18F-fluorodeoxyglucose (18F-FDG) Positron Emission Tomography in Oncology
Condition: Brain Neoplasms; Lung Neoplasms; Lymphoma; Melanoma; Colorectal Neoplasms
MeSH terms: Neoplasms; Colorectal Neoplasms; Lung Neoplasms; Brain Neoplasms
Study type: Observational

Summary: 
      Positron emission tomography (PET) is a nuclear medicine procedure based on the measurement
      of positron emission from radiolabelled tracer molecules. These radiotracers allow biologic
      processes to be measured and whole body images to be obtained which demonstrates sites of
      radiotracer accumulation. The most common radiotracer in use today is 18F-fluorodeoxyglucose
      (18F-FDG) which is a radiolabelled sugar (glucose) molecule. Imaging with 18F-FDG PET is used
      to determine sites of abnormal glucose metabolism and can be used to characterize and
      localize many types of tumours.

      Cancer treatment and outcome depend largely on the accurate diagnosis and staging of disease.
      There is extensive data in the literature indicating the importance of FDG-PET imaging in
      accurately characterizing disease, as well as determining stage and sites of recurrent
      disease in many cancer types. For these indications, functional imaging with PET provides
      unique information which is not available from standard medical imaging modalities such as
      ultrasound, X-ray, computerized tomography (CT) or magnetic resonance imaging (MRI).

      The objectives of this study are to document the safety and efficacy of 18F-FDG produced by
      the British Columbia Cancer Agency (BCCA) at its Tri-University Meson Facility (TRIUMF)
      production facility and to evaluate FDG-PET as a diagnostic and decision making tool in the
      management of oncology patients in British Columbia. With a population base of over 4 million
      people, standardized cancer treatment protocols, and evidence based guidelines for FDG-PET
      imaging, the BCCA is positioned to make an important contribution to defining the role of PET
      in the Canadian health care system.
    

Detailed description: 
      1.0 Background & Introduction

      In general, diagnostic imaging can address two issues: structure and function. One can either
      view structures in the body and image anatomy using structural imaging modalities such as
      plain film radiography (X-ray), Computerized Tomography (CT) and Magnetic Resonance Imaging
      (MRI), or one can view chemical processes and image biochemistry and function using
      biochemical imaging modalities such as Planar and Single Photon Emission Computerized
      Tomography (SPECT) imaging and Positron Emission Tomography (PET). The strength of the
      biochemical imaging methods is in distinguishing tissues according to metabolism rather than
      structure.

      18F-Fluorodeoxyglucose (FDG) is the most commonly used tracer for PET imaging; its use and
      safety are well established world wide. The 18F-FDG is injected intravenously and is
      transported from blood to tissues in a manner similar to glucose. It has been understood for
      over 50 years, that cancer cells, in general, have increased glucose uptake and anaerobic
      metabolism compared to normal tissues. Like glucose, FDG is taken up into cells through
      glucose transport proteins (GLUT) and then phosphorylated by hexokinase to FDG-6-phosphate.
      However, since FDG-6-phosphate is not a substrate for subsequent glucose metabolic pathways
      and has a very low membrane permeability, the FDG-6-phosphate becomes trapped in tissue in
      proportion to the rate of glycolysis. This accumulation of 18F-FDG-6-phosphate forms the
      basis of tumor metabolic imaging with PET.

      2.0 Indications

      Cancer treatment and outcome depend largely on the accurate diagnosis and staging of disease.
      There is extensive data in the literature indicating the importance of PET imaging in
      accurately characterizing disease, determining stage and sites of recurrent disease in many
      cancer types. For these indications, it is well documented in the literature that functional
      imaging with PET exceeds sensitivity, specificity and accuracy of conventional 3-D imaging
      modalities. The most widely cited reference for the efficacy of PET imaging is: A Tabulated
      Summary of the FDG PET Literature, published by Gambhir et al, JNM (2001) 42: 1S-93S. In this
      study the average FDG PET sensitivity and specificity across all oncology applications are
      estimated at 84% (based on 18,402 patient studies) and 88% (based on 14,264 patient studies),
      respectively. The average management change across all applications is estimated to be 30%
      (based on 5,062 patients). Data was obtained combining 419 total articles and abstracts on
      studies in which FDG PET was used. Various methods of analysis were applied to these data,
      which revealed only a small amount of variation in the ratio values. Specifically, the
      sensitivity of PET ranged from 84 - 87%, the specificity ranged from 88% - 93%, and the
      accuracy ranged from 87 - 90%.

      In the United States, the Food and Drug Administration (FDA) has approved 18F-FDG for use in
      all cancer types. On January 28, 2005 the Centers for Medicare and Medicaid Services (CMS)
      announced that it would reimburse PET imaging studies when performed for almost all
      previously non-covered oncology indications. All previous PET coverage remained fully in
      effect, and initial staging of cervical cancer was added without conditions but coverage was
      expanded conditionally to include all cancers and non-covered indications except breast
      cancer diagnosis and regional lymph node staging.

      (http://www.cms.hhs.gov/mcd/viewncd.asp?ncd_id=220.6.15&ncd_version=1&basket=ncd%3A220%2E6%2E
      15%3A1%3APET+%28FDG%29+for+All+Other+Cancer+Indications+Not+Previously+Specified)

      The indication for performing this diagnostic imaging test is the need for non-invasive,
      functional assessment of patients suspected of having or previously diagnosed with:

        -  Lymphoma

        -  Colorectal cancer

        -  Breast cancer

        -  Esophageal cancer

        -  Head & neck cancer

        -  Melanoma

        -  Brain tumors

        -  Cervical cancer

        -  Testicular (Germ Cell) cancer

        -  Thyroid cancer

        -  Lung cancer

        -  Sarcoma

      3.0 Study Objectives

      Objectives of this study are to validate the safety of 18F-FDG produced by BCCA and to
      evaluate 18F-FDG PET as a decision making and diagnostic tool in the management of oncology
      patients in British Columbia. With a population base of over 4 million people, standardized
      cancer treatment protocols, and evidence-based guidelines for PET imaging, the BCCA is
      positioned to make an important contribution to defining the role of PET in the Canadian
      health care system.

      4.0 Study Design

      This will be a single cohort observational study design in which additional safety data will
      be collected from the first patient being scanned from each of the first three batches of
      18F-FDG delivered to our clinical site. Data will be collected from referring physicians with
      respect to how the PET scan results affected patient management and results of the PET scan
      will be correlated with biopsy results when available. All subjects are informed of
      anticipated effects (none) and purpose of the injected substance. There is no intent to
      change the way this protocol is conducted or to in any way alter the effect or purpose of the
      injected tracer. Subjects are approached with respect to their willingness to participate in
      the proposed study based on clinical criteria and undergo a brief clinical assessment
      followed by scanning as outlined below.

      5.0 Study Time-Frame

      The B.C. Cancer Agency anticipates a start date in June 2005 and a potential completion date
      in August of 2015, at which time our on-site (Vancouver Cancer Centre) radiopharmacy and
      cyclotron will be operational. Ten years of data collection will provide meaningful numbers
      for analysis and support of an 18F-FDG New Drug Submission (NDS) to Health Canada.

      6.0 Patient Population and Sample Size

      A total of 40,000 patients will be entered into the study. This number is based on the
      anticipated number of PET scan referrals based on the criteria for study inclusion outlined
      below and our clinical capacity of 15 to 35 patients per day operating 220 days per year.
      This will be the only publicly funded PET program in the province of British Columbia. A
      sample size of 40,000 patients will allow the PET program in BC to operate until Phase B of
      the Functional Imaging Program is implemented and the BCCA is positioned to submit an NDS for
      18F-FDG.

      Assuming a response rate of 90% to the patient management survey and a change in patient
      management for 30% of the study participants, precision for the 95% confidence interval of
      the estimated proportion will be .013. Given the same response rate and change in patient
      management proportion, a tumour site with 100 patients will yield a precision of .089 for its
      95% confidence interval.

      A sensitivity (or specificity or accuracy) rate of 80% can be estimated for the full sample
      with a precision of .011 for its 95% confidence interval, or a precision of .080 for a
      sub-sample of 100.

      Additional safety data will be collected from the first patient imaged from each of the first
      three batches of FDG delivered to our clinical site (N=3). The chemical structure of our
      product is identical to authentic FDG. We have performed a minimum of five consecutive
      18F-FDG productions with all quality control passing and will have done many more in the
      course of this CTA review process. The safety record of FDG PET worldwide is undisputable and
      we expect the number of adverse events in our study to be zero. In addition to baseline
      assessment, these subjects will have their blood pressure, oxygen saturation, heart rate and
      temperature monitored every 15 minutes for 2 hours post-procedure. Patients will be
      questioned as to their general well-being after the scan. If there are concerns that the
      patients' health status has changed during or immediately following the scan, then a
      physician will provide a more detailed assessment. Each of these three patients will be
      followed up by telephone, usually the day after the scan to help insure there were no delayed
      effects. These whole body PET scan images will be reviewed independently by two Nuclear
      Medicine physicians to confirm an expected biodistribution of radioactivity. If a subject did
      experience a reaction post-injection that could not immediately be attributed to another
      condition or exposure, or if the biodistribution of FDG in normal tissue was altered and
      could not be explained on clinical grounds (eg. patient on G-CSF), the tracer would be
      re-examined and tested for impurities and pyrogens. The safety data collected from these
      three patients will verify that the FDG produced by the BCCA is behaving as expected.

      Patients considered appropriate for participation in this protocol are drawn from a
      population made up of the following parameters:

        -  Patients are between the ages of 19 and 90 years, although exceptions to these numbers
           may be made depending on the individual's ability to understand, give assent/consent,
           and tolerate the procedure. Health Canada can expect a separate CTA submission from the
           BCCA within the next few months for FDG-PET indications in the pediatric oncology
           population.

        -  Patients are both female and male and of any race with no preference for any group over
           another.

        -  Patients are those who are suspected of having or who have been previously diagnosed
           with cancer and meet BCCA evidence-based guidelines for FDG-PET.

      7.0 Inclusion Criteria

        -  Age 19 years or older.

        -  ECOG performance status 0 - 3.

        -  Able to provide written informed consent.

        -  Referred by a treating physician.

        -  Must meet BCCA Evidence-Based guidelines for FDG-PET in Oncology

        -  Patients must be able to tolerate the physical/logistical requirements of completing a
           PET scan including lying flat for up to 45 minutes and tolerating intravenous
           cannulation for injection.

      8.0 Exclusion Criteria

        -  Patients' blood glucose > 11.1 mmol/L (200 mg/dL) measured by glucometer immediately
           prior to scan.

        -  Pregnancy.

        -  Patients unable to provide informed consent.

        -  Patients who are medically unstable eg. acute cardiac or respiratory distress,
           hypotensive

        -  Patients who exceed the safe weight limit of the PET/CT bed (204.5 kg) or who cannot fit
           through the PET/CT bore (diameter 70 cm).
    

Intervention name(s): Positron Emission Tomography
Intervention type(s): Procedure
Intervention description(s): Each patient will receive an 18F-FDG PET/CT scan
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Oncology patients in British Columbia who meet the eligibility requirements.