoma. When the tests are completed, Ontario's Ministry of Health will decide if the technology should be funded province-wide.

In 2003, the Ontario Ministry of Health gave Ontario Clinical Oncology Group (OCOG) $2.3 million grant to assess the clinical relevance of PET scanning in patients with cancer (Ref. 12). In 2004, another $2.3 million was given to OCOG for trials. (Ref. 13)

Alberta:

Alberta’s acceptance of PET technology appears to follow Quebec closely. Alberta Ministry of Health believes that there is enough evidence to show that PET is a valuable tool. The analysis of what PET technology does best will be done in 2004 and decision will be made in determining how to make it available to the public. It is expected that before the end of 2004, Alberta Ministry of Health will announce who qualifies for a PET scan and how many more PET machines the province will need.

B.C and other provinces:

Presently, there are no government funded PET scans nor any feasibility studies being done.

4.2 Status

PET scan is widely available in the U.S., Japan and Western Europe. In the United States, clinical use of PET is covered by all standard insurance plans as well as Medicaid. Physicians performed 455,000 scans on more than 200 machines across the country last year. The major manufactures of PET are Siemens, CTI, GE, Philips-ADAC and Positron Corporation.

In Canada, PET has primarily been used as a research tool. However, the technology is emerging as a clinical tool. For example, PET scans have been used to detect cancer, stage its extent, examine the effects of therapy, and study myocardial viability. Evaluations of clinical applications are underway in some parts of the country. 13 PET is virtually unavailable to the majority of Canadians.

Across Canada, there were 14 PET scanners in January 2003, up from six in 1997. Most were located in hospitals or affiliated research centres, but one has recently been installed in a freestanding imaging facility in British Columbia and Ontario. Eleven of the 14 scanners installed as of January 2003 can accommodate full-body scanning; the others can only accommodate head scans. The distribution of PET across Canada hospitals and institute roughly is:

Table 3 PET Status in Canada

Quebec Alberta Ontario B.C Others

Location Hotel Dieu Hospital

Montreal General Hospital

Montreal Neurologica Institute (free-standing)

Cross Cancer Institute

CareImaging

McMaster University Medical Centre

London Health Science Centre

St Joseph’s Health Care

Sunnybrook Regional Cancer Centre (PET/CT)

Ottawa Heart Institute (free Standing)

PETScan centre (private)

Policy Approved for certain cancers,

Research Done. Approval for

Experimental, Research/ clinical trial

Private only, wait

Wait and see

10

ban private scanning

Public funded PET eminent

and see

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5 Conclusion

PET is a safe, non-invasive technology that can tell if a tumor is benign or cancerous and can diagnose disease often before it shows up in other test (MRI, CT, X-ray or UT). Based on the measurement of metabolic rates, PET can provide information on the extent of the cancer, thereby assist doctors in determining the treatment best suited for patients. Invasive procedures required during follow up care will be reduced with the knowledge obtained from PET scans. Early results are promising especially in hard to assess cancer care. The biology of the tumor can be categorized so they can predict /diagnose metastasis early enough for effective treatment. Combined application of PET with conventional imagery such as CT or MRI has been established to be an effective mean of locating and determining the size and shape of tumors.

The low levels of radiation in the short lived radioactive tracer have not been known to have any adverse effects to cells. Current research suggest that, like all exposure to ionizing radiation (including background), there might be a small increase in the long-term risk of inducing cancer, but this is thought to be far outweighed by the potential health benefits of the early diagnosis.

The two biggest barriers is the cost and technical complexity, hence the Canadian governments hesitation to fund PET. Ongoing research and advancement of the PET technology is expected to uncover the many potential benefits of PET, making it a powerful tool by itself or when used with other imaging technologies.

In summary, the use of PET scan, despite its cost, contributed to the high level of medical diagnostic care in nuclear medicine. PET contributes to bridge the gap between molecular biology and pathology and also help in the design of new drugs. As PET technology evolves, the cost of PET scanner is expected to reduce thereby making it available to a wider population of patients.

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6 References

1) Positron Emission Tomography: An Introduction. GE Medical System.

2) Wright KL. Oncology: Clinical PET facility returns to M.D.Andersan Cancer center

3) Brice J. Award winners confirm imaging’s essential role in medical practice. Diagnostic Imaging Online.

4) Hinton W. Planning for PET. Gene Burton and associates.

5) Valk P. LSO detection technology. CPS innovations.

6) Encyclopedia of Medical Devices and Instrumentation, John G. Webster, 1988.

7) Let's Play PET, UCLA School of Medicine, Crump Institute for Molecular Imaging.

8) Michael E. Phelps, Positron emission tomography provides molecular imaging of biological processes, Proceedings of the National Academy of Sciences USA. 2000 August 1; 97 (16): 9226–9233.

9) Health Canada Policy, June 10, 2004, Regulatory Requirement for Positron-Emitting Radiopharmaceuticals

10) Report, 2001, Positron Emission Tomography in Quebec

11) Canadian Institute for Health Information, 2003, “Medical Imaging In Canada”

12) Ontario Clinical Oncology Group, Newsletter, 2003, “New PET Scanning Trial”

13) Ontario Clinical Oncology Group, Newsletter, 2004, “New PET Scanning Trial”

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