Review of F-18 Fluoro-2-Deoxyglucose (F-18 FDG) Positron Emission
Tomography in the Evaluation of Malignancy-February 19, 1998

Florence Houn MD MPH FACP

I.  Introduction

This is a primary medical review of F-18 fluoro-2-deoxyglucose (F-18
FDG) radiopharmaceutical used in positron emission tomography (PET) to
determine abnormal glucose metabolism to assist in evaluating malignancy
in patients with abnormalities found by other testing modalities or in
patients with an existing diagnosis of cancer.

Positron emission tomography radiopharmaceuticals have been evaluated
and approved by the Food and Drug Administration (FDA) for use as
diagnostic imaging agents. Typically, PET radiopharmaceuticals have a
short physical half-life and they are manufactured using local
cyclotrons or generators. In addition, many of the manufacturers of PET
radiopharmaceuticals are located in hospitals and clinics, thus
differing from the traditional pharmaceutical and device manufacturers
that FDA regulates. In addition, many academic institutions have
developed several PET radiopharmaceuticals. FDA has been working with
the PET community to develop appropriate criteria and procedures to
evaluate PET products for safety and effectiveness. On November 21,
1997, the President signed the Food and Drug Administration
Modernization Act (FDAMA) into law. Section 121 of FDAMA requires FDA to
develop procedures under subsections (b) or (j) of section 505 (21 USC
355) for the approval of PET radiopharmaceuticals. FDA believes at this
time that it could support the approval of some commonly used PET
radiopharmaceuticals under section 505(b)(2) of the act (21 CFR
355(b)(2)).

There have been articles about F-18 FDG radiopharmaceutical used for
oncology imaging since the 1980s. F-18 FDG PET has been approved by the
FDA "for the measurement of regional glucose metabolism in human brain
to assist in the diagnosis of seizures." PET allows the measurement of
in vivo glucose metabolism with F-18 FDG, a positron-emitting
radiopharmaceutical. Under steady state conditions, F-18 FDG is taken up
by cells in competition with other sugars. Once inside cells, F-18 FDG
is phosphorylated by hexokinase. This phosphorylation results in a polar
entity that cannot diffuse out of the cell. The entity can be
dephosphorylated to F-18 FDG by glucose 6 phosphatase, but
dephosphorylation occurs slowly. The cellular concentration of F-18 FDG
is therefore closely representative of the accumulation of F-18 FDG and
of the glycolytic activity of exogenous glucose. The amount that
accumulates in the tissue over a specific period of time allows for the
calculation of the rate of glucose uptake by that tissue. Accelerated
glycolysis and decreased ability to make energy aerobically are features
of malignant cells as well as epileptogenic brain cells. These features
cause high rates of glucose uptake required to sustain the cells. Uptake
by malignant cells is facilitated by increased expression of the glucose
transporter molecules, GLUT1 through GLUT5, at the tumor cell surface.
Increased levels and activity of hexokinase and other glycolytic enzymes
are present in cancer cells. In cancer cells, which commonly lack or
have relatively low levels of glucose 6 phosphatase, dephosphorylation
of the polar entity occurs relatively slowly compared to non-cancerous
cells. Use of F-18 FDG PET in oncology is based on the differential
rates of glucose metabolism in benign and malignant tissues. However,
F-18 FDG uptake is also accelerated during inflammatory processes, such
as with infections, granulomas, abscesses, and other processes, leading
to false-positive results and lower specificity. Moreover, the uptake of
F-18 FDG varies greatly for different tumor types. High uptake on an
image is usually associated with a high number of viable tumor cells,
high expression of GLUT1 and GLUT3, and an increase in activity of
several glycolytic enzymes, such as hexokinase, phosphofructokinase, and
pyruvate dehydrogenase. Of note, lung cancer has among the highest
expressions of GLUT1 while renal cell carcinoma has the lowest.

F-18 FDG PET scanning in oncology has several important features. It is
minimally invasive, only requiring an intravenous injection. It
differentiates lesions based on a biochemical process, namely increase
glucose metabolism, rather than non-specific anatomical criteria
(primarily size and location) provided by computerized axial tomography
(CT) or magnetic resonance imaging (MRI). Finally, there are
mathematical models to quantify metabolic activity and actual
three-dimensional radioactive bio-distribution objectively, rather than
use of visual interpretation.

For anatomical areas of focal interest already detected by another
imaging modality, PET scanning of those areas can be performed to assess
metabolic activity. As an example, abnormal anatomy from fibrosis can be
differentiated from metabolically hyperactive malignant lesions. Or, in
cases when serial tumor markers show elevation in monitored cancer
patients, PET may be able to identify areas of hypermetabolic activity,
allowing focused use of anatomical imaging with CT or MRI.

Localized scan allows for attenuation correction to optimize image
quality. Many studies also utilized a semiquantitative measurement
called the standardized uptake value (SUV). This is a ratio of measured
radioactivity concentration in a lesion (or area of interest) to the
estimated body tracer concentration, assuming a uniform distribution
throughout the entire body volume. The use of lean body weight or body
surface area, rather than total body weight, has been investigated by
some because the distribution of F-18 FDG in the body is not uniform
with higher uptake in muscle tissue than fat. Correction for serum
glucose has also been explored. Because SUV values may change with time
after F-18 FDG injection due to variable and unknown tumor kinetics
related to tracer uptake, the time of image acquisition after F-18 FDG
injection must be standardized across institutions to compare results.
In addition, this might be problematic because the SUV from one
institution will vary from another institution depending on type of
scanning device.

The current Agency recommendation for evaluating the diagnostic
effectiveness of radiopharmaceuticals for imaging is to conduct studies
with an external reference standard of truth such as histopathology.
Also, other imaging modalities can be used as active controls, such as
MRI and CT. All F-18 FDG PET oncology studies that are in this review
contain biopsy information to derive sensitivity and specificity as
measurements of F-18 FDG PET performance in detecting malignancy.
Sensitivity and specificity are diagnostic efficacy measures that are
not dependent on prevalence of disease in a tested population. For this
reason, this review does not discuss positive and negative predictive
values of studies, as these are prevalence-dependent. Sensitivity and
specificity, however, do vary depending on the test population (what
types of cancer in the population, what concomitant conditions the
patients have, such as diabetes, which may affect the test, etc..)
Evaluating the prospective performance of a new diagnostic modality is
based on the initial classification of abnormality by conventional
standards. This process does not allow the new technology to assess
cases that are not picked up by conventional methods such as CT or MRI.
The literature has many studies of these tests' sensitivities and
specificities using pathology as a standard of truth. Defining the PET
study population prospectively based on abnormalities on CT, MRI, or
other modalities such as chest x-ray, precludes performance evaluation
of PET in patients who may be false-negatives by conventional testing.
While agreement of F-18 FDG PET results with those of CT or MRI in the
reviewed studies is useful information, no attempt has been made by this
review to comment on superiority of test performance. It should also be
noted that comparisons between CT or MRI scans and PET imaging may not
be appropriate as these other modalities provide anatomical data usually
stated as size and location, as opposed to biochemical metabolic data
provided by PET imaging.

This review of F-18 FDG PET literature serves as the clinical and
statistical evaluation of the peer-reviewed scientific literature
regarding the effectiveness and safety of F-18 FDG PET imaging for
determining abnormal glucose metabolism to assist in evaluating
malignancy in patients with abnormalities found by other testing
modalities or in patients with an existing diagnosis of cancer. Because
of the publicly available safety and effectiveness data documenting the
product's use cited in this review, safety and effectiveness
requirements of section 505(b)(2) of the act (21 USC 355(b)(2)) and part
314 (21 CFR part 314) for this product and this use may be met by citing
the docket number (Docket No.\_\_\_\_\_\_\_\_) of this review.

II\. Evaluation of the Effectiveness Data for F-18 FDG PET Imaging in
Oncology

A.  Data Sources

FDA's Center for Drug Evaluation and Research (CDER) conducted a
literature search of the recent peer-reviewed, medical journals to
evaluate F-18 FDG PET effectiveness data in oncology. Search criteria
included: full studies (not abstracts) published from January 1990 to
July 1, 1998 identified as human clinical trials with F-18 FDG in PET,
written in English, found by searching on-line databases of Medline,
Cancerlit, Derwent Drug File, Biosis Preview, International Pharmacology
Abstracts and Embase. Review articles on F-18 FDG PET imaging were
identified using the same criteria in the Cochrane Database for Systemic
Reviews and Cochrane Controlled Trials Register. Finally, FDA solicited
references from the PET community on F-18 FDG from any time period
published in peer-reviewed journals.

The search generated about 150 articles involving clinical trials with
F-18 FDG in oncology. Of these, the medical reviewer selected
prospective studies that allowed comparison of F-18 FDG PET imaging
results to pathology or an external reference standard. Other articles
were obtained using the reference sections of the primary articles
identified in the above searches. Only articles that had a study
population of greater than fifty, were controlled, prospective studies,
and had enough detail about PET imaging (dosage of radiopharmaceutical,
imaging acquisition, and image analysis) were included in this review.
The criteria of having fifty or more subjects in a study was chosen to
provide more confidence in study's estimate of PET performance efficacy.
Studies with fewer patients were reviewed (but not included in this
writing) and their results did not differ substantively from findings of
the larger study. Single studies with more than fifty patients and
multiple endpoints, such as use of F-18 FDG in managing patients who
underwent different types of treatments, or evaluating outcomes for
different stages of cancer, etc., were not reviewed unless there were
more than fifty patients in each strata (treatment group, stage, etc.)
to evaluate multiple outcomes. Moreover, the study hypothesis had to
pertain to evaluating F-18 FDG PET for accuracy of anatomical
definition, clinical diagnosis, or efficacy of management, therapy, or
outcomes for patients. Hypotheses related to experimental investigations
such as cellular growth rates, SUV exploratory data analysis, or
biochemical functionality were not reviewed. Finally, if multiple
articles were published by collaborating authors on the same or nearly
the same data set within 12 months, the article with the larger study
population was reviewed.

In all, 16 articles are included in this review of effectiveness.

B.  Published Literature

1\. Adequate and well-controlled studies. These published trials allowed
FDA to assess the effectiveness F-18 FDG PET imaging to determine
abnormal glucose metabolism to assist in the evaluation of malignancy in
patients with abnormalities found by other testing modalities or in
patients with an existing diagnosis of cancer by having the following
components in the trial design: there was comparison between F-18 FDG
PET and a "truth" standard for malignancy, namely pathology results; the
study population was prospectively enrolled; the entry criteria defined
the target clinical population in which F-18 FDG PET was intended to be
used; there were clearly defined endpoints; detailed data on findings
were presented; and there were procedures to minimize interpretation
bias, such as masking (also referred to as blinding) or randomization or
multiple independent readers.

*Lowe VJ, Fletcher JW, Gobar L, Lawson M, Kirchner P, Valk P, Karis J,
Hubner K, Delbeke D, Heiberg EV, Patz EF, Coleman RE. Prospective
investigation of positron emission tomography in lung nodules. J Clin
Oncol 1998;16:1075-1084.*

This is a prospective, multi-center trial to evaluate the sensitivity
and specificity of F-18 FDG PET imaging in evaluating solitary pulmonary
nodules. The study centers were the St. Louis University Health Sciences
Center, Missouri, Creighton University Medical Center, Nebraska, Good
Samaritan Hospital, St. Joseph's Hospital, Phoenix, AZ, University of
Iowa Hospitals and Clinics, Iowa, Northern California Positron Emission
Tomography Center, Los Angeles, California, University of Tennessee at
Knoxville Medical Center, Vanderbilt Medical Center, Tennessee, Duke
University Medical Center, North Carolina. This study enrolled 89
patients from October, 1993 to August, 1994.

[Inclusion Criteria]{.underline}: Consecutive patients with solitary
pulmonary nodules between 0.7 cm and 4.0 cm in size were considered
eligible. Lesions less than 0.7 were not included, because this was the
limit of resolution of the PET scanner. The nodule had to be seen on CT
and the nodule had to be considered indeterminant for malignancy by
conventional modalities (chest x-ray and CT scan). The study group
included 61 men and 28 women with a mean age of 63 [+]{.underline}9.5
years.

[Dose]{.underline}: After fasting for at least 4 hours, 370 MBq of F-18
FDG was injected and emission scans were initiated after 55 to 65
minutes.

[Schema of Trial]{.underline}: Comparison of visual interpretation of
F-18 FDG PET, semiquantitative SUV analysis, and histology to determine
sensitivity and specificity.

[Image Protocol]{.underline}: PET image acquisition and reconstruction
information is presented. Transmission scans were performed for
attenuation correction. Chest x-rays and chest CT imaging parameters
were stated.

Visual analysis of PET was performed independently by three nuclear
medicine physicians. They interpreted studies with which they were not
involved clinically to ensure masking of clinical history and
radiographic and CT results. PET scans were interpreted once by each of
the two independent readers for a total of two independent readings per
scan. PET scans were interpreted as positive or negative for malignancy.
The readers were presented film copies of PET images for interpretation.
Abnormalities with uptake greater than the mediastinal blood were
considered positive for malignancy. Disagreement was resolved by
consensus of the two readers. Results from the readers were compared and
a kappa value was calculated to assess interobserver variability. The
calculated kappa was 0.95, which is excellent agreement.

Chest radiographs and CT scans were interpreted independently by
pulmonary radiologists at two sites; studies conducted at one of the
sites were read at the other site. The interpreting physicians were
masked to clinical information of the cases. Abnormalities were graded
as definitely benign (an exclusion criteria) or indeterminate.

Those studies not meeting the study criteria of indeterminate were
excluded (4 studies).

Semiquantitative PET analysis involved placement of circular regions of
interests within the visible margins of the uptake and contained the
most intense activity. Analysis was performed by a physician at each of
the centers who was unaware of clinical data. Region of interest data
were then sent to the study's central site, Duke University, for
analysis. After correction for radioactive decay, SUVs were computed. An
SUV greater than 2.5 was considered indicative of malignancy.

[Primary Endpoints]{.underline}: Visual interpretation, SUV, histology
via surgery or transthoracic needle aspiration.

[Results]{.underline}: A total of 105 patients from 9 PET centers were
thought to be eligible. Of these 8 had no pathology results, 2 had
indeterminate pulmonary nodules in regions of the lung which are not
imaged by PET, 4 did not meet study criteria for indeterminant, and 2
did not have CT scan results available. Data from the remaining 89
patients were evaluated. Histopathological results of sixty of the 89
solitary pulmonary nodules were malignant and 29 were benign.
(Prevalence of malignancy was 67%.) Sixty patients underwent surgery and
29 patients underwent transthoracic needle aspiration to obtain biopsy
material. Individual patient data was published for all cases, which
included sex, age, visual reading, SUV, size of lesion, location, and
histology.

Fifty of the 60 histopathologically confirmed malignancies were primary
non-small cell lung cancer. The other histopathologies were 5 cases of
melanoma, and one case each of Hodgkin's lymphoma, small-cell lung
cancer, malignant neural tumor, malignant carcinoid, and colon cancer
metastasis. The benign findings were 7/29 granuloma, 7/29
coccidiomycosis, 4/29 benign cellular debris, 4/29 non-specific
inflammation, 3/29 necrotizing granuloma, 1/29 fibrosis, 1/29
hemangioma, 1/29 aspergillosis, and 1/29 metaplasia.

Visual analysis of PET-FDG in reference to histopathology provided a
sensitivity of 98% (59/60)(95% confidence intervals presented in the
article: 95-100%) and specificity of 69% (20/29) )(95% confidence
intervals presented in the article: 957-81%). SUV data generated a
sensitivity of 92% (55/60) and a specificity of 90% (26/29).

Detailed results stratified by visual and SUV analysis as well as by
nodule size were provided in a table. For single pulmonary nodules of
[\<]{.underline}1.5 cm (34 or 89 lesions) the sensitivity and
specificity of SUV and visual analysis were 80% and 95% and 100% and 74%
respectively.

[Safety Issues]{.underline}: No safety issues were mentioned in the
study.

[Commentary]{.underline}: This study is a multi-centered, masked study
of F-18 FDG PET visual interpretation. It also used a prospectively
determined SUV as a cutoff for malignancy to determine comparative
performance of SUV versus visual interpretation for F-18 FDG PET test
accuracy. This study presented detailed patient information and included
explanations of masking, tracking of inter-observer performance in
determining regions of interests, readings done twice by independent
observers per image, and CT image handling.

All patients had tissue diagnoses but the study excluded 16 patients who
were originally enrolled, from the analyses. No long term follow to
ensure accuracy of negatively classified subjects. In this study, the
number of cancers were twice as numerous as benign finding, which may
not fully challenge F-18 FDG PET's performance in the non-cancer
patients. Finally, the confidence intervals for sensitivity and
specificity were calculated using the normal theory, however, the sample
size being limited, justifies use of the exact method. Using the exact
method, the reported visual sensitivity of 98% has 95% confidence
intervals of 91-100% and visual specificity of 69% has 95% confidence
intervals of 49-85%.

Carr R, Barrington SF, Madan B, O'Doherty MJ, Saunders CAB, van der Walt
J, Timothy AR. Detection of lymphoma in bone marrow by whole-body
positron emission tomography. Blood 1998;91:3340-46.

This study of 50 patients performed at the United Medical and Dental
Schools of Guy's and St. Thomas's, London, United Kingdom determined
whether the increased marrow uptake of F-18 FDG PET observed in some
lymphoma patients during routine staging PET scans represented marrow
involvement by disease.

[Inclusion Criteria]{.underline}: Fifty consecutive patients with
Hodgkin's lymphoma or non-Hodgkin's lymphoma who were staged before
treatment by both PET and bone marrow biopsy were prospectively
enrolled. Staging determines treatment decisions and prognosis. Routine
lymphoma staging consisted of thoracic and abdominal CT scan, whole-body
F-18 FDG-PET, and unilateral iliac crest marrow aspirate and trephine
biopsy at this study facility. All patients had their PET scans
performed within 4 weeks of the marrow biopsy.

[Dose]{.underline}: After 6 hours of fasting, patients were injected
with 350 MBq of F-18 FDG and imaged 30 to 45 minutes later.

[Schema of Trial]{.underline}: Comparison of pathology results and PET
readings.

[Image Protocol]{.underline}: Acquisition and reconstruction were
discussed. The intensity and distribution of the F-18 FDG activity
within the marrow was visually scored by three nuclear medicine
physicians independently. The marrow was assumed to be abnormal where
the uptake was equal to or greater than uptake of the liver, provided
the liver uptake was greater than background. The pattern of increased
uptake was also noted, with patients who appeared to have focal disease
only within the marrow differentiated from those with diffusely abnormal
marrow changes. The kappa statistic was used to measure interobserver
variability to assess the reproducibility of the visual method used to
assess marrow disease on PET. Where there were differences in reporting
between observers, if two reporters concurred this was taken as the
final PET report.

Handling of biopsy specimens was discussed, including staining
techniques, preparation, and histologic criteria. The marrow biopsy
samples were examined for lymphoma infiltration by two hematologists and
a histopathologist, masked to the PET scan results. Classification
system was identified.

[Primary Endpoints]{.underline}: Marrow aspirates and F-18 FDG PET
results were primary endpoints.

[Results]{.underline}: F-18 FDG PET sensitivity was 81% (13/16) and
specificity was 76% (26/34) for detecting bone marrow involvement of
lymphoma using unilateral bone marrow biopsy as a standard of truth.
Discordant cases were discussed with pathological findings. There was
complete agreement between the three observers in 76% (22/29) of scans
showing normal marrow uptake and 71% (15/21) of scans showing abnormal
uptake. The kappa statistic was 0.64 showing good correlation.

[Safety Issues]{.underline}: No safety issues were mentioned.

[Commentary]{.underline}: This study combined Hodgkin's Disease patients
and non-Hodgkin's patients, which may not be appropriate as the
different diseases have different estimates of bone marrow involvement
in untreated patients. (Also see Moog, 1998.) This study provided
details about histology evaluation and interobserver variation of
interpretations of F-18 FDG PET. The study's protocol involved masking
pathologists and 3 independent readings by nuclear medicine physicians.
The study stated the criteria used for visual interpretation of
increased F18 FDG uptake. The study did not present 95% confidence
intervals for sensitivity and specificity. Using the exact method, the
reported visual sensitivity of 81% has 95% confidence intervals of
54-96% and visual specificity of 76% has 95% confidence intervals of
59-89%. No long-term follow-up was mentioned as a means of ensuring
accuracy of negatively classified patient. The study also suggests that
low-grade non-Hodgkin's lymphoma may have no increased F-18 FDG uptake.
Therefore, more studies are needed.

2.  Supportive studies. These studies supported the use of

F-18 FDG PET for determining abnormal glucose metabolism to assist in
evaluating malignancy in patients with abnormalities found by other
testing modalities or in patients with an existing diagnosis of cancer.
These studies may not have been masked to other imaging modalities or
had main hypotheses different from evaluating F-18 FDG PET accuracy
(such as determining retrospectively optimal SUV for receiver operating
characteristic curves).

Avril N, Dose J, Janicke F, Sense S, Ziegler S, Laubenbacher C, Romer W,
Pache H, Herz M, Allgayer B, Nathrath W, Graeff H, Schwaiger M.
Metabolic characterization of breast tumors with positron emission
tomography using F-18 fluorodeoxyglucose. J Clin Oncol 1996;14:1848-57.

This study of 51 women was conducted at the Universitat Munchen, Munich,
Germany. The purpose was to evaluate the diagnostic value of PET in
differentiating between benign and malignant breast tumors.

[Inclusion Criteria]{.underline}: Patients with abnormal mammography or
palpable breast tumors who were scheduled to undergo surgery were
eligible for enrollment. Patient selection was based on the availability
of PET imaging. Patients were excluded based on pregnancy, diabetes, or
younger than age 18. Patients with prior history of breast surgery
within the last 3 months, as well as those with chemotherapy or
radiation therapy, were excluded. Fifty-one women were enrolled in the
study.

[Dose]{.underline}: After fasting for at least 4 hours before PET
imaging, patients were injected with 270-390 (about 10 mCi) of F-18 FDG.
Patients were studied in the prone position with foam rubber well for
each breast. Emission scans were obtained from 40-60 minutes after
injection.

[Schema of Trial]{.underline}: Fifty-one patients underwent PET imaging
with qualitative image analysis before exploratory surgery. Quantitative
image evaluation using SUV was performed using PET images identified
with regions of interest placed over all histologically proven breast
lesions to determine regional F-18 FDG uptake. Only tumors greater than
1 cm in diameter were included in quantitative analyses. The analyses
were presented by tumor data, not patient data.

[Image Protocol]{.underline}: Emission data was corrected for dead time
and attenuation. Reconstruction was described. For quantitative
analysis, regions of interests were drawn retrospectively as circles
exactly around the histologically determined tumors to calculate SUV.
For lesions that appeared with focally increased tumor, the circle was
drawn exactly around the tumor. Reproducibility of circle positioning
was studied in a subset of 20 patients with a correlation coefficient
for interobserver variability of r=0.91. Intra-observer variability was
0.96. For lesions that could not be clearly identified by increased FGD
activity, the surgeon's report was additionally used to position the
circle. Partial volume correction was used for lesions with focally
increased F-18 FDG uptake using the tumor size obtained from histologic
examination. For qualitative analysis, two observers without information
on the patient's clinical history or prior clinical or technical
examinations visually analyzed PET images. Suspected areas of abnormal
F-18 FDG uptake in breast tissue were recorded. Regional uptake was
classified using 3 categories: unlikely, probable, or definite malignant
tissue. If regional F-18 FDG uptake was within the background activity
of normal breast tissue, PET scans were considered as unlikely. In cases
of focally marked increased F-18 FDG uptake, the scans were read as
representing malignancy. All PET scans with diffuse or moderately
focally increased F-18 FDG uptake were considered as probable malignant
tissue. A consensus interpretation was reached for each patient.

[Primary Endpoint]{.underline}: Qualitative visual analysis of PET
images was performed. SUV were calculated for all histologically
confirmed breast tumors. Only tumors greater than 1 cm in diameter were
included in SUV analysis. The ability of F-18 FDG to differentiate
between benign and malignant breast tumors was determined by calculating
the areas under the receiver operating characteristic curve based on
quantitative F-18 FDG SUV and partial-volume corrected SUV for tumors
greater than 1 cm. One pathologist using World Health Organization
classification analyzed all tissue specimens.

[Results]{.underline}: In 51 patients, a total of 72 breast tumors were
confirmed by histology, including 41 breast cancers and 31 benign breast
tumors. Size of tumors ranged from 0.3 to 9.0 cm, with a mean diameter
of 2.5 cm. Pathology findings included: for benign tumors, 23 mammary
dysplasia (75%), 5 fibroadenoma (16%), 1 each of ductal adenoma, fat
necrosis, and inflammatory tissue (3% each); for malignant lesions, 3 in
situ carcinoma (7%), 25 invasive ductal carcinoma (25%), 9 invasive
lobular carcinoma(22%), 4 miscellaneous breast carcinoma (10%).

On visual interpretation by physicians, PET had a sensitivity of 83%
(34/41) and a specificity of 84% (26/31) if "probable malignant"
readings were classified as positive.

Using quantitative analysis, malignant tumors (n=41) had a mean SUV of
3.3 [+]{.underline}1.8 (range 0.4 to 9.5), whereas in benign breast
tumors (n=31), the mean SUV was 1.4[+]{.underline}0.5 (range 0.3 to
2.3). This difference was statistically significant (P\<0.01). Receiver
operating characteristic curve analysis exhibited a sensitivity of 75%
and a specificity of 100% at a threshold SUV of 2.5. Sensitivity for
detection of small breast cancers (less than 1 cm in diameter) was
limited.

[Safety Issues]{.underline}: There was no mention of adverse events
reported with F-18 FDG administration.

[Commentary]{.underline}: This study had 51 patients with 72 lesions
undergoing biopsy. The data are presented by lesions and not analyzed by
patient. The numbers of benign and malignant lesions were fairly
comparable, allowing for F-18 FDG PET assessment over a spectrum of
breast lesions. There was partial masking of the readers during the
quantitative assessment of SUV in order to capture regions of interests
that correlated with histology. Visual interpretation was performed
under masked conditions.

Bury T, Dowlati A, Paulus P, Corhay JL, Hustinx R, Ghaye B, Radermecker
M, Rigo R. Whole-body 18-FDG positron emission tomography staging of
non-small cell lung cancer. Eur Respir J 1997;10:2529-2534.

This study from Liege, Belgium is a prospective study of 109 patients to
compare the accuracy of whole-body F-18 FDG PET and conventional imaging
methods for the staging of non-small cell lung cancer.

[Inclusion Criteria]{.underline}: Between September 1994 and October
1996, whole-body F-18 FDG PET and conventional imaging methods using
chest and abdominal CT and bone scans were performed to determine tumor
staging in 141 consecutive patients with newly diagnosed non-small cell
lung cancer. If a lesion was suspected by bone scan, confirmation was
obtained by bone x-ray. The analysis was performed on 109 patients who
had all test modalities and final histology results. There were 77 men
and 32 women (mean age 64, range 44-83).

[Dose]{.underline}: 200-300 MBq F-18 FDG was injected by way of an
antecubital vein in patients in a fasting state (the length of fasting
was not stated) and images were obtained 60-90 minutes after injection.

[Schema of Trial]{.underline}: Comparison of pathology results to PET
readings and conventional imaging modalities for metastatic work up
(bone scan and CT).

[Image Protocol]{.underline}: Acquisition and reconstruction of images
was described in the study. PET data were analyzed by visual
interpretation of coronal, sagittal, and transverse slices alone and in
cross-referenced situations. When PET or conventional imaging study
suggested mediastinal or extrathoracic metastatic disease, confirmation
was obtained by biopsy or standard radiological follow-up. For PET
images, nuclear physicians evaluated the images. When F-18 FDG PET
uptake increase was observed, two levels were identified in comparison
with normal activity: moderate (more or less twice the activity in a
contralateral or reference region) or intense (markedly higher than the
reference activity). These two levels of activity were considered
positive for metastasis. PET and conventional imaging were interpreted
separately and the results were than compared to each other and in
certain cases, with the histologic information.

Bone scans and CT images were read independently by two nuclear medicine
physicians and by two radiologists respectively. These readers had no
knowledge of the histological diagnosis of the primary tumor. When the
two readers did not agree, they reviewed the images together to reach a
consensus.

[Primary Endpoints]{.underline}: Surgical specimens were obtained within
21 days of the first of two examinations (PET or conventional imaging)
in all patients. PET visual interpretation and conventional imaging
interpretations were also primary endpoints. Mediastinal status and
metastasis status were analyzed.

[Results]{.underline}: One hundred nine patients had thoracotomy (61
patients), nodal biopsy of a distant site (39 patients), mediastinoscopy
(5 patients), and in four patients the primary tumor invaded mediastinal
structures and were classified as T4 although they did had no distant
metastases and did not undergo surgical verification. In the absence of
imaged metastatic disease, patients were evaluated regularly by imaging
and absence of clinical disease for 6 months after negative imaging was
accepted as evidence against metastasis. Final staging was: stage I, 32
patients; stage II 8 patients; stage III 30 patients; and stage IV 39
patients.

For mediastinal staging, only 66 patients underwent invasive exploration
of the mediastinum. F-18 FDG sensitivity was reported as 89% (95
confidence limits 72-96%) and specificity 87% (71-96%) for these 66
patients. For CT, the sensitivity was 79% and the specificity was 71%.

For metastasis evaluation for all 109 patients, PET had a sensitivity of
100% (91-100%) and specificity of 94 % (86-98%). CT had a sensitivity of
82% and a specificity of 86%.

[Safety Issues]{.underline}: No safety issues were mentioned.

[Commentary]{.underline}: The study mentions that brain metastasis were
not routinely assessed because it required a dedicated brain acquisition
and prolonged the procedure by 20-30 minutes. The study did not mention
how many readers read each PET image, whether readers were masked,
whether inter- and intra-variability of interpretation were tracked, and
how F-18 FDG PET images were evaluated. Confidence intervals for
sensitivity and specificity presented in the study reflect acceptable
performance. Nevertheless, the vast majority of patients had
histological data obtained and the performance of F-18 FDG PET could be
evaluated for mediastinal (local regional metastasis) and distant
metastasis detection.

Delbeke D, Martin WH, Sandler MP, Chapman W, Wright Jr K, Pinson W.
Evaluation of benign vs malignant hepatic lesions with positron emission
tomography. Arch Surg 1998;133:510-516.

This study included 97 patients and was performed at Vanderbilt
University Medical Center in Nashville, Tennessee. The main purpose was
to assess the value of F-18 FDG PET to differentiate benign from
malignant hepatic lesions.

[Inclusion Criteria]{.underline}: One hundred ten consecutively referred
patients with hepatic lesions 1 cm or larger on screening CT scan who
were seen and evaluated for potential resection underwent PET imaging.
There were 60 men and 50 women with a mean age of 59 [+]{.underline}14
years.

[Dose]{.underline}: After at least 4 hours of fasting, intravenous
administration of 370 MBq (10 mCi) of F-18 FDG was performed, then
emission scan began 68 [+]{.underline}33 minutes (mean [+]{.underline}
SD) later.

[Schema of Trial]{.underline}: F-18 FDG PET scan and biopsy, surgery, or
both were performed to assess sensitivity and specificity.

[Image Protocol]{.underline}: All PET images were correlated with a CT
scan of the abdomen to provide localization of lesions. However, the
investigators were unaware of the previous interpretation of the CT
scan. The PET images were interpreted visually, and the F-18 FDG uptake
in the lesions classified as follows: poor (same or less than liver
background), equivocal (mildly increased compared with normal liver
background), or definite for malignancy (more than twice the
radioactivity of normal liver background). The images were also analyzed
semiquantitatively using both the lesion-to-normal liver background
(L/B) ratio and the SUV. Regions of interest suspect for malignancy
measuring 1.0 [+]{.underline}0.5 cm2 (mean [+]{.underline}SD) were drawn
over the areas of maximum activity within the lesion. The region of
interest for the liver background was placed in a normal area of the
liver.

[Primary Endpoint]{.underline}: Endpoints were PET scan imaging
interpretation, biopsy or surgery results (providing pathological
samples within 2 months of PET imaging), and SUV and L/B ratio.
Correlation of these endpoints was determined.

[Results]{.underline}: On histopathology, there were 97 patients with
malignant lesions (6 of these 97 patients also had benign lesions) and
13 patients with 15 benign lesions. The malignant lesions included
metastases from colon cancer (n=53), pancreatic cancer (n=3), esophageal
cancer (n=1), cancer of unknown origin (n=6), sarcoma (n=2), and adenoid
cystic carcinoma of the parotid (n=1) in 66 patients, cholangiocarcinoma
in 8 patients, and hepatocellular carcinoma in 23 patients. The benign
lesions were 2 adenomas, 3 fibronodular hyperplasia, 1 cavernous
hemangioma, 1 biliary cyst, 1 simple cyst, 1 hamartoma, 1 hematoma, 6
regenerating nodules, 4 benign postoperative sites, and 3 granulomatous
abscesses.

Visual interpretation of F-18 FDG PET yielded readings of 87/97 (90%)
malignant lesions and 22/23 (96%) benign lesions.

The SUV for malignant lesions was 7.8[+]{.underline}4.5, significantly
higher than that obtained for benign lesions (2.0 [+]{.underline}1.7;
P\<0.001).

[Safety Issues]{.underline}: No adverse safety events were reported.

[Commentary]{.underline}: There were more malignant lesions than benign
lesions in this study, suggesting FDG PET's ability to differentiate
benign from malignant lesions may not have been fully tested.
Nevertheless, viewed in conjunction with Schiepers (1995) (see page 30),
the specificity of F-18 FDG PET in liver evaluation is supported. All
patients had pathological diagnoses. CT scan was used for localization
purposes in this study and while CT interpretations were not provided,
this may have biased readers. Ideally, sequential unmasking may be
useful in future protocols. However, in clinical practice, radiologists
would be able to use data from all previous diagnostic testing when
interpreting PET, so use of CT scans in this study in consistent with
intended use of PET. There is no statement about how many readers read
each PET image, or how inter or intra-variability was tracked.

Dietlein M, Scheidhauer K, Voth E, Theissen P, Schicha H. Fluorine-18
fluorodeoxyglucose positron emission tomography and iodine-131
whole-body scintigraphy in the follow--up of differentiated thyroid
cancer. Eur J Nucl Med 1997;24:1342-48.

This study of 58 patients was conducted at the University of Cologne,
Germany. F-18 FDG PET, I-131 whole-body scintigraphy, and pathology were
compared in patients with a diagnosis of thyroid cancer.

[Inclusion Criteria]{.underline}: Fifty-eight consecutive, unselected
patients (43 women, 15 men; aged 19-72 years, median 45 years) with
differentiated thyroid cancer underwent thyroidectomy and radioiodine
ablation or radioiodine therapy. Forty-five of the 58 patients had
received the first I-131 application for ablation of thyroid remnants 3
months previously. The other 13 patients were examined 6 months to 2
years after radioiodine ablation. Patients with a papillary
micro-carcinoma or diabetes mellitus were not included in the study.
From February 1995 to May 1996 FDG PET, I-131 whole-body scan, MRI, and
ultrasound of the neck examinations were carried out, along with
thyroglobulin levels monitored. All examinations were carried out within
the same week.

[Dose]{.underline}: After fasting over 12 hours, with blood glucose
levels before PET scans below 100 mg/dl, emission scans were obtained.
Then a dose of 370 MBq F-1 FDG was injected intravenously. The study did
not state what time elapsed prior to acquisition of emission scans.

[Schema of Trial]{.underline}: F-18 FDG interpretative results were
compared to I-131 results and histologic diagnosis.

[Image Protocol]{.underline}: All imaging studies (I-131 whole body
scans and F-18 FDG PET, and others) were evaluated prospectively by two
experienced observers without knowledge of prior examinations. Any
disagreement was resolved by consensus.

[Primary Endpoints]{.underline}: F-18 FDG PET scan interpretations,
I-131 interpretations, and histology.

[Results]{.underline}: Thirty-eight patients presented with papillary
carcinomas, 15 patients with follicular carcinomas, and five patients
with variants of follicular carcinoma. For the detection of metastases,
F-18 FDG PET was found to have a sensitivity of 50% (14/28) and a
specificity of 97% (29/30). For I-131 whole body scans, the sensitivity
was 61% (17/28) and specificity was 100% (30/30). If F-18 FDG PET had
been limited to patients with an elevated thyroglobulin level in
hypothyroidism (after thyroid-stimulating hormone (TSH) suppressive
therapy withdrawal) and a negative I-131 scan, then the complete status
would have been diagnosed correctly in 23 of 28 patients.

[Safety Issues]{.underline}: No safety issues were reported.

[Commentary]{.underline}: This study did not present detailed
information on the imaging protocol, interpretative criteria, how
masking was done in relation to different imaging modalities, and
information about how pathology data were acquired. F-18 FDG sensitivity
was lower than I-131 scan sensitivity. Post-hoc analysis revealed a
greater sensitivity in patients with elevated thyroglobulin level when
hypothyroid after TSH suppression withdrawal and a negative I-131 scan,
but this was not part of the original hypothesis.

Friess H, Langhans J, Ebert M, Beger HG, Stollfuss J, Reske SN, Buchler
MW. Diagnosis of pancreatic cancer by 2\[18-F\]-fluoro-2-deoxy-D-glucose
positron emission tomography. Gut 1995;36:771-777.

This study of 80 patients and 10 controls from the University of Berne,
Switzerland and the University of Ulm, Germany was a masked study to
evaluate the ability of F-18 FDG PET to confirm the presence of cancer
in patients with histologically confirmed pancreatic cancer and to
define its specificity in patients with histologically confirmed chronic
pancreatitis.

[Inclusion Criteria]{.underline}: All patients admitted to the hospitals
for elective pancreatic surgery and consented to the study were
included. Eighty patients entered the prospective trial between February
1992 and November 1993. In addition, 10 controls (patients without
gastrointestinal disease) were enrolled.

[Dose]{.underline}: Patients were injected with 250-350 MBq after
fasting for at least 6 hours. Acquisition and image reconstruction was
presented. The patient was injected intravenously with furosemide (20
mg) and was instructed to urinate as often as possible to avoid
unnecessary exposure of the bladder and to reduce measurement artifact
caused by radioactivity in the urinary collection system. Forty-five
minutes after F-18 FDG administration, emission scans were recorded.

[Schema of Trial]{.underline}: Comparison of interpretations of F-18 FDG
PET images, SUV, and histology results to determine sensitivity and
specificity and receiver operating characteristic curve.

[Image Protocol]{.underline}: Transmission scans were recorded to permit
correction for photon attenuation. In preliminary studies without
diuretic, image quality was reduced. This data was not presented in the
study. The patients had to leave the measurement area to urinate. Upon
return they were carefully repositioned in the gantry using
laser-supported markings. The authors estimated this led to a
misalignment of maximum 1 cm in all directions, which in turn would
cause an error of [+]{.underline}20% in the calculation of SUV assuming
a change of 2cm in the diameter of the target volume. Images of
transverse, coronal, and sagittal slices were evaluated by two
independent observers who had no prior knowledge of the patients'
clinical status. Pancreatic cancer was assumed if an intense focal
activity accumulation was detected in the pancreatic region that
exceeded the activity concentration in the liver. Circular regions of
interest were drawn on the hot spots of the pancreas, corresponding
regions of the head of the pancreas in patients without focal pancreatic
activity, and the control regions. The size of the circles was about
1500 pixels. SUV was calculated. Additional control regions in the
skeletal muscle group of the back were chose for the calculation of
tumor/background ratios.

CT scans were performed between 4 and 14 days before surgery. There was
no statement on how these images were handled.

[Primary Endpoint]{.underline}: Sensitivity and specificity of F-18 FDG
for detecting pancreatic cancer in suspicious patients. Comparison of CT
results to PET and histology.

[Results]{.underline}: Group I was comprised of 42 patients (30 male and
12 female; median age 60.5) with pancreatic cancer confirmed at the time
of surgery. Group II was comprised of 6 patients (3 male and 3 female;
median age 58.5) with periampullary cancer histologically confirmed at
the time of surgery. Group III had 32 patients (27 male and 5 female;
median age 50) with chronic pancreatitis confirmed by pathology. The 10
controls did not have surgery. No correlation between F-18 FDG uptake
(SUV) and tumor/background ratio with plasma glucose was found. Follow
up in patients with chronic pancreatitis (7-25 months) after surgery did
not disclose any false diagnosis.

F-18 FDG PET identified 41/42 patients with pancreatic cancer and 4/6
with periampullary carcinoma, giving an overall sensitivity of 94% for
detection of pancreatic cancer. There were 3 false-negative PET scans in
this group of 48 patients with cancer. F-18 FDG scans were read as
negative for cancer in 28/32 patients who had chronic pancreatitis,
giving a sensitivity of 88%. The remaining 4/32 were read as
false-positive. The standard uptake value of the patients with
pancreatic cancer was significantly higher than for patients with
chronic pancreatitis (3.09 [+]{.underline}2.18 versus
0.87[+]{.underline}0.56 SUV, P\<0.001) but the difference between cancer
patients' mean SUV (3.09 [+]{.underline}2.18 SUV) and controls' SUV
(0.73 [+]{.underline}1.02 SUV) was not statistically significant, as the
standard deviation for the ten controls is wide.

CT scan identified 33/42 patients with pancreatic cancer and 2/6 with
periampullary carcinoma, giving an overall sensitivity of 73%. CT had a
specificity of 69% (22/32).

[Safety Issues]{.underline}: Radiochemical purity was 98.5%
[+]{.underline}0.7%, the specific activity was greater than 10,000
Ci/mmol.

[Commentary]{.underline}: The selection of subjects was appropriate. The
controls were patients with chronic pancreatitis. This diagnosis is the
leading differential diagnosis for patients with suspected pancreatic
carcinoma. The patients all had pathological diagnoses to correlate with
imaging results. F-18 FDG performance in differentiating these controls
from cancer cases is important to define and the study results show
acceptable accuracy. Masking was performed for qualitative
interpretation. Reading methodology was not well-described for the 2
independent readers and there was no evaluation of inter- and
intra-observer variability for PET images and CT interpretations. A
detailed line listing of all 80 patients was provided with demographic
data, stage (if applicable), CT, PET SUV, tumor background ratio, and
operation performed were presented in the study. The study also
commented that in preliminary data that were not presented, without
diuretic treatment there was poor image quality and analysis because of
the urinary system collection of excreted F-18 FDG. More data on use of
furosemide and its potential affect on F-18 FDG imaging is needed
because of it's known affects on serum glucose levels and glycolysis.

Gupta NC, Maloof J, and Gunel E. Probability of malignancy in solitary
pulmonary nodules using fluorine-18-FDG and PET. J Nucl Med
1996;37:943-948.

This study was conducted at the West Virginia University Hospital to
assess radiographically indeterminant pulmonary nodules for malignancy
in 61 patients.

[Inclusion Criteria]{.underline}: Sixty-one patients (16 women, 45 men;
aged 24-89; mean age 65) presented for evaluation of indeterminant
solitary pulmonary nodule 0.6-3.0 cm in size. With the exception of one
patient, all solitary pulmonary nodules were noncalcified and considered
indeterminant on the bases of the prior tests.

[Dose]{.underline}: After fasting for at least 4 hours prior to PET
imaging, 10 mCi of F-18 FDG was intravenously injected and image
acquisition began one hour after injection.

[Schema of Trial]{.underline}: Determination of sensitivity and
specificity of F-18 FDG PET.

[Image Protocol]{.underline}: All patients had chest x-rays and thoracic
CT scans that were interpreted independently before the PET study.
Transmission scanning was performed prior to F-18 FDG administration for
attenuation correction. All subjects underwent two acquisitions to
include the entire lung in the field of view. Images were analyzed
qualitatively using visual analysis for focal areas of increased F-18
FDG uptake in both lungs' field and mediastinum by two experienced
observers. Images in the transverse, coronal and sagittal vies were
reviewed for the presence of focal abnormalities. The emission images
were also superimposed over transmission scans for anatomic correlation.
Semiquantitative analysis, to compute the SUV, was performed in all
patients by drawing a region of interest 0.8cm2 over the solitary
pulmonary nodule on the transaxial images. The interobserver variability
to calculate SUV by drawing circles for regions of interests was \<5%.
Average counts per pixel in the region of interest were used to compute
the SUVs. The circle was drawn over the hottest region in the nodule. In
some patients, no nodules could be detected on the PET scans, so the
circle was drawn in its location as extrapolated from the chest x-rays
or CT scans. The counts were normalized to the patient's body mass and
the injected dose.

[Primary Endpoints]{.underline}: Final diagnoses were established by
obtaining tissue from thoracotomy (n=43), percutaneous transthoracic
needle aspiration biopsy (n=13) or bronchoscopy (n=4). One subject who
showed no change in nodule size for a period of 2 years was presumed to
have a benign nodule.

[Results]{.underline}: Forty-five patients had malignancies. Forty-two
of the 45 patients had a diagnosis of bronchogenic carcinoma (22
adenocarcinoma, 9 squamous-cell, 7 non-small cell, and 4 small-cell).
There were also 2 patients with melanoma and one with a teratoma. Six of
the 61 patients had a prior history of cancer (2 breast, 2 melanoma, 1
prostate, and 1 lung). Five of these 6 patients also had malignant
solitary pulmonary nodules.

Histology revealed benign lesions in 15 patients; one patient was
presumed to have a benign lesion after 2 years of follow up. The benign
lesions included 6 granuloma, 4 histoplasmosis, 2 nonspecific
inflammation, 1 carcinoid, and 1 pneumonia. The carcinoid nodule was
included in the benign group because on follow up, the clinical behavior
of the carcinoid nodule was benign.

Using qualitative analysis, 42/45 (93%) malignancies were identified by
PET (there were 3 false negatives) and 14/16 (88%) benign lesions were
identified (there were 2 false positives).

Semiquantitative SUV indices ranged from 0.12 to 3.38 in benign nodules.
For malignant nodules the values were 0.9 to 13.11. The mean values for
benign nodules was 1.15 [+]{.underline}0.98 as compared to 6.28
[+]{.underline}3.247 in malignant nodules. This was a statistically
significant difference.

[Safety Issues]{.underline}: No safety issues were mentioned in the
study.

[Commentary]{.underline}: All patients except one had a diagnosis based
on tissue specimens. While the numbers of benign cases were fewer than
malignant cases, taken with the other lung cancer studies, the
estimation of specificity of F-18 FDG PET is supported. The study made
attempts to study inter-observer variation in identifying delineating
regions of interest. For qualitative F-18 FDG PET image assessments, the
readers were not masked to findings of conventional imaging evaluation.
They were masked to histologic data. SUV data was determined
retrospectively. This study, along with Lowe (1998), support the use of
PET in evaluating indeterminant chest x-rays and CT scans of solitary
pulmonary nodules.

*Holder Jr. W, White RL, Zuger JH, Easton Jr. EJ, Greene FL.
Effectiveness of positron emission tomography for the detection of
melanoma metastases. Annals of Surg 1998;227:764-771.*

This study of 76 patients from Carolinas Medical Center, North Carolina
determined the sensitivity and specificity of F-18 FDG total body PET
scanning for the detection of metastases in patients with malignant
melanoma.

[Inclusion Criteria]{.underline}: The first 103 PET scans at the site
done on 76 non-randomized patients having AJCC stage II to IV melanoma
were included. Sixty-three of the 76 patients were derived from an
immunotherapy protocol, which required whole-body PET, CT (oral and IV
contrast) and MRI for staging. The remaining thirteen patients had PET,
CT, and MRI for clinical evaluations, but were not part of a protocol.
There were 52 males and 24 females; mean age was 55.1 years (range, 26
to 81). Histology or cytology was obtained on at least one lesion in
patients with positive CT or PET scan. Patients with a fasting glucose
value of over 100 mg/dl were excluded or restudied after appropriate
diabetic treatment.

[Dose]{.underline}: After a solid food fast of at least 4 hours,
patients were hydrated with 16 to 24 ounces of water within 4 hours
before the examination. An intravenous adapter was placed into the
patient for intravenous injections of F-18 FDG and furosemide. All
patients were given 10 mg of oral diazepam before the F-18 FDG injection
to reduce potential muscle activation artifacts. A dose of 444 to 740
MBq (12 to 20 mCi) of F-18 FDG was given using the PRN adapter. At the
end of 50 minutes, 10 mg intravenous furosemide was administered to
reduce excessive renal and bladder activity. After voiding twice in the
next 20 minutes, the emission images were acquired.

[Schema of Trial]{.underline}: Results of F-18 FDG PET visual
interpretation were compared to biopsy or cytology results. The PET
results were also compared to CT results.

[Image Protocol]{.underline}: Image acquisition and reconstruction was
stated in the study.

Two radiologists reviewed the images immediately after completion of
each study to determine technical image quality. Qualitative assessment
was performed while reading from the monitors. The images were
manipulated and displayed and processed into transverse, coronal,
sagittal, and normalized whole-body projection and volume views. PET
scans were compared to CT images in a non-masked manner. Interpretations
were rendered.

[Primary Endpoints]{.underline}: Visual interpretation of F-18 FDG PET
studies, CT results, and histology or cytology.

[Results]{.underline}: AJCC stages of the patients were: 28 stage II, 28
stage III, and 20 stage IV.

Of the 103 scans, 100 were evaluable. The sensitivity of PET scanning
for the detection of melanoma metastases was 49 of 52 cases (94%) and
specificity was 40 of 48 cases (83%).

CT scans were considered false negative if they failed to identify all
lesions detected by PET scanning. Because not all PET identified lesions
were biopsied, CT results were not considered by this medical reviewer

A table summarizing PET and CT scan results relative to biopsy results,
sites of positive tests was presented.

[Safety Issues]{.underline}: The study stated each lot of F-18 FDG was
analyzed to confirm radionuclide, radiochemical, and chemical purity as
well as sterility and pyrogenicity.

[Commentary]{.underline}: This study's endpoint of comparing PET to CT
was not appropriate because it used F-18 FDG PET results as a standard
of truth. Therefore, this review only considered the results of F-18 FDG
PET and histology. The study only presented results by scan and not by
patient. F-18 FDG PET scans were read with CT scans, which may have
biased PET readings. There is no mention of how the two readers decided
on a single interpretation and there was not accounting of inter- and
intra-reader variability. As with Friess (1995), intravenous furosemide
was used, but no data is presented on this drug's affect on F-18 FDG
imaging despite the drug's known affects on glycolysis and serum glucose
levels.

Lowe VJ, Hoffman JM, DeLong DM, Patz Jr. EF, Coleman RE.
Semiquantitative and visual analysis of FDG-PET images in pulmonary
abnormalities. J Nucl Med 1994;35:1771-1776.

This study of 88 patients from the St. Louis University Medical Center,
Missouri prospectively analyzed F-18 FDG PET images in patients with
pulmonary abnormalities to evaluate use of SUV or qualitative visual
interpretation. The study concluded that SUV and visual interpretation
were both accurate methods of F-18 FDG PET data analysis in
differentiating malignant from benign focal pulmonary abnormalities.

[Inclusion Criteria]{.underline}: Between November 1991 and March 1993,
107 patients found to have radiologically indeterminant focal pulmonary
abnormalities were referred to F-18 FDG PET imaging. Ninety-three
patients had a definitive diagnosis made by histology, but 5 patients
were excluded from the analyses because their PET data was not
retrievable or there were technical problems related to patient
positioning. Four patients had type II diabetes.

[Dose]{.underline}: After fasting at least 4 hours, 10 mCi of F-18 FDG
was injected intravenously and emission images were obtained 30 minutes
after injection.

[Schema of Trial]{.underline}: Comparison of SUV versus visual
interpretation of F-18 FDG PET scans for pulmonary lesions using
receiver operating characteristic curve analysis.

[Image Protocol]{.underline}: Transmission scans were performed on all
patients either prior to injection of F-18 FDG or prior to emission
image acquisition. Acquisition and reconstruction were described. A
nuclear medicine physician and a chest radiologist used CT and chest
radiographs to locate abnormalities on F-18 FDG PET images. The
physicians were masked to biopsy results. Regions of interest were
placed over the most intense area of F-18 FDG activity
(2.7[+]{.underline}1.4 cm2). After correction for radioactive decay, the
regions of interests were analyzed by computing SUVs. No partial volume
correction was applied.

Two nuclear medicine physicians masked to biopsy results and anatomical
data were shown transmission and emission scans. They visually compared
transmission and emission image abnormalities. They individually graded
the images depending on their confidence of malignancy based on their
knowledge of normal F-18 FDG update within the thorax on a five-point
scale with 5= definitely tumor, 4= probably tumor, 3=equivocal,
2=probably not tumor, and 1= definitely not tumor. They also graded
lesions compared to mediastinum uptake on a five-point scale with 5\>\>
mediastinum, 4\> mediastinum, 3= mediastinum, 2\< mediastinum, and 1\<\<
mediastinum. Anatomical information from chest x-ray and CT was given to
the nuclear medicine physicians who then individually regraded the PET
studies. On review, if the two readers did not concur on their grading
of the lesion, the readers discussed their differences and reached a
consensus interpretation. Receiver operating characteristic curves were
then generated for the different techniques of evaluation using a
nonparametric approach.

[Primary Endpoints]{.underline}: SUV in abnormal regions of interest and
normal regions of the lung were calculated. SUV of \>2.5 was considered
positive. Visual interpretation graded on a 5-point scale was obtained
(4 or 5 considered positive for malignancy). F-18 FDG uptake in the
abnormality was also visually graded in comparison to mediastinal
activity. Biopsy information was obtained for a definitive diagnosis.
Receiver operating characteristic curves were generated.

[Results]{.underline}: Of the 88 patients with biopsy information, 61
had malignancy and 27 patients had a benign finding. Seventy-eight of
the 88 patients had well-defined abnormalities on conventional imaging
with 72 of the 78 being pulmonary nodules of [\<]{.underline}4 cm.
Diagnoses were made by bronchoscopy, transthoracic thin-needle
aspiration, thoracotomy, or, in one patient, radiographic stability for
over 8 years.

The area under the receiver operating curve characteristic for SUV was
0.96 (95% confidence interval 0.91 to 1.0) and for visual analysis by
consensus reading was 0.96 (95% confidence interval 0.90 to 1.0). Both
readers had performance of visual interpretation tracked and comparison
revealed excellent agreement. Tracking was also done on reader
performance with and without anatomic information provided at the time
of F-18 FDG PET interpretation. Results of the performance were
presented in a table and revealed no difference of performance when
using or not using chest x-rays and CT scans for localization of
abnormalities for each reader.

Of the four patients who had diabetes (all type II), all were correctly
identified by SUV and visual interpretation.

[Safety Issues]{.underline}: The study mentions F-18 FDG was tested for
sterility, pyrogenicity, and radiochemical purity on each production
run.

[Commentary]{.underline}: This study provided information on visual
interpretation and SUV accuracy. Of note, the authors studied use of
visual information with and without anatomical data to assist in
locating abnormalities found on conventional imaging. Because many
studied used conventional imaging to locate lesions, this has been
raised as a possible mechanism that would bias readers. This study
presented detailed information on the affect of anatomical information
for each reader's interpretation of the probability of tumor and on F-18
FDG activity relative to mediastinum activity on the area of the
receiver operator characteristic curve. The affect appears to have been
minimal for the study's readers.

One consistent weakness that is reflected in this study and others is
that a significant SUV to define malignancy was derived retrospectively
rather than tested has a hypothesis.

Moog F, Bangerter M, Kotzerke J, Guhlmann A, Frickhofen N, Reske SN.
18-F-fluorodeoxyglucose-positron emission tomography as a new approach
to detect lymphomatous bone marrow. J Clin Oncol 1998;16:603-9.

Bone marrow biopsy of the iliac crests is the standard for diagnosing
bone marrow involvement with malignant lymphoma. However, its
sensitivity is less than optimal. This study of 78 patients from the
University of Ulm, Germany, investigated the efficacy of F-18 FDG PET as
a new method to evaluate bone marrow involvement in patients with
malignant lymphoma.

[Inclusion Criteria]{.underline}: Between July 1992 and October 1996, 78
consecutive patients with biopsy-proven and untreated lymphoma were
prospectively enrolled into the study. Thirty-nine patients had
Hodgkin's lymphoma, 18 patients had nodular sclerosis, 18 had mixed
celluarity, and 3 had lymphocyctic predominance. The remaining 39
patients had non-Hodgkin's lymphoma. The 42 women and 36 men ranged in
age from 7 to 73 years. All patients were examined with F-18 FDG PET and
bone marrow biopsy (70 bilateral and 8 unilateral) within 3 weeks
(median 8 days) before therapy.

[Dose]{.underline}: Patients fasted for at least 8 hours before the
examination. A mean dose of 270 MBq (range, 250 to 350 MBq) was injected
intravenously. Static emission scans were taken 50 to 60 minutes after
injection.

[Schema of Trial]{.underline}: Comparison of visual analysis of F-18 FDG
PET images and iliac crest biopsies.

[Image Protocol]{.underline}: Acquisition and reconstruction were stated
in the study. Attenuation correction was performed. Patients were
repositioned using laser-guided landmarks for emission and transmission
scans. Evaluation of PET images was performed by masked and independent
visual interpretation by two board-certified nuclear medicine
physicians. Transaxial, coronal, and sagittal sections were reviewed on
film. In individual cases, additional evaluation on the monitor was
performed with alteration of the gray scale. Any foci with significant
increase in F-18 FDG uptake in comparison with the surrounding bone
marrow were considered suspect for lymphoma. These visual findings were
graded on a three-point scale as "mild," "moderate," or "marked."
Malignancy was defined as all "marked" cases and "moderate" cases with
increased size, asymmetry, and irregular shape. Quantitative analysis of
F-18 FDG uptake was not performed. The final diagnosis was determined by
consensus of both observers. Bone marrow biopsies and F-18 FDG PET
images were evaluated masked to each other.

To clarify the 10 negative biopsy/positive F-18 FDG PET findings, four
patients underwent a second biopsy, one patient underwent a polyermase
chain reaction, and two cases underwent MRI, and 3 cases did not undergo
dispute resolution or further work up.

[Primary Endpoints]{.underline}: Primary endpoints were diagnosis on
iliac crest biopsies and PET visual interpretations.

[Results]{.underline}: There were 78 patients who had F-18 FDG PET
finding compared with bone marrow biopsy. Seven of eleven patients who
had a positive bone marrow biopsy had a positive F-18 FDG PET scan
giving a sensitivity of 64%. Fifty-seven of sixty-seven patients who had
negative biopsies had negative F-18 FDG PET scans giving a specificity
of 85%. The study goes on to present data on the 10 patients who had a
negative bone marrow biopsy but positive PET scan. These discordant test
results underwent further testing or clinical examination to reveal 8 of
the 10 having marrow involvement.

Patient information is presented for all F-18 FDG PET positive and
biopsy positive patients.

[Safety Issues]{.underline}: No safety issues were reported in the
study.

[Commentary]{.underline}: This study, similar to Carr (1998), presented
combined results of both Hodgkin's lymphoma and non-Hodgkin's lymphoma,
which may not be appropriate. The authors note that untreated
non-Hodgkin's lymphoma may have bone marrow involvement in roughly 19 to
83% of patients. For Hodgkin's lymphoma, the estimates are from 5 to
14%. These differing estimates suggest the disease entities with respect
to bone marrow involvement may be different. This study also used
discrepancy resolution of only the PET positive, bone marrow biopsy
negative cases. This is a biased approach to resolving discordant cases
favoring the new technology. It also assumes that no errors in
classification are made with respect to the other cells of the 2x2 table
(PET negative, biopsy negative; PET positive, biopsy positive; and PET
negative, biopsy positive).

*Sazon DA, Santiago SM, Soo Hoo GW, Khonsary A, Brown C, Mandelkern M,
Blahd W, and Williams AJ. Fluorodeoxyglucose-positron emission
tomography in the detection and staging of lung cancer. Am J Respir Crit
Care Med. 1996;153:417-21.*

This study is from the Veteran's Administration Medical Center West Los
Angeles, California. Sensitivity and specificity of F-18 FDG PET imaging
for the diagnosis and staging of lung cancer in 107 patients with an
abnormal chest x-ray was determined based on pathological diagnosis
established by a variety of means. Chest CT scans were also performed
and these results were compared to F-18 FDG PET results.

[Inclusion Criteria]{.underline}: One hundred and seven patients who
were being evaluated for abnormal chest x-rays between August 1992 and
March 1994 were studied with whole-body F-18 FDG PET imaging. All
patients except for one were men (mean age 62 [+]{.underline}9 years of
age). Radiographic abnormalities ranged from interstitial infiltrates to
masses.

[Dose]{.underline}: IV administration of 10 mCi F-18 FDG; patients
imaged in the fasting state (the duration of fasting is not stated) 40
minutes after injection.

[Schema of Trial]{.underline}: A comparison of results from F-18 FDG PET
with pathology. Chest CT scan of the mediastinum was performed in those
patients needing mediastinal evaluation and these results were compared
to F-18 FDG PET and pathology.

[Image Protocol]{.underline}: PET scan results were interpreted by
nuclear medicine physicians who were masked to the patient's diagnosis.
Chest CT was performed from supraclavicular region to the adrenal glands
to assess mediastinal nodes in a subset of patients needing mediastinal
evaluation. CT results were interpreted by staff radiologists masked to
the patient's diagnosis. The CT studies were interpreted independently
from the PET studies. The article mentions how PET images were obtained
and reconstructed. There was no mention how many physicians read each
image and if inter- or intra-variability of interpretations was tracked.
The PET and CT scans were performed in close temporal proximity as part
of the immediate evaluation of the patient.

[Primary Endpoints]{.underline}: PET Scan results were interpreted
qualitatively as either positive or negative based on the presence or
absence of any increased F-18 FDG uptake in the lungs and/or
mediastinum. Chest CT were interpreted as either positive or negative
based on the presence or absence of mediastinal node enlargement defined
as node \> 1 cm in diameter on transaxial images. Pathologic diagnosis
was established by sputum examination, bronchoscopy, percutaneous fine
needle aspiration biopsy, or thoracotomy. Mediastinal nodal evaluation
was accomplished by transbronchial needle aspiration biopsy,
mediastinoscopy, thoracotomy, or autopsy. Absence of mediastinal nodal
metastasis was reported only if confirmed at thoracotomy or autopsy.

[Results]{.underline}: One hundred seven patients with abnormal chest
x-rays underwent evaluation with PET and pathological diagnoses were
obtained in all of them. Eighty-two patients had lung cancer, and 25
patients had non-malignant diseases of the chest. Of the 82 patients
with malignancy, 73 patients had non-small cell cancer (33 squamous
cell, 28 adenocarcinoma, 12 undifferentiated), five had small cell
cancer, and four had lung metastasis. Mediastinal evaluation was
performed in 32 patients with non-small cell carcinoma. The rest of the
patients were assessed to be nonsurgical candidates by other criteria,
and confirmation of nodal involvement was not pursued. Of the 32
patients who had mediastinal evaluation, 22 underwent thoracotomy, two
had mediastinoscopy, four by transbronchial biopsy, four by autopsy), 16
were found to have nodal metastasis. PET scans were positive in all
sixteen cases that were found to have metastasis on tissue confirmation.
Sixteen PET scans were negative for those 16 patients who did not have a
tissue diagnosis of mediastinal involvement. CT scans were positive in
13/16 patients with confirmed mediastinal tissue diagnosis of cancer;
9/16 CT scans were negative in patients without mediastinal tissue
diagnosis of cancer.

The results for F-18 FDG PET in this study show a sensitivity of 100%
and a specificity of 52% in patients with an abnormal chest x-ray.

The study also published all pathology findings of non-malignant cases.
There were 25 non-malignant cases: 10 cases of sarcoidosis, 4
coccidiodomycosis, 3 mycobateria, and 8 others. For the 12 F-18 FDG PET
scans that were false positive, the study reports 4 were cases of
sarcoidosis, 3 of coccidiodal pneumonia, 3 of mycobacteria, and 2
others. Of note, the study does describe differences between the
observed pattern for true positive scans and false positive scans. For
lung cancer, the pattern of uptake was focal and discrete; for patients
with false positive PET scans, the pattern was consistently less intense
and more diffuse.

[Safety Issues]{.underline}: The study did not mention any adverse
events associated with F-18 FDG administration.

[Commentary]{.underline}: The study encompassed the proper study
population for F-18 FDG PET oncology imaging: those who have an existing
chest x-ray abnormalities undergoing further evaluation. There are
pathology results for all patients. Absence of mediastinal nodal
metastasis was reported only if confirmed at thoracotomy or autopsy. The
broad spectrum of disease ranging from different types of lung cancers
and metastasis to benign inflammatory processes was included in the
study. Image acquisition and reconstruction was documented in the study.
Readers were masked to the clinical diagnoses of the patients. PET and
CT images were read separately by nuclear medicine physicians and staff
radiologists respectively.

Deficiencies of the study include the absence of intra-reader and
inter-reader variability and the absence of CT scan results except in
patients with mediastinal nodal evaluation.

*Schiepers C, Penninckx R, De Vadder N, Merckx E, Mortelmans L, Bormans
G, Marchal G, Filez L, Aerts R. Contribution of PET in the diagnosis of
recurrent colorectal cancer: comparison with conventional imaging. Euro
J of Surgical Oncology 1995;21:517-522.*

This study from the University Hospital Gasthuisberg, Belgium
investigated total body F-18 FDG PET in 76 patients presenting with or
suspected of recurrent local or distant colorectal cancer. PET results
were compared to routine imaging (CT pelvis, CT/ultrasound of liver, and
chest x-ray).

[Inclusion Criteria]{.underline}: From May 1990 through June 1993, 76
consecutive patients were referred for work up of suspected recurrent
colorectal cancer. There were 45 men and 31 women, mean age was 59
years. They had been followed at 6-month intervals with clinical
examination, proctoscopy, serum CEA, ultrasound of the liver and chest
x-ray. Routine colonscopy was performed 1 year after surgery.

[Dose]{.underline}: A dose of 400-550 MBq F-18 FDG was administered
intravenously. Imaging began 50 minutes later. Patients were studied in
the fasting state (\> 6 hours). The bladder was continuously flushed via
a triple lumen catheter

[Schema of Trial]{.underline}: In total, 83 studies were performed in 76
patients. PET results were compared to a final diagnosis obtained in 52
studies with surgery or biopsy, and in 31 studies with clinical follow
up for at least 14 months. A subgroup of 74 studies had CT-pelvis and
another subgroup of 80 studies had CT and/or ultrasound of the liver

to compare with PET images.

[Image Protocol]{.underline}: The images were not corrected for tissue
attenuation. Acquisition is described in the study. Masking was not
stated.

[Primary Endpoint]{.underline}: Pathology results from biopsy or
surgery, or clinical follow up for at least 14 months.

[Results]{.underline}: The mean interval between PET and surgery/biopsy
was 42.5 days (median 24). For 31 studies, the final diagnosis was
established with clinical follow of at least 14 months. For recurrence
in liver and pelvis, total body PET had a sensitivity of 94% (45/48) and
a specificity was 97% (34/35).

For local recurrent disease in the pelvis, 74 studies had a PET and
CT-pelvis within 2.5 months. Final diagnosis for 27 of 74 studies was
derived from clinical follow up of at least 14 months and the remaining
47 studies had surgical or biopsy diagnoses. PET had a sensitivity of
93% (42/45) and specificity of 95% (28/29). CT had a sensitivity of 60%
(27/45) and specificity of 72% (21/29). Results according to clinical
follow up and surgery/biopsy are also presented.

For metastatic disease to the liver, 73 patients had 80 studies with PET
and liver examination with CT and/or ultrasound within 2.5 months. Final
diagnosis for 28 studies was obtained from clinical follow up of at
least 14 months and the remaining 52 studies had surgery or biopsy. PET
sensitivity was 94% (32/34) and specificity was 100% (46/46). CT and/or
ultrasound had a sensitivity of 85% (29/34) and specificity of 98%
(45/46). Results according to clinical follow up and surgery/biopsy are
also presented.

Distant lesions discovered with total body PET are presented. PET
detailed 25 unexpected lesion locations in 20 patients; 14 lesions (56%)
were confirmed with pathology results or directed radiography or CT. All
false-positive readings occurred in the thorax, 10 in the lungs and 1 in
the axilla. Absence of disease was confirmed with long term clinical
follow up. There was also one false negative, an ovarian cancer
metastasis discovered during laparotomy, which was not seen on the PET
study 6 months earlier.

[Safety Issues]{.underline}: No adverse events were mentioned with F-18
FDG administration.

[Commentary]{.underline}: The study population was appropriate. There
were 45 patients with malignant recurrence and 29 patients with benign
conditions. The standard of truth in this study varied from use of
pathology to other imaging modalities that are routine in cancer follow
up to long term clinical observation. While validation of tumor in liver
and distant sites depended in part on imaging, there was also long term
follow up of at least 14 months to address possible false-negatives.

The image protocol was not well described. In particular, the study did
not mention masking nor who read the images with what criteria. There is
no mention of reader variability. CT results were only available for
mediastinal work ups.

*Utech C, Young CS, Winter PF. Prospective evaluation of fluorine-18
fluorodeoxyglucose positron emission tomography in breast cancer for
staging of the axilla related to surgery and immunocytochemistry. Eur J
Nucl Med 1996;23:1588-93.*

This study is from the University of Illinois College of Medicine and
Downstate Clinical PET Center at the Methodist Medical Center of
Illinois. This study investigated noninvasive staging of axillary lymph
nodes for metastases in 124 patients with a diagnosis of breast cancer
prior to surgery by F-18 FDG PET.

[Inclusion Criteria]{.underline}: Prior to any therapeutic intervention,
124 patients with newly diagnosed and histologically proven breast
carcinoma were studied by F-18 FDG PET. The average age of the patients
was 59 years (range 32-94 years). Clinical staging revealed lymph nodes
in then patients, while mammography reports mentioned axillary lymph
nodes in four patients.

[Dose]{.underline}: Patients fasted for 4 hours prior to the study, with
the majority of patients undergoing an overnight fast. Transmission
scans were performed and then 10 mCi of F-18 FDG was injected
intravenously through a previously placed catheter on the side
contralateral to the primary breast tumor (except in one patient). Sixty
minutes after injection the emission scan was acquired.

[Schema of Trial]{.underline}: Comparison of lymph node metastasis
status with F-18 FDG PET readings. Other immunocytochemistry parameters
were also measured to assess correspondence with PET scan.

[Image Protocol]{.underline}: Acquisition and reconstruction was
discussed. Images were corrected for randoms, detector efficiency,
photon attenuation, dead time, and radioactive decay. Differential
uptake ratios were calculated for axillary nodal uptake. A cutoff point
of DUR values of 1-3 for metastases and 3 and higher for tumor.

The images were initially reviewed by three experienced nuclear
radiologists and the final reading for the study was made by an
experienced nuclear medicine physician from films and a video monitor
using gray-scale display. The reader was masked to the patients lymph
nodes status, but the reader did know the diagnosis of breast cancer. A
scan was read as positive if a discrete focal uptake greater than
background was identified. Otherwise, scans were read as negative.

The diagnosis of cancer was made by core biopsy in 52 patients, by
excisional lumpectomy in 67, and by wide excision in five.

Of the 124 patients, 68 underwent modified radical mastectomy, 28
partial mastectomy and lymph node dissection, ten lumpectomy and lymph
node dissection, and seven re-excision and lymph node dissection after
biopsy. One patient had a bilateral modified radical mastectomy. Ten
patients did not undergo additional surgery after biopsy since the tumor
was completely excised, but underwent separate nodal dissection. The
anatomic levels of axillary lymph nodes were determined by their
position relative to the musculature markings. The written pathology
report was the basis for evaluating the number and extent of involved
lymph nodes.

[Primary Endpoints]{.underline}: F-18 FDG PET scan interpretation of
axillary nodes and pathology findings. Differential uptake ratios were
calculated and correlated with size, grade, S-phase, receptor status,
and ploidy.

[Results]{.underline}: PET correctly identified all 44 tumor-positive
axillary lymph nodes for a sensitivity of 100%. Sixty tumor-negative
axillary nodes were negative by PET and 20 tumor-negative nodes were
positive by PET giving a specificity of 75%. A weak correlation was
found between the differential uptake ratio and tumor size and S-phase
of the tumor. Clinical follow up for 1-2 years showed no recurrence of
the disease in patients identified as false-positive by pathology.

Average number of nodes dissected for the true-positives was 20 (range
7-39), 16 (range 7-36) for the true-negatives, and 20 (range 9-46) for
the false-positive.

Detailed tables with patient results are presented.

[Safety Issues]{.underline}: No safety issues were mentioned in the
study.

[Commentary]{.underline}: This study does not provide information on
selection criteria, interpretative criteria, and why the protocol called
for 2 readers than another reader making a definitive reading. There is
no statement on whether the diagnosis, known to the reader, included
laterality of cancer. There is a possibility that initial diagnostic
surgery may have interfered with the F-18 FDG PET scanning. However, the
study reports only two of the twenty false positives had reactive nodes
on pathology. The study also notes that there were differences in level
of node dissection, with some patients having nodes dissected to Level I
and others to Level III.

*Valk PE, Pounds TR, Hopkins DM, Haseman MK, Hofer GA, Greiss HB, Myers
RW, Lutrin CL. Staging Non-small cell lung cancer by whole-body positron
emission tomographic imaging. Ann Thorac Surg 1995;60:1573-82.*

This study is a prospective evaluation of regional and whole-body PET
imaging for staging lung cancer carried out by the Northern California
PET Imaging Center, California in 99 patients.

[Inclusion Criteria]{.underline}: All patients who were referred to the
Northern California PET Imaging Center for staging of histologically
diagnosed non-small cell lung cancer from October 1992 to January 1995
were included. Also included were patients who were initially imaged for
diagnosis of indeterminant pulmonary nodules and who proved to have
non-small cell lung cancer on subsequent histologic diagnosis.
Ninety-nine patients were enrolled in the study, including 53 men and 46
women, ranging from age from 46 to 87 years (mean, 66 years).
Sixty-seven patients were referred for staging of known lung cancer and
32 were referred for diagnosis of lung nodules.

[Dose]{.underline}: Patients fasted for at least 4 hours before
intravenous injection of 0.143 mCi/kg of F-18 FDG, for an average dose
of 10 mCi. Whole-body imaging were acquired 30 minutes after injection.

[Schema of Trial]{.underline}: An evaluation of regional and whole-body
PET imaging for staging of lung cancer. Mediastinal PET and CT results
were compared with surgical staging and clinical and imaging follow up.

[Image Protocol]{.underline}: Acquisition, image reconstruction, and
display were mentioned in the study. Whole body images were not
corrected for attenuation. First whole-body imaging was performed and
then two static 20-minute emission acquisitions were performed with the
imaging volume centered first on the mediastinum and then on the liver.
Transmission imaging was performed in the first 42 patients before
injection and in the remaining patients it was performed after emission
scans. All PET images were interpreted at the time of the study by one
or two nuclear medicine physicians. Images were viewed in axial,
coronal, and sagittal planes using an interactive video display system.
When CT images of the chest were available, these were used for
localization and measurement of the primary tumor and other pulmonary
opacities. Mediastinal CT findings were disregarded. No other images
were available at the time of interpretation. Overlays of emission and
transmission PET images were used to localize metabolically active
peripheral lung lesions in some cases. PET images of the chest and
abdomen and whole-body were read as positive or negative for metastatic
tumor.

SUV were determined for primary lesions that were 2 cm or more in
diameter.

All mediastinal images were reread at the conclusion of the study by two
authors to evaluate the effect of increase in experience in PET
interpretation during the study. Images were reread independently by the
two investigators without knowledge of patient information or histologic
data. Readings were subsequently compared, and consensus was reached by
discussion. At rereading, mediastinal images were graded on a 3-point
visual scale: 0=activity less than or equal to the mediastinal blood
pool activity; 1+= activity slightly but definitely above the
mediastinal blood pool activity; 2+= activity markedly above the
mediastinal blood pool activity. A score of 1+ or 2+ was considered
positive for malignancy.

CT scans were performed before the PET study in all cases in one of 6
imaging centers. Sixty-two studies were performed after intravenous
injection of 100 to 200 cc of contrast material. Fifty-two of the 99
patients had also undergone contrast-enhanced CT imaging of the abdomen
and pelvis. All chest CT scans were reinterpreted for mediastinal
staging by two authors. Lymph node measurements of greater than 1 cm
were considered positive for metastasis. Each study was read as positive
or negative for mediastinal metastasis. Readers were masked to the
clinical data, PET findings, and histologic diagnosis.

[Primary Endpoints]{.underline}: Tissue for histologic diagnosis was
obtained at thoracotomy or mediastinoscopy. The side of the mediastinum
that was explored was assessed as involved or uninvolved according to
the histologic diagnosis obtained from sections of lymph node specimens.
Midline nodes were considered ipsilateral to the primary lesion. In ten
patients with CT abnormalities, absence of clinical disease 6 to 28
months after imaging was accepted as evidence against metastasis.
Sensitivity, specificity, mean values of SUVs of lesions were
determined.

[Results]{.underline}: Ninety-nine patients with 102 primary lung
cancers were studied. The histologic tumor types included adenocarcinoma
(43 cases), squamous cell carcinoma (35), large cell carcinoma (8),
undifferentiated carcinoma (17) and unspecified non-small cell (5),
bronchoalveolar (2), and adenosquamous (2). No validation of mediastinal
findings was obtained in 25 patients and their studies were excluded
from analysis.

N2 nodal stage was demonstrated in 24 patients of 76. PET study was
positive in 20 of 24 cases (83%) for mediastinal metastasis and negative
for 49 of 53 cases without mediastinal metastasis (94%). CT had a
sensitivity of 15 of 24 cases (63%) and specificity of 38 of 52 cases
(73%).

Eleven patients had evidence of unsuspected distant metastatic disease
on PET with eight of these eleven having confirmation on biopsy (2
cases) or clinical progression of the disease on other scans (bone scans
or CT scans (5 cases), or death, 1), with three cases without any follow
up data. Normal PET findings were obtained at distant sites of computed
tomography abnormality in 19 patients. Fourteen of these 19 had
histologic confirmation (1 case) or clinical confirmation (14 cases)
that the PET diagnosis was correct. In one lung lesion, the PET result
proved to be falsely negative at a 5 month follow up CT scan. The
remaining 4 cases did not have follow up data. The minimum follow up
time for 13 cases was a mean of 12 months (range 6 months to 26 months).

The mean SUV was 9.6 [+]{.underline}3.7 (range 3.2 to 22.3) for 68
histologically confirmed malignancies.

[Safety Issues]{.underline}: No safety issues were mentioned in the
study.

[Commentary]{.underline}: This study provides data on F-18 FDG PET
imaging detection performance in evaluating mediastinal nodal status and
distant metastasis. The study was not a controlled trial of F-18 FDG PET
versus CT scan. CT scan results were used in PET evaluation to identify
locations of some abnormalities. PET scans were initially read and then
they were reread retrospectively with readers masked to histology and
other imaging. SUV were analyzed retrospectively. Resolving
discrepancies between F-18 FDG PET and CT are difficult, but the authors
made attempts either to biopsy lesions or have the patients followed.
Despite this, 3 of 11 PET positive/ CT negative for distant metastasis
and 4/19 PET negative/CT positive cases for distant metastasis did not
have follow up data.

*Vansteenkiste JF, Stroobants SG, De Leyn PR, Dupont PJ, Bogaert J,,
Maes A, Deneffe GJ, Nackaerts KL, Verschakelen JA, Lerut TE, Mortelmans
LA, Demedts MG. Lymph node staging in non-small cell lung cancer with
FDG-PET scan: a prospective study of 690 lymph node stations from 68
patients. J Clin Oncol 1998;16:2142-2149.*

This study of 68 patients from the University Hospital Gasthuisberg,
Belgium compares the accuracy of CT scan and F-18 FDG PET visually
correlated with PET plus CT in the local and regional lymph node staging
of non-small cell lung cancer.

[Inclusion Criteria]{.underline}: Eligible patients had suspected or
biopsy-proven non-small cell lung cancer. Standard staging for distant
metastases was negative. Exclusion criteria were a fasting blood glucose
level greater than normal (5.8 mmole/L), diabetes mellitus, treatment
with corticosteriods more than 0.125 mg/kg of prednisone, congestive
cardiomyopathy preventing lying down flat for scans, direct mediastinal
invasion by the primary tumor, and obvious bulky mediastinal
adenopathies, schedule limitations of the imaging or surgery department.
Sixty-eight patients were studied between September 1995 and January
1997. Their mean age was 64 years (range, 40 to 83 years).

[Dose]{.underline}: Patients fasted for at least 6 hours before being
injected with 6.5 MBq/kg of F-18 FDG into the opposite arm of the tumor.
A 60-minute dynamic emission study of the upper half of the thorax was
started at the time of injection, followed by a 10-minute static
acquisition.

[Schema of Trial]{.underline}: CT, F-18 FDG PET and invasive surgical
staging were performed in one month of each other. Sensitivity and
specificity of CT and CT with PET was calculated. SUR and ROC analysis
for metastasis of lymph nodes were also studied.

[Image Protocol]{.underline}: All data were corrected for decay and
photon attenuation. Acquisition and reconstruction information was
provided in the study. Transaxial, sagittal, and coronal images were
used for interpretation by reading on the image display. This was
performed prospectively and masked to surgical pathological data by two
readers from nuclear medicine and one chest physician. A five-point
scale was used for the interpretation of lymph nodes: 1= not visible on
the image display; 2= lower intensity than mediastinal blood pool
activity; 3= equal to mediastinal blood pool activity; 4= more intense
than mediastinal blood pool activity; and 5= much greater intensity than
mediastinal blood pool activity. A lymph node was considered to be
metastatic when the F-18 FDG-uptake was classified as grade 4 or 5.
Grades 1 through 3 were considered benign. Localization of lymph node
uptake zones on PET was performed by a projection of the hot spots on
the reconstructed transmission images on which the trachea and main
bronchi are more visible, and by visual comparison of PET and CT.
Abnormal uptake of nodes was recorded on a nodal map. PET findings
determined nature of the lymph nodes and CT determined localization for
analyses.

CT was performed from adrenals to supraclavicular regions. A power
injector was used to perform a bolus injection of 2 cc per second of
contrast medium during 40 seconds. Lymph nodes 1.5 cm or greater at
their maximum cross-sectional diameter were considered to be metastatic.
All examinations were prospectively interpreted by a chest radiologist
and a chest physician unaware of the surgical pathology results. The
nodal stage determined by CT and the suspect lymph node stations were
noted on a map.

[Primary Endpoints]{.underline}: PET interpretations, CT interpretation,
and histology were primary endpoints. SVU of lymph nodes using regions
of interests drawn manually on transaxial images around focal uptake
areas provided information for a retrospective analysis to determine the
relationship between the SUVs of the lymph nodes and diagnosis through
ROC analysis. Invasive surgical staging is described in detail, midline
nodes were considered ipsilateral.

[Results]{.underline}: Sixty-eight patients had final pathologic nodal
staging of: N0 in 34 patients, N1 in six patients, N2 in 24 patients,
and N3 in four patients. Histology was available for 690 nodal stations
based on 45 patients undergoing surgery, 22 patients undergoing
mediastinal exploration only, and 1 patient had a fine-needle biopsy of
a supraclavicular node only.

CT correctly identified the nodal stage of 40 of 68 patients (59%).
Understaging occurred in 12 patients and overstaging in 16 patients. PET
plus CT was accurate in 59 of 68 patients (87%). Understaging occurred
in 5 patients and overstaging in four patients.

In the detection of locally advanced disease (N2/N3), the sensitivity
and specificity were 75% (21/28) and 63% (25/40) for CT. For PET plus
CT, this was 93% (26/28) and 95% (38/40) respectively. In the receiver
operator characteristic curve, the best SUV threshold to distinguish
benign from malignant lymph nodes was 4.40. The analysis with SUV
threshold was not superior to the use of a five-point visual scale.

[Safety Issues]{.underline}: No safety issues were mentioned in this
study.

[Commentary]{.underline}: This study compared the addition of F-18 FDG
PET to CT in diagnosing local and regional lymph node metastasis for
non-small cell cancer of the lung. In the study, use of CT scan for
localization did not bias interpreters as this was accounted for in the
hypothesis. However, in a true factorial design to assess contribution
of each modality, PET alone imaging should have been done. Histology
data is present for all patients. All tests and histology were obtained
within one month of the each other. Inter- and intra-reader variability
, how images were read between the two or three readers, and how a
diagnosis was derived were not mentioned.

C. Discussion of Effectiveness

The efficacy data supporting the indication for F-18 FDG PET imaging for
the determination of abnormal glucose metabolism to assist in the
evaluation of malignancy is derived from the published medical
literature. As outlined in FDA's guidance for industry, *Providing
Clinical Evidence of Effectiveness for Human Drug and Biological
Products* (May 1998), FDA can, in certain circumstances, rely on
published reports alone to support approval of a new product. FDA has
outlined factors that increase the possibility of reliance on published
reports alone to support approval of a new product. These include: 1)
multiple studies conducted by different investigators where each of the
studies clearly has an adequate design and where findings across studies
are consistent; 2) a high level of detail in the published reports,
including clear and adequate descriptions of statistical plans, analytic
methods (prospectively determined), study endpoints, and a full
accounting of all enrolled patients; 3) clearly appropriate endpoints
that can be objectively assessed and are not dependent on investigator
judgment; 4) robust results that yield a consistent conclusion of
efficacy and do not require selected post hoc analyses; 5) conduct of
studies by groups with properly documented operating procedures. As a
body of literature taken together, the 16 reviewed studies, including
two adequate and well-controlled studies (Lowe (1998) and Carr(1998)),
provide the cumulative evidence to support effectiveness of F-18 FDG PET
for the determination of abnormal glucose metabolism to assist in the
evaluation of malignancy in humans. See Table 1.

The 16 studies encompassed a variety of cancers: non-small cell lung
cancer, colo-rectal, pancreatic, breast, thyroid, melanoma, Hodgkin's
disease, non-Hodgkin's lymphoma, and other metastatic cancers to lung,
liver, bone, and axillary nodes. There were 1,311 patients from all the
studies combined. The majority of studies were conducted with patients
who were fasting for at least 4 hours (range, at least 4 to at least 12
hours) prior to intravenous injection of F-18 FDG. The dose used was
between 200 MBq to 740 MBq F-18 FDG (mean dose, 376 MBq). Two studies
provided dosing information based on patient weight: Valk (1995) used
5.3 MBq/kg (0.143 mCi/kg) and Vansteenkiste (1998) used 6.5 MBq/kg. Only
one study, Holder (1998), utilized a dose over 550 MBq. The averaged
dose of 370 MBq presently has pharmacologic/toxicologic data from a
previously approved new drug application of F-18 FDG to support that
dose's safety and would be acceptable for labeling purposes for this
review's indication. A range of doses could be provided in the clinical
studies labeling section. After intravenous administration of F-18 FDG,
static emission scans were acquired after at least 30 minutes from the
time of injection (range, 30 to 101 minutes; mean, 53 minutes).

F-18 FDG was approved in 1994 for PET imaging for the identification of
regions of abnormal glucose metabolism associated with foci of epileptic
seizures. The approved labeling recommends a dose for adults within the
range of 185 to 370 MBq. This review of the PET oncology literature
finds a maximum dose about twice the maximum previously approved dose.

This review included studies of various malignancies that met the
inclusion criteria. For some malignancies, such as melanoma, pancreatic
and thyroid cancer, there was only one article reviewed, while for other
cancers such as lung and breast cancer, more articles were reviewed. It
must be remembered that many other articles exist about F-18 FDG
performance in these cancers, but they did not meet this review's
inclusion criteria. While it is recognized that cancer is not one single
disease process, most cancerous cells do share increased rates of
glucose metabolism, which is the basis for F-18 FDG PET imaging. This
differential in glucose metabolism compared to normal or benign tissue
is the basis for F-18 FDG PET effectiveness to assist in the evaluation
of malignancy for patients with abnormalities found by other testing
modalities or in patients with an existing diagnosis of cancer. However,
as shown in the studies, the performance of F-18 FDG PET differs from
study to study, from among same tumor types, and across different tumor
types. For example, there is suggestion that low-grade non-Hodgkin's
lymphoma and bronchioalveolar carcinoma may not have increased F-18 FDG
uptake. Moreover, there were benign conditions that also demonstrated
similar patterns of increased glucose metabolism. Despite this
variability, there still are acceptable levels of performance and
clinical benefit to permit generalization of use to evaluate malignancy.

There are, however, limitations with using published literature in
evaluating safety and effectiveness. Publication bias may be reflected
in that positive studies of the new technology are more likely to be
published than negative findings. The inclusion criteria used in this
review of English language articles and publications found in electronic
data bases may have also introduced bias. In addition, surgery and
clinical oncology journals may not wish to devote space to publishing
detailed methodology for image acquisition, imaging interpretation
procedures, and image interpretation criteria. Many details about image
evaluation were absent from the studies. Inter- and intra-reader
variations in interpretation were, on the whole, either not mentioned,
or discussed in limited fashion. For example, only three studies, Avril
(1996), Lowe (1998), and Carr (1998), presented correlation coefficients
for readers. However, Avril (1996) correlated readers' circling regions
of interest for SUV analysis and not qualitative interpretation. Lowe
(1998) and Carr (1998) presented information on reader agreement using
the kappa statistic and explanation of how many cases and how
disagreements were resolved. One study (Lowe, 1994) did present ROC
information on image interpretation for both readers with and without
anatomical (CT) information, providing area under the curve, standard
deviation and 95% confidence intervals. Although there is some
experience in the medical community with F-18 FDG PET imaging in
oncology, variations of interpretation can still be expected given the
subjective nature of the image interpretation process, the varying
capabilities of the physical imaging detection systems, and the still
growing understanding of the field. Therefore, mechanisms to assess and
control interpretation variation should be part of imaging protocols.
However, should F-18 FDG PET quantitative analysis develop into an
accurate, precise, and standardized methodology across different PET
facilities, this would decrease concerns about subjective interpretation
although the other causes of variability would have to be addressed.
Finally, in the imaging community there has been debate on whether kappa
statistic is appropriate. This statistic corrects for agreement, in this
case imaging interpretation agreement, due to chance. This implies a
model in which there are ranges of image features or stimulus strength
for which the reader is guessing (leaving to chance) about the presence
or absence of disease. This model belongs to a family of so-called
"threshold models." However, these models are inconsistent with the form
of ROC curves measured in diagnostic imaging. Reader are not guessing
about the presence of a signal or disease, but are able to report on the
strength of the image features as they perceive them. This is done
through confidence-ratings (on a point system of 1-100 with 100 being
100% confidence that disease is present) or probability scales (also
from 1-100%). It is the range of reading skills and the inability of
image readers to maintain, or remember, a constant mindset (how
aggressive they choose to be for detecting disease in terms of human and
economic cost-benefits) that suggests models of guessing (or chance).

There are other limits of the published literature that was reviewed.
Many studies did not include qualitative criteria used by the readers to
distinguish positive from negative F-18 FDG PET scans. When present,
these criteria were included in the review. The majority of studies did
not included information on how pathological diagnoses were made: how
sampling was determined, who read the slides, how many readers per
slide, were pathologists masked to imaging information, etc. Specimen
sampling of mediastinal lymph nodes was described in detail by only one
article, Vansteenkiste (1998). Lymphoma biopsy protocols were presented
in detail by Carr (1998). Variations on how the pathological diagnosis
was made may influence study results.

Also, many journals do not have space to devote to patient listings,
although some articles did include detailed patient information ((Moog,
1998),(Friess, 1995),(Lowe, 1998)). Finally, the studies did not state a
priori criteria for statistical parameters: type I error, type II error,
and power. Were these limits encountered in a new drug application, a
usual recourse would be to obtain clarification or more data from the
sponsor. While many of the published studies may have, in fact, all the
information, processes, and procedures cited here as absent,
unfortunately this review has no means to assess that.

Most patients were selected after having been diagnosed with an abnormal
test leading up to biopsy or were already diagnosed with cancer and
having follow-up for recurrence. These populations are appropriate in
testing the performance of F-18 FDG PET's diagnostic capacity. The
studies reviewed show F-18 FDG PET has effectiveness in detecting
malignancy in these populations. No prospective studies about efficacy
of F-18 FDG PET for population screening were found or reviewed.
Therefore, use of F-18 FDG PET in population screening for malignancy
has not been determined to be safe or effective by this review.

Some studies, Delbeke (1998), Lowe (1994), Valk (1995), used CT for
localization of the lesions to circle regions of interest for SUV
analysis. This may have biased the readings of the F-18 FDG PET images.
However, F-18 FDG PET may be used as a follow up test to CT scans when
results are indeterminant. In that case, the use of CT scans with F-18
FDG PET may be acceptable in the study design. This review also included
studies that performed SUV region of interest identification without CT
on PET images or with CT but as a separate procedure from qualitative
visual interpretation (Avril (1996), Moog (1998), Schiepers (1995), Bury
(1997) Lowe (1998), Vansteenkiste (1998), Gupta (1996), Sazon (1996)).

Interpretations of CT scans and other tests, such as bone scans, may not
have been under the control of the study authors. Because some studies
did not explicitly publish how non-PET image interpretations were
obtained, there may be variations on how these tests were read: some
studies may have used interpretations from outside referring practices
and other studies may have re-read these images as part of the study.
For example, Valk (1995) and Sazon (1996), did reinterpret these other
imaging scans as part of their study protocol. Despite the possibility
of variation of how interpretations were obtained, the results appear to
still be consistent in supporting the performance of PET imaging.

One study did not indicate whether CT was used or not with PET
interpretation (Friess (1995)). The studies which used CT scans in
conjunction with F-18 FDG PET image assessment or compared performance
of F-18 FDG PET and CT did not always mention if the CT scans were
performed with oral or intravenous contrast or both. Although the
assumption may be that intravenous contrast is often used in oncology
imaging, this absence of stated information about the CT scans makes
limits comparison of CT results across the studies.

Verification of distant metastases is inherently a problem in diagnostic
test evaluations. It is hard to obtain pathology on all "test positive"
lesions found by conventional imaging and F-18 FDG PET. In addition,
follow up of all negative test results to ensure true negativity is also
hard because the duration of follow-up may need to be years. All
reviewed studies did biopsy patients based on their conventional imaging
abnormality. This would be appropriate as conventional imaging is the
standard of practice. One study did biopsy F-18 FDG PET positive cases
in which conventional imaging was negative (Holder, 1998) but this
process is biased in favor of the new technology because its leads to
either improvement or unchanged sensitivity. There is no potential to
decrease the sensitivity of the new technology using this form of
discrepancy resolution. However, this review does include studies with
follow up of from 7 to 25 months to ensure negative results were true
(Schiepers (1995) and Friess (1995)).

Timing of when F-18 FDG PET was performed relative to when definitive
histology was obtained was acceptable in the reviewed studies that
stated the time frame. The time frame was short to prevent affects of
time on clinical presentation. Because F-18 FDG PET was performed prior
to biopsy in all studies except the lymphoma bone marrow and breast
cancer axillary node studies, those studies that did not state a time
frame most likely had biopsies performed in a relatively short time
frame to meet clinical practice standards of diagnosing malignancy.

Two studies used intravenous furosemide, Lowe (1994) and Friess (1995),
and one study, Holder (1998), used intravenous diazepam. Furosemide is
an inhibitor of sodium, potassium, and chloride symport in the thick
ascending limb of the loop of Henle. It can also inhibit glycolysis and
may cause hyperglycemia. Diazepam is a benzodiazepine intravenous
anesthetic with no known affect on glucose metabolism. More information,
referred to in the studies as unpublished data, should be presented to
ensure no adverse affect of furosemide on PET imaging.

The F-18 FDG PET imaging literature in oncology has been reviewed
systematically by the Veterans Health Administration (VHA) in October
1996 and by the Blue Cross and Blue Shield Association Technology
Evaluation Center (TEC) in March 1997. These reports' conclusions differ
from this FDA medical review of the F-18 FDG PET imaging literature in
oncology because the statutory requirement for substantial evidence of
safety and effectiveness differs from the criteria used by these other
organizations. The FD&C does not mandate drug approval based on criteria
requiring incremental value of PET information on treatment planning,
health outcomes, or clinical utility of PET in selected conditions
relevant to the veteran population.

The TEC criteria stated in the report are: 1) the technology must have
final approval from the appropriate governmental regulatory bodies
(FDA), 2) the scientific evidence must permit conclusions regarding the
effect of the technology on health outcomes, 3) the technology must
improve the net health outcomes, 4) the technology must be as beneficial
as any established alternatives, and 5) the improvement must be
attainable outside the investigational setting. The report concluded
that for five specific indications related to differential diagnosis of
intracranial masses, differentiation of low-grade and high-grade brain
tumors, for the guidance of stereotactic biopsy or biopsies of
intracranial mass, differentiation of recurrent brain tumor from
radionecrosis, or for monitoring response to treatment in patients with
brain tumors, PET does not meet the TEC criteria. The TEC report implies
that criteria 2-5 differ from criteria 1, FDA approval. In fact,
criteria 2-5 are outside the statutory mandates for evaluation of
effectiveness established by the FD&C.

The VHA review of the F-18 FDG PET literature in diagnosing cancer
concluded that "the knowledge base supporting clinical diagnostic
applications of PET has significant deficiencies" and that the
"usefulness and contribution to improved outcomes" has not been
adequately evaluated to support the VHA's establishment of additional
PET centers. The review cited several problems with the PET literature
of 1991-1995, the time period of the articles. These problems include
retrospectively analyzed case series data, small patient numbers, uneven
numbers of cases and controls, lack of control group, and lack of
masking the image interpreters or lack of addressing interobserver
variation. The VHA review also discussed VHA specific issues relating to
difficulties in supporting and maintaining the cost of this technology.
This FDA medical review of safety and efficacy data focused on whether
substantial evidence for effectiveness, as defined by the FD&C and its
implementing regulations and legislative history, is present in the
current literature. Many of the weakness of studies that the VHA
identified have been addressed. Only articles that had a prospectively
enrolled population, utilized pathology as a standard of truth, and, as
a group, had numbers of cases or lesions that were useful in assessing
test performance are included in this review. While the number of
subjects varied in the studies, only studies having fifty or more
patients were reviewed. Many of the studies had mechanisms to reduce
bias, such as masking. This medical review contains only three of the 35
studies the VHA originally included in their oncology review in 1996. An
updated VHA report is due in 1999.

This review finds that multiple, prospective clinical studies conducted
by different investigators produced consistent results that support the
clinical use of F-18 FDG PET to detect increases of glucose metabolism
for the evaluation of malignancy in patients with abnormalities found by
other imaging modalities and in patients with an existing diagnosis of
cancer. The studies reviewed all compared F-18 FDG PET results to
histologic standards of diagnosis. The findings from the cumulative F-18
FDG PET literature for the reviewed cancer types are robust and the
functional aspect of the test is applicable to cancer in general. As
such, this review supports the use of F-18 FDG PET to detect abnormal
glucose metabolism to assist in the evaluation of malignancy in patients
with abnormalities found by other imaging modalities, or patients with
an existing diagnosis of cancer. The limitations of the studies should
be reflected in the labeling of the product. The label should also state
that F-18 FDG PET results are not diagnostic for a specific malignancy
and there are limits to its sensitivity and specificity. F-18 FDG does
not replace the need for histopathology for diagnosis.

III. Safety Evaluation

F-18 FDG PET radiopharmaceutical is radioactively labeled fluorine
analog of glucose. It is administered intravenously for PET imaging. The
overall distribution, metabolism, and excretion of F-18 FDG PET is well
understood after roughly two decades of use. A dose of 185-370 MBq(5-10
mCi) of F-18 FDG was approved by FDA in 1994 for PET imaging to identify
regions of abnormal glucose metabolism with foci of epileptic seizures
with this same dosimetry information. No adverse reactions have been
reported from this use.

In the reviewed F-18 FDG PET studies, patients generally fast for 4 or
more hours before imaging in an effort to reduce serum insulin levels to
near basal levels. This is important because insulin can direct F-18 FDG
away from the blood and into muscle and fat. In addition, the fasting
state minimizes competitive inhibition of F-18 FDG uptake. Following
this, patients were injected with about 200-740 MBq of F-18 FDG
intravenously and imaging usually began 30-101 minutes after injection.
The effects of diabetes and serum hyperglycemia on the uptake of F-18
FDG have not been studied adequately. A few studies, Holder (1998),
Dietlein (1997), Vansteenskiste (1998), excluded diabetic patients or
they were restudied when fasting glucose was less than 100 mg/dl. In the
approved labeling for F-18 FDG for epileptic foci diagnosis with PET, it
states, "Diabetic patients may need stabilization of blood glucose on
the day preceding and on the day of the F-18 FDG scan."

The physical half-life of F-18 FDG is 109.8 minutes. Once injected, it
is rapidly distributed to all organs of the body. F-18 FDG is taken up
by cells and phosphorylated to F-18 FDG-6-phosophate at a rate
proportional to the rate of glucose utilization within a given tissue.
F-18 FDG-6-phosophate presumably is metabolized to
2-deoxy-2-\[F-18\]fluoro-6-phospho-D-mannose and
\[F-18\]FDM-6-phosphate. \[F-18\]FDG contains 2-deoxy-2-cholor-D-glucose
(ClDG) as a known impurity. Distribution and metabolism of this is
presumable similar to that of F-18 FDG. The phosphorylated deoxyglucose
compounds are dephosphorylated, and the resulting compounds, including
those related to ClDG, presumably leave cells by passive diffusion. F-18
FDG and related compounds are largely excreted unchanged in the urine
within 3 to 24 hours (except from cardiac tissue, which may require more
than 96 hours). Unlike glucose, F-18 FDG and related compounds are not
reabsorbed in the renal tubules. Dosimetry data from the literature and
from the previously approved new drug application for F-18 FDG has been
evaluated by the biopharmacologist. For an average dose of 370 MBq (10
mCi) of F-18 FDG, the target organ (the bladder) absorbs 6.29 rads based
on a fixed bladder content over a three hour period of time. Increasing
the voiding frequency and bladder capacity (250cc) brings the exposure
down to 3 rads in adults. Thus, for higher doses, the level and extent
of radiation absorbed by the bladder walls can be manipulated with
hydration and shorter voiding intervals to decrease radiation exposure.

The dosimetry data mentioned above are the same data that were
acceptable for F-18 FDG's approval in 1994. Therefore, for a labeled
dose based on the literature review the averaged dose from the studies
of 370 MBq can be recommended.

For a dose of 370 MBq (10mCi), the typical quantity of F-18 FDG is \<1.5
micrograms, sodium chloride is 198 mg, glucose [\<]{.underline}8 mg and
2-chloro-2-deoxy-D-glucose of less than 0.1 mg. For doses to 25 mCi,
increasing these amounts by 1.5 fold is still acceptable for human use.

In the published literature concerning safety of PET drugs, in 1996,
Edward Silberstein, Janet Ryan and the Pharmacopeia Committee of the
Society of Nuclear Medicine published in the Journal of Nuclear Medicine
in a five year prospective study of 18 collaborating institutions using
a questionnaire which enumerated monthly the number of procedures used
and the adverse reactions noted for radiopharmaceuticals and
non-radioactive drugs used in nuclear medicine. The study utilized
operational definitions for adverse reactions and significant adverse
reactions and devised an algorithm to categorize probability of
causation. The published study included a copy of the actual
questionnaire, which required itemization of any and all
radiopharmaceuticals administered, adverse reactions to
radiopharmaceuticals, dose, route, reaction, etc., as well as total
non-radiopharmaceuticals (such as adenosine or dipyridamole)
administered and adverse reactions to these agents. For
radiopharmaceuticals, there were a reported 18 total adverse reactions
for 773,525 injections. No reactions are reported for F-18 FDG PET. The
study also performed a reference check of listed adverse reactions by
references and no adverse reactions were listed by the U.S.
Pharmacopeial Convention's Drug Information for the Health Care
Professional, 1995. Dr. Silberstein and the Pharmacopeia Committee of
the Society of Nuclear Medicine also conducted a retrospective and
prospective study of the prevalence of adverse reactions to PET
radiopharmaceuticals published in 1998 in the Journal of Nuclear
Medicine. Dr. Silberstein reported 22 PET centers provided monthly
adverse reaction data from 1994 to 1997 related to PET drug
administration in 47,876 dosages. In addition, retrospective data was
collected from the opening of these centers on 33,925
radiopharmaceutical dosages. In no case were there any adverse
reactions.

The published clinical trials literature is not an appropriate data base
to evaluate chemistry and manufacturing safety issues related to drug
purity and identity. Different production pathways may lead to different
concentrations of F-18 FDG and to different by-products and impurities.
These specific topics will be addressed by the FDA PET Chemistry and PET
Good Manufacturing Practice working groups.

Because radiation is a known carcinogenic and mutagenic agent, standard
radiation precautions for using F-18 FDG PET with respect to patients,
pregnant women, and occupational exposure are needed.

IV. Conclusions

The well-controlled studies of Lowe (1998) and Carr (1998) permit
estimates of sensitivity and specificity of F-18 FDG PET performance for
assessing malignancy in patients with abnormalities found by another
imaging modality and in patients with an existing diagnosis of
malignancy. The supportive studies included in this review provide
independent corroboration of the increased glucose metabolism in
association with a variety of other malignancies. However, the test's
sensitivity is restricted by biologic variability of cancer glucose
utilization such that false negative examinations may occur.
Furthermore, increased glucose utilization is not restricted to
malignant cells. Therefore, F-18 FDG PET imaging does have limitations
in specificity. In the reviewed studies, the sensitivity and specificity
varied with the type of cancer, size of cancer, and other clinical
parameters. The trial designs and hypotheses tested did not study how
F-18 FDG might be used prospectively. However, given the long history of
use of F-18 FDG PET and the numbers of studies showing consistent
findings, these studies collectively demonstrate the clinical relevance
of performing F-18 FDG studies in patients with suspicious abnormalities
from other testing modalities or pre-existing diagnoses of cancer.
However, more studies would be needed if labeling claims were to contain
cancer-specific diagnostic or management claims.

The studies reviewed all were diagnostic studies, not population
screening. The studies did have well-defined populations in which
effectiveness was derived: patients with abnormalities on another
imaging modalities, such as x-ray or CT scan, or patients with an
existing diagnosis of cancer. These populations are sufficiently
different from other types of populations to not permit generalization
of results to other populations. As such, this review finds
effectiveness for those specifically studied populations, namely,
patients undergoing diagnostic evaluation for known abnormalities, not
population screening. Safety information reveals manageable radiation
risk and unknown performance and risk to patients with diabetes. In
summary, F-18 FDG PET may provide additional information based on
glucose metabolism to assist physicians in the evaluation of malignancy
in patients with abnormalities found by other testing modalities or in
patients with an existing diagnosis of cancer.

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Florence Houn MD MPH date

References

Avril N, Dose J, Janicke F, Sense S, Ziegler S, Laubenbacher C, Romer W,
Pache H, Herz M, Allgayer B, Nathrath W, Graeff H, Schwaiger M.
Metabolic characterization of breast tumors with positron emission
tomography using F-18 fluorodeoxyglucose. J Clin Oncol
1996;14:1848-57*.*

Bury T, Dowlati A, Paulus P, Corhay JL, Hustinx R, Ghaye B, Radermecker
M, Rigo R. Whole-body 18-FDG positron emission tomography staging of
non-small cell lung cancer. Eur Respir J 1997;10:2529-2534.

Carr R, Barrington SF, Madan B, O'Doherty MJ, Saunders CAB, van der Walt
J, Timothy AR. Detection of lymphoma in bone marrow by whole-body
positron emission tomography. Blood 1998;91:3340-46.

Delbeke D, Martin WH, Sandler MP, Chapman W, Wright Jr K, Pinson W.
Evaluation of benign vs malignant hepatic lesions with positron emission
tomography. Arch Surg 1998;133:510-516.

Dietlein M, Scheidhauer K, Voth E, Theissen P, Schicha H. Fluorine-18
fluorodeoxyglucose positron emission tomography and iodine-131
whole-body scintigraphy in the follow--up of differentiated thyroid
cancer. Eur J Nucl Med 1997;24:1342-48.

Friess H, Langhans J, Ebert M, Beger HG, Stollfuss J, Reske SN, Buchler
MW. Diagnosis of pancreatic cancer by 2\[18-F\]-fluoro-2-deoxy-D-glucose
positron emission tomography. Gut 1995;36:771-777.

Gupta NC, Maloof J, and Gunel E. Probability of malignancy in solitary
pulmonary nodules using fluorine-18-FDG and PET. J Nucl Med
1996;37:943-948.

Holder Jr. W, White RL, Zuger JH, Easton Jr. EJ, Greene FL.
Effectiveness of positron emission tomography for the detection of
melanoma metastases. Annals of Surg 1998;227:764-771.

Lowe VJ, Fletcher JW, Gobar L, Lawson M, Kirchner P, Valk P, Karis J,
Hubner K, Delbeke D, Heiberg EV, Patz EF, Coleman RE. Prospective
investigation of positron emission tomography in lung nodules. J Clin
Oncol 1998;16:1075-1084.

Lowe VJ, Hoffman JM, DeLong DM, Patz Jr. EF, Coleman RE.
Semiquantitative and visual analysis of FDG-PET images in pulmonary
abnormalities. J Nucl Med 1994;35:1771-1776.

Meyer GJ, Waters SL, Coenen HH, Luxen A, Maziere B, Langstrome B. PET
radiopharmaceuticals in Europe: current use and data relevant for the
formation of summaries of product characterizatics (SpCs). Eur J Nucl
Med 1995;22:1420-32.

Moog F, Bangerter M, Kotzerke J, Guhlmann A, Frickhofen N, Reske SN.
18-F-fluorodeoxyglucose-positron emission tomography as a new approach
to detect lymphomatous bone marrow. J Clin Oncol 1998;16:603-9.

Sazon DA, Santiago SM, Soo Hoo GW, Khonsary A, Brown C, Mandelkern M,
Blahd W, and Williams AJ. Fluorodeoxyglucose-positron emission
tomography in the detection and staging of lung cancer. Am J Respir Crit
Care Med. 1996;153:417-21.

Schiepers C, Penninckx R, De Vadder N, Merckx E, Mortelmans L, Bormans
G, Marchal G, Filez L, Aerts R. Contribution of PET in the diagnosis of
recurrent colorectal cancer: comparison with conventional imaging. Euro
J of Surgical Oncology 1995;21:517-522.

Silberstein EB, Ryan J, and the Pharmacopeia Committee of the Society of
Nuclear Medicine. Prevalence of adverse reactions in nuclear medicine. J
Nucl Med 1996;37:185-92.

Silberstein EB and the Pharmacopeia Committee of the Society of Nuclear
Medicine. Prevalence of adverse reactions to positron emitting
radiopharmaceuticals in nuclear medicine. J Nucl Med 1998;39:2190-2.

Utech C, Young CS, Winter PF. Prospective evaluation of fluorine-18
fluorodeoxyglucose positron emission tomography in breast cancer for
staging of the axilla related to surgery and immunocytochemistry. Eur J
Nucl Med 1996;23:1588-93.

Valk PE, Pounds TR, Hopkins DM, Haseman MK, Hofer GA, Greiss HB, Myers
RW, Lutrin CL. Staging Non-small cell lung cancer by whole-body positron
emission tomographic imaging. Ann Thorac Surg 1995;60:1573-82.

Vansteenkiste JF, Stroobants SG, De Leyn PR, Dupont PJ, Bogaert J,, Maes
A, Deneffe GJ, Nackaerts KL, Verschakelen JA, Lerut TE, Mortelmans LA,
Demedts MG. Lymph node staging in non-small cell lung cancer with
FDG-PET scan: a prospective study of 690 lymph node stations from 68
patients. J Clin Oncol 1998;16:2142-2149.