WHITE PAPER

Reproducible
Quantification
in PET•CT: Clinical
Relevance and
Technological
Approaches

Partha Ghosh, MD

www.siemens.com/mi
Table of Contents

The Influence of Quantification on Clinical Decision Making 1

The Factors Influencing the Accuracy and Reproducibility of Quantitative Results 2

Patient Preparation and Protocol 2

Patient Size 2

Post Injection Delay Times 2

Plasma Glucose Levels 2

Acquisition and Reconstruction Parameters 2

Instrumentation 5

Detector System 5

Calibration Method 6

Registration and Attenuation Correction Methods 7

Quantification Software 11

PET Oncology Follow-up with SUVpeak 11

PET Cardiac Perfusion with Myocardial Blood Flow 13

Conclusion 16

References 16
 INDICATIONS AND USAGE
Fludeoxyglucose F18 Injection is indicated for positron emis-
sion tomography (PET) imaging in the following settings:
• Oncology: For assessment of abnormal glucose metabolism
to assist in the evaluation of malignancy in patients with
known or suspected abnormalities found by other testing
modalities, or in patients with an existing diagnosis of cancer.
• C ardiology: For the identification of left ventricular
myocardium with residual glucose metabolism and
reversible loss of systolic function in patients with coro-
nary artery disease and left ventricular dysfunction,
when used together with myocardial perfusion imaging.
• Neurology: For the identification of regions of abnormal glucose
metabolism associated with foci of epileptic seizures (1).
The Influence of Quantification on
Clinical Decision Making
Metabolic imaging with PET/CT using 18 F Fludeoxyglucose
( 18F FDG) * as well as other imaging biomarkers has achieved
wide acceptance in oncology, cardiology and neurology not only
because of the unique metabolic information generated by this
modality, but also because of its ability to quantify biological
processes. Such quantitative parameters generated by PET/CT
imaging act as valuable tools for characterization of lesions as
well as for monitoring response to therapy.
The fundamental quantitative parameter in PET is the Standard-
ized Uptake Value (SUV), which is calculated as follows:
Activity Concentration (kBq/ml)
SUV =
Inj. dose (MBq)
BodyWt (kg)
This value can be normalized to body weight as in the above
equation or normalized to body surface area or lean body mass.
Traditionally the SUV max (pixel with the highest SUV within a
given region of interest (ROI) in a tumor) has been used for tumor
characterization and follow up although the reproducibility of
this measurement is subject to significant variation.
*Important safety information on Fludeoxyglucose 18F injection can be found on the previous page.
The full prescribing information can be found on pages 18-25.
IMPORTANT SAFETY INFORMATION
Radiation Risks
Radiation-emitting products, including 18F FDG, may increase
the risk for cancer, especially in pediatric patients. Use the
smallest dose necessary for imaging and ensure safe handling
to protect the patient and health care worker.
Blood Glucose Abnormalities
In the oncology and neurology setting, suboptimal imaging
may occur in patients with inadequately regulated blood
glucose levels. In these patients, consider medical therapy
and laboratory testing to assure at least two days of normo-
glycemia prior to 18F FDG administration.
Adverse Reactions
Hypersensitivity reactions with pruritus, edema and rash have
been reported; have emergency resuscitation equipment and
personnel immediately available.
Full prescribing information may be found at the end of this
white paper.
Accurate and reproducible measurement of SUV is critical to the
clinical efficacy of PET/CT imaging since the quantitative parameter
is often used to guide clinical decision making. This is especially
true for characterization of equivocal lesions like lung nodules
where an SUV of 2.5 or higher has been traditionally regarded as
the criteria to label a lesion as malignant and subject it to biopsy1.
A prospective study1 attempted to differentiate malignant from
benign lung nodules in 87 patients. When a mean SUV of greater
than or equal to 2.5 was used for detecting malignancy, the
sensitivity, specificity and accuracy were 97 percent, 82 percent
and 92 percent, respectively. In addition, there was a significant
correlation between the doubling time of tumor volume and
the SUV.
SUV-based quantification is also critical for proper evaluation of
response to therapy of tumors using PET/CT, an approach which
is being increasingly adopted in oncology for monitoring chemo-
therapy and chemoradiation therapy, as well as to modify therapy
regimes in cases of non-response which may be ascertained early
using sequential PET/CT imaging during therapy. Initial tumor
response to effective chemotherapy is usually a decrease in tumor
metabolic activity with subsequent decrease in tumor size based
on the degree of cell killing and resulting intratumoral necrosis
and fibrosis. Often the time lag between metabolic response
and morphological response is significant, measured in weeks. A
series of studies involving response evaluation of various tumors
using PET/CT has shown the advantage of PET/CT in demonstra-
tion of early response or non-response to therapy much before
decrease in tumor volume could be detected on CT. Although
1
the RECIST criteria based on morphological parameters of tumor
has been widely used, it is very often inappropriate in assessing
therapy response in certain tumors. Several newer cancer thera-
pies have a more cytostatic than cytocidal effect and good tumor
response may be associated predominantly with a decrease in
metabolism, even in the absence of a major shrinkage in tumor
size. Quantitative evaluation of tumor metabolism, as indicated
by PET SUV, is increasingly being adopted as an adjunct to RECIST
for clinical trials involving therapy response evaluation, especially
those related to such cytostatic and targeted therapies. Therapy
response evaluation using molecular imaging biomarkers corre-
lates better with patient outcome than do size measurements,
which could significantly reduce the costs of drug development
and, thereby, eventually decrease drug costs in clinical practice.
The percentage decline of SUV that fits into the profile of a
responding tumor differs among cancer types. In lung, gastric
and esophageal cancers, declines in SUVmax of 20 to 35 percent
after one to two doses of therapy have been shown to be
predictive of favorable outcomes 2 . However, in lymphomas
and ovarian carcinoma, a larger drop in SUVmax following initial
therapy is observed in responding lesions3,4. The levels of SUV
change required to conform to the clinical profile of a favorable
response varies widely and depends primarily on tumor biology.
Thus a relatively modest decrease in SUVmax may constitute a
good response in some tumors. Cytostatic chemotherapy agents
may block tumor growth but the SUV max may remain constant
or decrease slightly. Studies have demonstrated significant vari-
ability of SUV max values in test-retest measurements, ranging
between 6 to 10 percent5 with increase in variability with higher
SUVmax values. Due to such variability, the level of SUVmax change
which is to be considered a positive indicator for therapy response
is subject to controversy. The European Organization for Research
and Treatment of Cancer (EORTC) PET study group 6 suggested a
reduction of a minimum of 15 percent to 25 percent in tumor
SUVmax or SUVmean to reflect a partial metabolic response (PR)
after one cycle of chemotherapy and greater than 25 percent
after more than one treatment cycle. Decrease in test-retest
variability of SUV secondary to technological innovations and
improved standardization of data acquisition and reconstruction
should improve criteria for therapy response assessment. On
the road to reliable response assessment based on quantitative
results, it is therefore desirable to define true thresholds for
progressive disease and partial response. As a prerequisite, scan-
ners would have to be accurate to within a small margin.
Tumor volume estimation based on PET as well as delinea-
tion of gross tumor volume (GTV) for PET/CT-based radiation
therapy planning usually involves determining a threshold as a
percentage value of the SUVmax of a tumor. Thus the accuracy of
the highest SUV of a tumor is a key component for accurate delin-
eation of tumor margins if threshold-based Volume of Interest
(VOI) generation tools are used.
In view of the clinical relevance of accurate and reproducible SUV
in PET imaging, it is important to look at the variables that affect
SUV and patient-specific, as well as system- and technology-
specific measures, that could reduce such variability.
2
The Factors Influencing the
Accuracy and Reproducibility of
Quantitative Results
SUV is subject to several sources of variability arising from the
patient and the PET/CT system, including acquisition and recon-
struction parameters, as well as statistical variations related to
system calibration and evaluation methodology.
Patient Preparation and Protocol
Patient Size
Body habitus is a source of variability in SUV since conventional
SUV normalizes for body weight. However, fat has a much lower
18F FDG uptake compared to muscle and organs, such as the liver.
Several tissues show progressive increase in SUV with increasing
body weight due to the proportionally higher fat content7. SUV
normalized to lean body mass (SUL) reduces body fat percentage
related variability. However, not all centers may use standardized
SUV normalization criteria and thus intersystem variability may
persist.
Post Injection Delay Times
The waiting period between 18F FDG injection and PET/CT acquisi-
tion has been shown to have an impact on SUV8. Several studies
have demonstrated progressive increase in SUV in malignant lung
tumors subjected to dual time point acquisitions9. These observa-
tions suggest that SUV can vary widely depending on delay in
acquisition post injection, and standardization of the post injec-
tion delay is important for reproducible and reliable results, as
has been adopted in most current clinical trials. The European
Association of Nuclear Medicine (EANM) procedure guidelines for
oncologic PET imaging10 recommend the interval between 18F
FDG administration and the start of acquisition to be 60 minutes.
Recording of the actual interval and time of injection is also
recommended. Adherence to same post injection delay for repeat
imaging of the same patient with a tolerance of +/- 5 minutes is
recommended in the context of therapy response assessment.
Plasma Glucose Levels
The plasma glucose level also has a major effect on SUV. Hyper-
glycemia has been shown to cause a significant reduction in tissue
FDG uptake and consequently a reduction in SUV11. Such variations
demand strict monitoring and management of plasma glucose level
prior to PET/CT studies in order to reduce SUV variability.
Acquisition and Reconstruction Parameters
Accurate measurement of injected dose is key to accurate and
reproducible SUV calculation. Attention to calibration of the dose
calibrator as well as measurement of residual activity in syringe
after injection is of utmost importance. SUV calculation depends
on the measurement of activity concentration in kBq/ml and is
thus affected by factors such as recovery coefficients (RC) and
partial volume effects (PVE). The recovery coefficient of a PET/
CT system can be defined as the ratio of the measured activity in
a lesion divided by the true activity. It decreases when the struc-

ture is smaller than a few times the practical image resolution or
when such structure occupies a portion of the voxel due to inad-
equate sampling. In both situations, the recovery coefficient is
typically less than 100 percent and SUV may be calculated lower
than the actual value. Hoffman et al 12 evaluated this problem
and assessed the recovery coefficient for images of cylinder with
uniform radioactivity distribution. He demonstrated a relation-
ship between system resolution, cylinder diameter and recon-
struction parameters, especially the Full Width at Half Maximum
(FWHM) of the reconstruction filter. He concluded that RC of
a cylinder with diameter equal to the resolution FWHM of the
imaging system was only 50 percent. Such RC equally affects the
SUV calculation. Typically, Gaussian filters of 5 to 10 mm FWHM
are applied resulting in a clinical image resolution of 7 to 12 mm.
PVE increases with decreasing image resolution. PVE becomes
mainly important for lesions smaller than three times the FWHM,
such as lesions 20 mm or less. Recovery coefficient and partial
volume effects also strongly depend on object geometry with
maximum effect in irregular shaped tumors.
With iterative reconstruction methods, a sufficient number of
iterations need to be applied to ensure sufficient convergence
of the algorithm. SUV increases of up to 70 percent have been
shown when using higher numbers of iterations.
Data acquisition settings such as time per bed position, the
amount of overlap between subsequent bed positions, acquisi-
tion mode (2D or 3D) and 18F FDG dose affect scan statistics and/
or the noise equivalent count rate of PET studies. Poorer scan
statistics and lower image signal-to-noise ratio (SNR) result in an
upward bias of SUV, especially when using the SUV max as final
outcome parameter. CT attenuation correction (CT AC) can influ-
ence SUV in cases with patient motion (e.g., breathing), which
may cause a mismatch between PET and CT and thus result in
incorrect attenuation correction. The latter may be minimized by
breathing instructions (breath holding at mid-inspiration volume
or shallow breathing) during CT scanning. Truncation of CT due
to smaller CT field of view (FOV) may lead to faulty attenuation
correction and SUV errors and should therefore be avoided.
Patient- and system-specific
factors influence the accuracy
and reproducibility of SUV.
Improvements in image quality,
attenuation correction method­
ology, system calibration and
quality control, as well as adequacy
of quantitative software tools,
together influence the ultimate
SUV accuracy and diagnostic
confidence.
Such variability can be significantly improved by technological
developments including higher performance PET detector mate-
rial (LSO) with higher count rate efficiencies; higher resolution
scanners with smaller crystal elements and voxel sizes (HI-REZ
crystals) as well as newer reconstruction algorithms that improve
lesion contrast and resolution throughout the entire FOV (Point
Spread Function (PSF) reconstruction such as HD•PET). More-
over, acquisition and reconstruction with time of flight (TOF)
(Siemens ultraHD•PET) dramatically reduce background noise
and increases lesion contrast, which can impact small lesion
detectability. Higher system resolution with smaller voxel size
reduces partial volume effects, improving the accuracy of SUV.
Attempts are being made to improve standardization of PET/
CT-based clinical trials in order to enhance the reliability of SUV
across multiple systems in order to reduce variability. A PET
imaging working group was formed by the Netherlands Society
of Haemato-Oncology 13. The group specifically aimed at stan-
dardization of 18F FDG PET studies in order to allow inter-institute
interchangeability of SUV. This group recommended well-defined
guidelines for patient preparation, data acquisition, image recon-
struction and inter-institutional standardization of image quality
parameters based on standardized phantom studies. Several of
the recommendations are discussed below.
The Netherlands study group recommended a strict adherence
to injected dose, post injection delay and iterative reconstruc-
tion guidelines among centers in order to improve SUV reliability.
Matching of image resolution as closely as possible among
centers in multi-centre trials to avoid differences in SUV was
recommended. The group also recommended guidelines for
ROI selection in lesions to help standardization. Fixed size ROI
providing ‘SUVpeak’, maximum pixel values providing ‘SUV max’ or
the average ROI value within a 2D or 3D ROI providing ‘SUVmean’
were all put into standardized guidelines. Recommendations
for patient preparation were specified in order to minimize
patient-related or other physiological effects on SUV accuracy
and reproducibility. Moreover, guidelines aimed at optimizing
3
18F FDG uptake in the tumor, minimizing uptake in surrounding
tissues (muscle, brown fat) and minimizing SUV variability were
put forward. Recommendations for the administration procedure
were given to ensure that the net dose given to the patient is
exactly known, primarily by avoiding unknown remaining
activities during preparation and administration. 18F FDG dose
was specified as a function of patient weight, scanning mode,
percentage bed overlap and acquisition time per bed position.
Interchangeability of SUV between acquisitions in different scan-
ners and in different institutions is affected by the overall spatial
resolution of the PET images after reconstruction, filtering or
smoothing and processing. Comparison of data from different
scanners requires standardized reconstruction and filtering in
order to match image resolution across scanners so as to allow
for SUV interchangeability. SUV outcome is also determined by
data analysis procedures. Common ROI strategies are the use of
fixed sized 2D or 3D ROI, manually defined ROI in one or more
axial slices and 3D ROI based on region growing procedures while
applying a user-specified threshold.
Boellaard et al 14 performed a simulation study to determine
the effects of noise, image resolution and ROI definition on the
accuracy of SUVs. Experiments and simulations were based on
thorax phantoms with tumors of 10, 15, 20 and 30 mm diameter
and tumor-to-background ratios (TBRs) of 2, 4 and 8. Fifty sino-
grams were generated at three noise levels. All sinograms were
reconstructed using ordered subset expectation maximization
(OSEM) with two iterations and 16 subsets, with or without a
6 mm Gaussian filter. For each tumor, the maximum pixel value
and the SUVmean (from ROI based on isocontour and on adaptive
threshold of 50 percent and 70 percent), as well as 3D ROI of
one cubic centimeter volume (SUVpeak) placed in the zone of the
highest uptake were calculated. The results indicated that the
maximum pixel value within an object increases with image noise
level and with increasing object size. Based on this experimental
evidence, the Netherlands group advocates phantom-based
standardization of PET/CT systems as a prerequisite for partici-
pation in clinical trials. The guidelines mandate the maximum
voxel value or SUV max to be always reported. However, use of
larger VOI may provide SUV estimates with better precision.
Therefore, in response monitoring settings, use of 3D VOI with a
threshold of 41 percent, 50 percent or 60 percent of the SUVmax
is recommended to be used consistently in all sequential scans of
a patient13. When such threshold-based VOIs are not adequate,
smaller VOI obtained with higher percentage threshold values
can be applied. The guidelines included quality control (QC)
measurements using torso abdominal phantom with multiple 18F
FDG-filled spheres of various sizes with a lesion-to-background
ratio of 8 to be used to calculate reproducibility of SUVmax and
SUVmean at different threshold-based VOIs. VOIs based on adap-
tive threshold of 41 percent of maximum SUV provide VOI with a
volume close to real sphere volumes used.
As reflected by the studies and observations of working groups
for standardization of PET-based therapy clinical trials, the vari-
ability of SUV between sequential observations on the same
system or different systems exert considerable influence on
the interpretation of such trials. This highlights the need for
adequate PET/CT hardware and software optimization to reduce
system-related variability of quantification parameters. Such
variability may be related to non-optimized quality control and
calibration procedures, photomultiplier drifts due to tempera-
ture and other factors, system sensitivity fluctuations, PET and
CT misregistrations related to minor patient motion, etc. Special
focus on PET/CT hardware design and engineering to reduce or
eliminate such variability introducing factors by optimizing and
automating quality control and calibration procedures, as well as
software-based autoregistration of PET and CT and automated
use of appropriate quantitative measures like SUVpeak in order
to reduce statistical variability, would possibly increase the reli-
ability of SUV for response monitoring.

Figure 1: PET Detector Materials Properties

PET Detector Material Properties

Property Characteristic Desired Value LSO BGO GSO Nal

Density (g/cc) High 7.4 7.1 6.7 3.7

Defines detection efficiency of detector and
scanner sensitivity
Effective atomic number High 65 75 59 51

Decay time (nsec) Defines detector dead time and randoms rejection Low 40 300 60 230

Relative light output (%) Impacts spacial and energy resolution High 75 15 35 100

Energy resolution (%) Influences scatter rejection Low 10.0 10.1 9.5 7.8

Nonhygroscopic Yes Yes Yes Yes No

Simplifies manufacturing, improves reliability
and reduces service costs
Ruggedness Yes Yes Yes No No

4
Instrumentation
As discussed in the preceding chapters, the accuracy of quantita-
tive values, like SUV derived from PET/CT imaging, depends not
only on patient-specific variables such as injected dose and blood
glucose level but, more importantly, on system-specific factors
like detector sensitivity and resolution, as well as consistency of
system calibration, PET and CT coregistration and appropriate
algorithms for image reconstruction.
Detector System
The detector system is at the heart of the PET scanner. Its design
determines the key performance characteristics. The elements of
the detector system are the crystal, the photomultiplier tube and
the processing electronics. Opposing crystals in a PET detector
ring receive the coincident photons emitted secondary to a posi-
tron annihilation and convert them into a light signal, which is
then received and amplified by a photomultiplier tube. In order
for the opposing photons to be recognized as a single coincident
event, they must strike the detectors located opposite each other
in the PET gantry within a small duration of time. This is called
the coincidence window. The detector material is key to count
rate efficiency. The detector performance characteristics are
determined by the material, crystal size, detector geometry and
the quantity of crystal elements in a PET/CT system.
Crystal Material
Count rate efficiency of a PET crystal depends on factors like scin-
tillation decay time and light output. Crystal and photomultiplier
tubes, along with system electronics, need to optimally perform
to obtain very short coincidence windows. A short coincidence
window leads to higher true count rates and lower scatter and
random events, which constitute noise. Crystal decay time and
light output contribute to the ability to achieve shorter coinci-
dence windows. Coincidence windows for current generation
PET detector materials are in the range of 4.1 nanoseconds.
Conventional PET scintillator materials like bismuth germanium
oxide (BGO), gadolinium oxyorthosilicate (GSO) or sodium iodide
doped with thallium (Nal) are characterized by larger coincidence
windows. Adoption of newer crystal material, like lutetium oxyor-
thosilicate (LSO), pioneered by Siemens, has increased count rate
efficiency and made 3D scanning possible, which has significantly
improved acquisition speeds and image quality.
As shown in the comparative chart of various PET detector
materials (Figure 1), LSO has high density and a high atomic
number for fast scintillation decay time and a high light output
for improved energy and position determination. This enables
Siemens Biograph™ PET•CT systems to achieve high count rate
efficiencies even with low injected dose.
With LSO, seemingly opposing requirements are achieved at the
same time: for oncology imaging, superb image quality is demon-
strated even at fast acquistion speeds, while for dynamic perfu-
sion imaging, high count rates are recorded without detector
saturations due to rapid decay times.
*Based on competitive literature available at time of publication; data on file.
Crystal Geometry
The size of individual crystal elements in a detector block in
the PET gantry is a key factor that influences the resolution of
acquired PET image. High resolution images not only improve
lesion detection and diagnostic accuracy, but also improve the
accuracy of quantification due to lower partial volume effects,
as mentioned previously in this paper. Biograph mCT achieves
the industry’s finest volumetric resolution* of 87 cubic mm with
a maximum image matrix of 400x400 due to the OptisoHD detec-
tion system, with an arrangement of 13x13 crystals per detector
block of 4x4x20 mm crystal elements. Such high resolution
imaging decreases partial volume effects compared to conven-
tional detector designs and achieves the highest NEMA and
volumetric resolution for clinical PET.* Due to the high resolution
and optimum count rate efficiency of Biograph mCT, visualization
of small lesions is enhanced along with the quantitative accuracy
of the SUV generated.
13x13 LSO array
Crystals
Light guide
2x2 PMT array
Voltage divider
OptisoHD detector design with 13x13 LSO crystal matrix and
photomultiplier tube assembly.
Crystal Volume
The volume of crystal material available in a gantry not only deter-
mines the FOV per PET bed position and the coverage, but also
the count rate during 3D acquisition. As the amount of crystal
increases, the amount of coincident photons also increases along
with an increase in the true count rate capability. Siemens has
pioneered the concept of increasing the amount of crystal mate-
rial within a system by increasing the number of detector rings
in order to create a larger solid angle for PET acquisition with
consequent increase in true count rate capability in 3D mode.
As a result, the number of bed positions and the time per bed
decrease at the same time for a compounded effect on scan time
reduction. Therefore, a unique four ring detector design (TrueV)
on the Biograph system is available to enable scans at half
the time or half the dose compared to conventional three ring
designs. When combined with TOF technology (ultraHD•PET),
imaging can be performed at half the time and half the dose
compared to conventional three ring designs. The increase in
count rate efficiency also helps achieve optimum counting statis-
5
tics even at very high resolutions in order to achieve superb quan-
titative accuracy even with significant reductions in acquisition
time. Quantitative accuracy is compromised with low count rate
and high noise levels. Thus improved count rate capabilities due
to crystal and detector-related innovations help improve quantita-
tive accuracy of the system.
Calibration Method
As mentioned earlier, the reproducibility and accuracy of a quan-
titative parameter like SUV is influenced by the overall system
performance. Factors such as inherent detector drift, shifting
PMT gains due to temperature and voltage variations and other
factors may affect quantification accuracy. To compensate for
these effects and ensure consistent results, appropriate calibra-
tion mechanisms need to be employed. Simpler methods use
line sources with spread out calibration intervals that measure
a subset of performance parameters. However, more compre-
hensive methods are required to more closely replicate the char-
acteristics of a patient15 and also to allow for more advanced
acquisition technologies, like TOF. In order to optimize the
procedure for consistent system calibration and to ensure repro-
ducibility and accuracy of quantitative measurements, Biograph
mCT incorporates a daily phantom-based quality control and
calibration protocol termed as Quanti•QC. Quanti•QC measures
and calibrates a large array of system parameters on a regular
basis in order to fine tune the system for optimum performance
and reproducible quantitative measurements and to eliminate
system-related variables. In addition, the tightly regulated water-
cooled gantry ensures system temperature stability for consistent
performance.
Quanti•QC
The process employs daily system calibration using a cylindrical
20 cm diameter, 27 cm long phantom with approximately two
mCi of 68Ge and, among other steps, performs 11 automated
steps to achieve normalization of the PET scanner:
1. Block Noise
2. Block Efficiency
3. Measured Randoms
4. Scanner Efficiency
5. Scatter Ratio
6. Scanner Efficiency Correction Factor
7. Image Plane Efficiency
8. Block Timing Offset
9. Block Timing Width
10. Time Alignment Residual
11. Time Alignment Fit (x/y)
6
Individual crystal efficiencies, like light output, may change
within a detector block and may lead to inaccuracies in counting
efficiency. The block noise check analyzes the efficiencies of
each crystal within a detector block. The efficiency of each
crystal is compared to the average efficiency of all crystals in
the same location in all blocks. Any crystals with large deviation
are flagged as defects while others are effectively compensated
through calibration. This ensures consistent performance among
all crystal elements within a detector block.
With multiple detector blocks within a detector ring, inconsisten-
cies within individual detector blocks can increase noise and arti-
facts. The block efficiency checks the efficiency of entire detector
blocks against each other. Deviations >20 percent are flagged as
failed; those below the threshold can effectively be calibrated to
ensure a uniform image.
3D PET acquisition benefits from short coincidence windows
to decrease random coincidences which may severely increase
image noise. Thus the objective of every PET detector design and
calibration method is to improve true count rates and eliminate
randoms. The measured randoms test compares the measured
amount of randoms from the phantom against the calculated
number given by the singles rate squared. A variation above 3
percent is classified as a failed test. The obvious source of error
is an improperly set coincidence window. Thus the measured
randoms test helps ensure the proper operation of the coinci-
dence detection system.
The scanner efficiency, also called sensitivity, is defined as the
counts per second per Becquerel per cubic centimeter (cps/Bq/
cc). Sensitivity is primarily determined by the amount of LSO in
the scanner and should not change over time. However, sensi-
tivity may vary due to the phantom activity or volume being
entered incorrectly or hardware failures leading to failure to
detect true coincidence events. Measurement and calibration for
optimized sensitivity can be performed only with a phantom, since
a volume reference is required. The phantom activity in Bq/cc is
required to calculate the sensitivity in cps/Bq/cc from the corrected
cps rate. The test is passed with a deviation < 30 percent from the
expected sensitivity. Utilization of a daily QC protocol based on a
68Ge phantom calibrating for system sensitivity, as well as all other
parameters mentioned earlier, marks the key difference of Biograph
mCT from the conventional line source-based calibration approach
and defines the commitment of Siemens to reproducible quantita-
tive accuracy.
Scatter of photons is an essential component of PET acquisition
and can degrade image quality and add to image noise. The
scatter ratio check, which is a part of the daily calibration, also
requires a phantom, since only volumes exhibit scattering. The 20
cm diameter 68Ge polyethylene phantom used for daily calibra-
tion in Biograph mCT has a known scatter fraction of 32 percent
on a 4-ring PET system. Based on the relationship between scatter
fraction and tube drift in the PET photomultiplier tubes (PMT),
the scatter test is a highly sensitive indicator of PMT drift. If the
scatter test fails, a detector setup is required.
Further checking of the accuracy of calibration is performed by
the scanner efficiency correction factor check which determines
if the absolute image calibration has been computed correctly.
Again, a volumetric phantom is required to compare the fully
corrected PET image to the actual current radioactivity in the
phantom. The test is passed with a deviation <30 percent from
the expected value. The test is similar to the scanner efficiency
test, but based on actual reconstructed images rather than the
raw sinogram.
The image plane efficiency test is an additional validation to
check if normalization is achieved in all image planes. In the
world of 3D PET scanning, there are many more counts in the
center of each ring than between the rings and at the ends of the
FOV. The normalization corrects for these statistical differences
by computing a plane efficiency for each axial slice in the image.
If these corrections are not accurate, there would be streaks in
the coronal view of a patient.
TOF acquisition involves determination of the time interval
between two coincident photons and using that information
to determine the origin of the coincidence photons. This tech-
nique reduces background activity and improves lesion contrast
significantly. The block timing offset and width test is related
to TOF calibration. Since the test is performed with the 20 cm
phantom in the center of the FOV, it is expected that the blocks
on opposite sides of the gantry would have the majority of their
emission events in the center time bin of the TOF sinogram. This
phenomenon can be observed by histogramming all the emission
events into the 13 time bins provided in the TOF sinogram. These
histograms should also have a characteristic width based on the
phantom size. Regular calibration for such TOF specific factors
ensures optimal image quality since introduction of TOF adds
additional variables to the PET acquisition process.
The time alignment fit and residual analyzes the consistency
between the spatial and temporal dimensions of the TOF sino-
gram. In order to improve image quality using TOF reconstruction
methods, the information in the TOF sinogram must be consis-
tent between the time and spatial domains of the sinogram.
Phantom-based daily Quanti•QC based on measurement, calibra-
tion and optimization of such a wide range of parameters is key
to the consistent and reproducible quantitative accuracy and
image quality performance of Biograph mCT. Such a comprehen-
sive calibration approach performed as a daily routine is a key
differentiator of Biograph mCT from other approaches.
Registration and Attenuation Correction Methods
Correct attenuation correction (AC) of PET is of crucial impor-
tance not only for optimum image quality but also for the accu-
racy of measured quantitative values. In addition to relevance
to oncologic imaging, PET quantification expands to parameters
like myocardial blood flow relevant to PET myocardial perfusion
imaging. Since CT-based attenuation correction is key for proper
image generation for both whole-body PET/CT for oncology as
well as PET in cardiology and neurology, any approach to improve
attenuation correction also helps quantitative accuracy.
The key to correct CT attenuation correction (CT AC) is accurate
coregistration of PET and CT. For whole-body PET/CT acquisition,
inaccurate coregistration can be based on several factors: system-
related CT and PET misregistrations may be related to patient
bed deflection and misregistration due to minor patient motion
between PET and CT acquisitions. Specific artifacts related to
such misregistrations have been defined in the literature and are
recognized by clinicians. However, the impact of such misregis-
trations on quantitative accuracy have not yet been clearly delin-
eated. Similar misregistrations between CT and PET in cardiac
PET myocardial perfusion or reversibility studies have been more
widely studied since the artifacts can often be significant and
may lead to clinical interpretation errors. In the era of quantita-
tive myocardial blood flow imaging with PET, improper attenua-
tion correction due to CT and PET misregistration due to different
breathing patterns and diaphragmatic positions during CT and
PET acquisition may cause inaccurate flow values and create
attenuation correction-generated perfusion abnormalities16.
7
Figure 2: Conventional vs Cantilever Patient Handling System
Conventional SMART PHS
CT PET
Cantilever Patient Handling System Design
Biograph mCT eliminates system-introduced misregistration
by ensuring absence of any patient bed deflection between
the CT and PET by a unique cantilever patient handling system
(SMART PHS). Although PET/CT systems are integrated, the PET
and CT scanner components are still placed in sequential order.
Changes in patient position due to mechanical variations within
the patient handling system need to be avoided between the
PET and CT scans. Conventional designs, where the imaging
pallet alone supports the patient within the CT and PET imaging
field, incur various degrees of deflection, which may lead to an
offset between the PET and CT acquisitions. A cantilever design
where the patient handling system moves as one avoids deflec-
tion, resulting in consistency between the two scans, thereby
improving registration accuracy.
Auto Cardiac Registration
Misregistration in PET/CT in cardiac imaging is common since
the position of the heart and diaphragm can be vastly different
during the short CT acquisition compared to the longer PET acqui-
sition. Respiratory cycles can cause the left ventricle (LV) to be
translated up to 22 mm17, and heart motion during the CT acqui-
sition can also lead to stepping artifacts in the CT AC images18.
This may cause parts of the LV in the emission image, typically in
the lateral mid-apical region, to invade the lung parenchyma in
the CT AC and lead to incorrect µ values. The resulting emission
image will then have a decrease of counts in such areas, which
may be misread as a real perfusion defect caused by cardiovas-
cular disease19.
8
The conventional patient bed design
(left) shows significant deflection
between the CT and PET which leads
to systematic misregistration between
the CT and PET. The cantilever design of
the SMART PHS of Biograph mCT (right)
shows no deflection between the two
gantries and the resulting image also
shows perfect coregistration.
CT PET
The most common correction method used in clinical practice is
a manual checking and alignment after the data is acquired20,
though this can be subject to inter and intra-user variability. It
is also time-consuming21. A different approach is to acquire a
number of fast, low-dose CT scans during free breathing, and then
choose the best-aligned CT in order to perform AC22. However, it
is still time-consuming to consider each CT in turn, and leads to
additional imaging time and radiation dose to the patient.
An automated process of registration of PET and CT data has the
potential to significantly improve quality and accuracy of cardiac
PET by eliminating faulty CT AC-related artifacts and consequent
quantitative inaccuracies and also by eliminating time consuming
and often inaccurate manual coregistration required for correct
alignment. SMART Auto Cardiac Registration, a feature on
Biograph mCT, is an automatic translation algorithm to align the
PET image with a single CT in order to reduce time spent manu-
ally aligning datasets, improve reproducibility, and reduce dose,
by only requiring one CT.
For the Auto Cardiac Registration on Biograph mCT, a translation-
only registration algorithm has been implemented that uses the
Mutual Information similarity function23 and a Powell optimizer24
to determine the optimal translation. Mutual Information is
a popular image similarity measure for registration of multi-
modality images. It is a measure of the statistical dependence
between two random variables or the amount of information
that one variable contains about the other. It can be qualitatively
explained as a measure of how well one image explains the other.
Figure 3: Conventional vs Auto Cardiac Registration

Improvement in anterolateral wall uptake (arrow) following correct alignment of cardiac perfusion PET and CT prior to attenuation correction. Inferior wall
attenuation correction is evident in spite of slight misalignment of CT and PET in the upper row. However, subtle decrease in anterolateral wall in the corrected
image due to misalignment (upper row) is absent when the CT and PET are correctly aligned (bottom row).

Misaligned CT and PET

Uncorrected PET PET and CT Fusion Attenuation-

Corrected PET

Correctly aligned CT and PET

Uncorrected PET PET and CT Fusion Attenuation-

Corrected PET

Given that both PET and CT images show certain clearly discern-
able similarities as in landmarks like clearly defined organs,
discernable differences in uptake and Hounsfield Unit (HU) levels
between various organs and surrounding tissues like heart and
lungs, liver and abdomen, etc., an image intensity histogram is
able to measure the amount of information available in the two
images combined and the similarities between the two in order
to achieve coregistration. The similarity function is modified by
means of a weighting function that ensures that the algorithm
focuses on the alignment of the LV, not on other structures.
and the CT dataset is then registered to it. While the registra-
tion is calculated mainly using the information inside the LV, the
whole CT image volume is translated with respect to the emission
image prior to reconstruction.
Auto Cardiac Registration has been validated to perform at least
as well as a clinical manual registration for the purpose of AC of
PET/CT when separate free breathing CT scans are acquired for
both rest and stress, and for healthy and diseased patients25.

The location of the LV is identified during an automated pre-

processing step, where the LV is detected and cropped in the
axial, coronal and sagittal dimensions of the PET non-AC dataset,

9
Figure 4: Conventional vs Neuro AC Attenuation Correction

Conventional CT AC
18
F FDG brain PET following
CT mu-map Attenuation-Corrected PET Neuro AC without CT appears
identical to the same data
attenuation corrected using
CT. Note absence of any
discernable difference in
uptake patterns and intensity
between the two corrected
PET images.

SMART Neuro AC

Calculated mu-map Attenuation-Corrected PET

PET-only Attenuation Correction
Recent focus on neurological applications of PET, including
epileptic foci determination with 18F FDG as well as potential new
applications like brain amyloid imaging have led to innovations
in attenuation correction for PET brain acquisition. Attenuation
correction approaches for PET brain without a CT is desirable due
to avoidance of radiation dose as well as eliminating radiation to
sensitive organs like the lens of the eye. However, such attenua-
tion correction algorithms need not only maintain image quality
but also ensure quantitative accuracy similar to brain PET with
CT AC.
The SMART Neuro AC algorithm on Biograph mCT takes advan-
tage of the brain’s fairly simple and consistent geometry and
tissue distribution. It approximates the mu-map for a PET only
brain scan based on the ability to find the tissue/air boundary
around head from a non-attenuation corrected (NAC) PET scan.
To accommodate all possible tracers in brain imaging, an adap-
tive thresholding of the edge map is required, using a method of
polar boundary processing. Once the perimeter of the head has
been determined, bone inside the air/skin boundary is modeled

10
 using image morphology. At 4 mm from the boundary, a 4 mm
segment of bone is introduced. The assigned mu values for the
three classes of mu are:
air = 0.000 cm-1
tissue = 0.093 cm-1
bone = 0.140 cm-1
Testing was performed on a total of 129 patient scans using both
qualitative and quantitative methods. The patient population
covers a variety of tracers 3, scanner types 2 and sites 4. Results
indicate that 60 percent of the brain pixels are below 5 percent
error and almost 99 percent of brain pixels are below 10 percent
error (absolute value) as defined to be the percent difference
between the reconstructed PET values using the calculated
mu-map vs. the values using the CT-based mu-map. The algo-
rithm also demonstrated good timing performance by creating a
mu-map from an uncorrected PET in about six seconds.
Quantification Software
PET Oncology Follow-up with SUVpeak
Current practice incorporates SUVmax (the maximum value of SUV
in a single voxel within a tumor ROI) as the major quantitative
parameter. However, since SUV max is essentially a single voxel
ROI, it is subject to larger statistical variation compared to other
SUV measurement criteria. Average SUV within a tumor ROI has
been used in several studies but suffers from a lack of reproduc-
ibility, since it depends on the tumor ROI, which may be subject
to individual variations based on physician preferences regarding
thresholding or manual margin drawings. Thus, for the majority
of studies and clinical trials, SUVmax has remained the default
choice in spite of its limitations. SUVmax is highly dependent on
the statistical quality of the images and the voxel size depending
on the acquisition matrix. The SUVmax variability increases as the
lesion matrix size is increased from 128x128 to 256x256. Vari-
ability increases with fewer counts as the patient size increases

Figure 5: Conventional SUVmax vs SUVpeak quantification

Conventional Siemens syngo.via

1 Pixel (SUVmax) 1 cm3 (SUVpeak)

Graphical representation of individual voxels with SUV involving a lung tumor after (top) and before (bottom) therapy. Pre-therapy and post-therapy
SUVmax evaluation (left) shows a 17.6 percent decrease in metabolic activity, which reflects inadequate tumor response. SUVpeak calculation (right)
based on an average of multiple voxels involving the region with highest uptake shows a far more significant tumor response with a 30.3 percent
decrease in metabolic activity.

Since SUVmax is subject to significant statistical variation, SUVpeak promises to be more reflective of true response as well as more robust to statistical variations.

11
Figure 6: Comparison of SUVmax, SUVpeak and tumor volume across three time points

May 8, 2008 May 20, 2008 June 4, 2008

SUVmax 20.73 SUVmax 15.19 SUVmax 9.12

SUVpeak 16.30 SUVpeak 8.81 SUVpeak 5.4
Tumor Vol 20.7 cm3 Tumor Vol 6.22 cm3 Tumor Vol 2.81 cm3

and the count statistics decrease 5 . The measured activity
concentration in a small volume of a PET image depends on the
activity in neighboring voxels. Activity levels in the neighboring
voxels may cause a spill-in or spill-out of activity in any voxel
being evaluated for SUV. This partial volume effect, combined
with sensitivity to image noise, is the reason SUVmax in a single
voxel within a tumor ROI is subject to inaccuracies. SUV max will
increase with a higher level of image noise, which may be due to
shorter acquisition time. Lower injected dose may also contribute
to higher noise due to suboptimal count statistics for a standard
acquisition time.
SUVs obtained from larger, fixed ROIs are more reproducible than
single pixel SUVs as is usual for calculation of SUVmax. Nahmias
and Wahl et al 26 studied 26 patients with 18F FDG PET in two
separate occasions with a mean interval of 3+/-2 (SD) days with
comparable dose and post injection delays. SUVmax and SUVmean
were determined for tumor ROI drawn on the first study and
transferred onto the second study. SUVmax changes between two
studies were significantly higher than SUVmean and in some cases
it increased by 1.5 SUV units in which the SUVmax was above 7.5.
Thus the variability in hottest tumors was higher than the ones
with lower 18F FDG uptake. This calls into question the reliability
of depending on SUVmax for therapy response evaluation in varie-
gated tumors with fluctuating metabolic levels. SUVmean, on the
other hand, was more reproducible and the variation from large
ROIs did not differ more than 0.5 units. SUVpeak measurements
(a fixed sphere of one cubic cm volume centered on the hottest
area of the tumor) are more reproducible since they involve
representing the mean value of a few voxels representing the
hottest tumor area. This makes it close to SUVmax in terms of its
representation of the maximum tumor metabolism, yet it could

12
avoid the statistical fluctuations of SUVmax due to incorporation
of a larger number of voxels within the hottest tumor area. Velas-
quez et al27 assessed the repeatability of SUVmax, SUVpeak, and
SUV mean in 62 patients in a multicenter phase I oncology trial
who underwent double baseline 18F FDG PET studies. The varia-
tion of SUVmax between two baseline studies was much larger
than the other parameters including SUV peak and SUVmean. This
suggests that values obtained from regions with multiple voxels
are more statistically reproducible and dependable for clinical
trials. Although SUVpeak promises to have less statistical variation,
the parameters used to calculate SUV peak, like sphere diameter,
impacts the reproducibility. A recent study28 evaluated the impact
of different volumes for SUVpeak estimation on the reproducibility
of SUV peak and tumor response using pre- and post-therapy
18F FLT ** PET/CT studies in a series of 17 patients with various
solid tumors. In this study, 24 different SUVpeaks were determined
for each FLT avid tumor. There was substantial variation in both
SUVpeak and percentage tumor response with changes in SUVpeak
sphere diameter. SUVpeak of a lesion was calculated to be up to 49
percent higher or 46 percent lower than the mean when values
obtained using 24 different sphere volumes were compared.
Similar variation (from 49 percent above to 35 percent below the
mean) was also seen for percentage tumor response. The study
supported the recommendation of adopting a 1.2 cm diameter
sphere with a volume of 1 cubic cm as a standard for SUV peak
definition for tumors larger than 2 cm in diameter.
The sequential 18F FDG PET study in Figure 6 illustrates the
variation between SUVmax and SUVpeak for evaluation of therapy
response. The lung mass shows decrease in 18F FDG uptake and
SUVmax as well as SUVpeak. SUVmax and SUVpeak varies between 21
to 40 percent for individual acquisitions. Decline in SUVmax is less
pronounced compared to SUVpeak with 56 percent vs. 66 percent,
respectively. This is inherent to the SUVmax metric of the highest
SUV in a VOI and could be more influenced by statistical variation.
PET Cardiac Perfusion with Myocardial Blood Flow
Myocardial perfusion imaging at peak stress and at rest using
PET/CT with 13N NH3 or 82Rb has been widely accepted as a reli-
able method of detection of myocardial ischemia secondary to
coronary artery disease29. Standard methods of evaluation based
on relative perfusion where the image is normalized to the region
of highest perfusion may occasionally underestimate the degree
of ischemia and in some cases of balanced ischemia (secondary
to triple vessel disease), miss the ischemia completely. A normal
relative perfusion in patients with multivessel balanced disease
is not uncommon.
**18F FLT is an investigational drug and is not approved for clinical use in the U.S.
Dynamic PET myocardial perfusion imaging using list mode
acquisition can be used to calculate absolute myocardial blood
flow (MBF) values in different myocardial segments as well as
Coronary Flow Reserve (CFR) which is defined as the ratio of
MBF at peak stress to that at rest. In normally perfused healthy
myocardium, blood flow at peak stress is 3 to 4 times higher than
that at rest. A CFR of 2.5 or higher is usually associated with
absence of significant coronary artery or microvascular disease 29.
Unlike standard 82Rb and 13N NH3 MPI acquisitions that start
around 90 seconds and three minutes post-radionuclide admin-
istration respectively, dynamic list mode acquisition starts with
radionuclide administration to obtain data upon radionuclide
arrival in the right and left ventricle. The List Mode (LM) acquisi-
tion continues for 6-8 minutes and 6-10 minutes for 82Rb and 13N
NH3, respectively. Rest and stress radiopharmaceutical admin-
istration consist of approximately 1110 MBq (30 mCi) 82Rb or
370-740 MBq (10-20 mCi) 13NH3. Time activity curves are gener-
ated for myocardial segments as well as for a voxel in the LV for
generation of the arterial input function. MBF is calculated from
the time activity curves using tracer kinetic modeling based on a
one tissue compartment (82Rb) or two tissue compartment (13N
NH3) models.
AMMONIA N 13 INJECTION
INDICATIONS AND USAGE
Ammonia N 13 Injection is a radioactive diagnostic agent
for Positron Emission Tomography (PET) indicated for
diagnostic PET imaging of the myocardium under rest or
pharmacologic stress conditions to evaluate myocardial
perfusion in patients with suspected or existing coronary
artery disease.
IMPORTANT SAFETY INFORMATION
Ammonia N 13 Injection may increase the risk of cancer.
Use the smallest dose necessary for imaging and ensure
safe handling to protect the patient and health care worker.
ADVERSE REACTIONS
No adverse reactions have been reported for Ammonia
N 13 Injection based on a review of the published litera-
ture, publicly available reference sources, and adverse drug
reaction reporting system.
13
Figure 7: Conventional relative perfusion vs. myocardial blood flow31

Conventional Siemens syngo.via

Relative Perfusion Absolute Flow

Graphical representation of perfusion imaging in patient with global ischemia (top) and in a normal patient (bottom). In conventional relative perfusion
imaging, the polar plot display results are normalized to the highest activity observed. The relative perfusion pattern on the polar map in the upper left
illustration would appear normal since the region with the highest perfusion itself is already ischemic. In cases of overall depressed perfusion, an adequately
perfused reference section is missing, which may result in misleading information.

With myocardial blood flow, an absolute measure is available that can be compared to established normal values. In the top right illustration, the peak
stress values in all segments range from 0.76 to 0.99 ml/min/g while the lower limit of normal is at around 2.0 ml/min/g. This suggests significant ischemia
in all myocardial segments (balanced ischemia) which reflects uniform levels of stenosis in all coronary arteries (triple vessel disease). This helps reduce
inconclusive results even in cases of balanced disease.

In comparison, a polar plot of stress myocardial perfusion in normal patients (bottom left) again shows a uniform perfusion pattern and the stress
myocardial blood flow values (bottom right) are also in the normal range with values between 2.39 and 3.11 ml/min/g29,31.

14
Figure 8: Relative perfusion compared to myocardial blood flow in case of balanced ischemia.
The syngo® MBF software offers a simplified method of calcu-
lation of MBF and CFR values for both 13N NH3 and 82Rb with
automated delineation of myocardial margins and placement of
the LV ROI for the arterial input function generation. MBF and
CFR values of individual myocardial voxels and arterial territories
as well as multiple distinct myocardial segments are depicted as
numerical values as well as parametric polar plots with appro-
priate scaling.
The mean +/- standard deviation (SD) of MBF and CFR in normal
controls using 13N NH3 and syngo MBF is 0.86 +/-0.29 ml/g/min
(rest MBF), 2.05 +/-0.73 ml/g/min (stress MBF), and 2.65 +/- 1.17
(CFR). Rubidium-82 values in normal controls also have similar
stress and resting flow values29,31.
Inducible ischemia due to coronary artery disease is commonly
associated with reduced MBF response to stress. A stress MBF
of 1.8-2.0 ml/g/min is usually regarded as the lower limit of
normal 29,31 . Resting flow rates have a larger normal range
although flow rates below 0.40 ml/gm/min are usually associated
with resting ischemia.
Reduced stress MBF response is also seen in microvascular
disease such as that associated with diabetes. Thus MBF needs
to be interpreted with caution in the absence of clearly defined
suspicion of coronary artery disease.
Several factors affect the accuracy of MBF. These include
injected dose, volume and speed of injection, patient motion
and adequacy of CT attenuation correction. Since the cardiac
and diaphragm positions during the fast CT may be different
compared to that in the PET acquisition acquired for longer time,
the potential for misregistration and artifacts related to faulty
attenuation correction is significant and this may impact MBF
accuracy as well. Biograph mCT incorporates automated coreg-
istration for CT and PET for accurate attenuation correction of
cardiac PET which improves the accuracy for CT attenuation
correction and also the reliability of MBF.
15
Several studies have established the value of MBF measurements
in the evaluation of coronary artery disease as well as the charac-
terization of luminal stenosis and myocardial microvasculature.
A recent study30 evaluated MBF using 13N NH3 and correlated
with stenosis on CT angiography. Myocardium supplied by vessels
with significant stenosis showed significantly lower stress MBF
(1.63 +/- 0.51 ml/g/min) compared to those with normal coronary
arteries (2.13 +/ 0.54 ml/g/min).
The clinical example depicted in Figure 8 illustrates the value of
MBF in diagnosis of balanced ischemia related to triple vessel
disease in a patient with suspected coronary artery disease where
visual interpretation of relative perfusion did not clearly demon-
strate any segmental ischemia.
Figure 8 shows a 13N NH3 myocardial perfusion PET•CT of a
65-year-old woman with progressive dyspnea and signs of heart
failure. The stress rest PET images do not show well-defined hypo-
perfused areas. However, the MBF values show grossly decreased
MBF throughout the entire LV at peak stress with normal MBF at
rest, suggestive of balanced ischemia probably related to triple
vessel disease. Anterior wall MBF at peak stress is 0.92 ml/g/min
(lower limit of normal 2 ml/g/min) while resting MBF is 0.75 ml/g/
min which is within normal limits.
Conclusion
When evaluating the factors influencing the accuracy and repro-
ducibility of quantitative results on PET, it becomes obvious that
all elements in the imaging workflow need to be controlled and
optimized in order to avoid variations across devices, patients and
time as postulated by the RSNA Quantitative Imaging Biomarkers
Alliance (QIBA).
Biograph mCT together with syngo.via quantification software***
helps minimize system-based sources of variation by effectively
reducing manual interaction and automating steps, such as
quality control and image quantification.
Now, for the first time, Biograph mCT gives you quantifiable
results that are accurate and reproducible over time, along
with high count rate efficiency and superior resolution. With its
unique combination of intelligent software, daily calibration and
precise anatomical and functional co-registration, Biograph mCT
makes a quantifiable difference in diagnostic confidence, therapy
planning and treatment monitoring.
16 *** syngo.PET MBF is not yet commercially available in the U.S.
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17
HIGHLIGHTS OF PRESCRIBING INFORMATION ----------------DOSAGE FORMS AND STRENGTHS----------------
These highlights do not include all the information needed Multi-dose 30mL and 50mL glass vial containing 0.74 to 7.40
to use Fludeoxyglucose F 18 Injection safely and effectively. GBq/mL (20 to 200 mCi/mL) Fludeoxyglucose F18 Injection and
See full prescribing information for Fludeoxyglucose F 18 4.5mg of sodium chloride with 0.1 to 0.5% w/w ethanol as a
Injection. stabilizer (approximately 15 to 50 mL volume) for intravenous
administration (3).
Fludeoxyglucose F 18 Injection, USP
For intravenous use ------------------------CONTRAINDICATIONS------------------------
Initial U.S. Approval: 2005 None

----------------------RECENT MAJOR CHANGES--------------------- -------------------WARNINGS AND PRECAUTIONS------------------

Warnings and Precautions (5.1, 5.2) 7/2010 • Radiation risks: use smallest dose necessary for imaging (5.1).
Adverse Reactions (6) 7/2010 • Blood glucose abnormalities: may cause suboptimal imaging (5.2).

----------------------INDICATIONS AND USAGE--------------------- ----------------------ADVERSE REACTIONS----------------------

Fludeoxyglucose F18 Injection is indicated for positron emission Hypersensitivity reactions have occurred; have emergency resus-
tomography (PET) imaging in the following settings: citation equipment and personnel immediately available (6).
• Oncology: For assessment of abnormal glucose metabolism to To report SUSPECTED ADVERSE REACTIONS, contact PETNET
assist in the evaluation of malignancy in patients with known Solutions, Inc. at 877-473-8638 or FDA at 1-800-FDA-1088 or
or suspected abnormalities found by other testing modalities, www.fda.gov/medwatch.
or in patients with an existing diagnosis of cancer.
• Cardiology: For the identification of left ventricular myocar- ------------------USE IN SPECIFIC POPULATIONS------------------
dium with residual glucose metabolism and reversible loss • P regnancy Category C: No human or animal data. Consider
of systolic function in patients with coronary artery disease alternative diagnostics; use only if clearly needed (8.1).
and left ventricular dysfunction, when used together with • Nursing mothers: Use alternatives to breast feeding (e.g., stored
myocardial perfusion imaging. breast milk or infant formula) for at least 10 half-lives of radio-
• Neurology: For the identification of regions of abnormal glucose active decay, if Fludeoxyglucose F 18 Injection is administered
metabolism associated with foci of epileptic seizures (1). to a woman who is breast-feeding (8.3).
• Pediatric Use: Safety and effectiveness in pediatric patients have
-----------------DOSAGE AND ADMINISTRATION----------------- not been established in the oncology and cardiology settings (8.4).
Fludeoxyglucose F18 Injection emits radiation. Use procedures
to minimize radiation exposure. Screen for blood glucose See 17 for PATIENT COUNSELING INFORMATION
abnormalities.
• In the oncology and neurology settings, instruct patients to fast Revised: 1/2011
for 4 to 6 hours prior to the drug’s injection. Consider medical
therapy and laboratory testing to assure at least two days of
normoglycemia prior to the drug’s administration (5.2).
• In the cardiology setting, administration of glucose-containing
food or liquids (e.g., 50 to 75 grams) prior to the drug’s injec-
tion facilitates localization of cardiac ischemia (2.3).
Aseptically withdraw Fludeoxyglucose F18 Injection from its
container and administer by intravenous injection (2).
The recommended dose:
• for adults is 5 to 10 mCi (185 to 370 MBq), in all indicated
clinical settings (2.1).
• for pediatric patients is 2.6 mCi in the neurology setting (2.2).
Initiate imaging within 40 minutes following drug injection;
acquire static emission images 30 to 100 minutes from time of
injection (2).

18
FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE 8 USE IN SPECIFIC POPULATIONS

1.1 Oncology 8.1 Pregnancy
1.2 Cardiology 8.3 Nursing Mothers
1.3 Neurology 8.4 Pediatric Use
2 DOSAGE AND ADMINISTRATION 11 DESCRIPTION
2.1 Recommended Dose for Adults 11.1 Chemical Characteristics
2.2 Recommended Dose for Pediatric Patients 11.2 Physical Characteristics
2.3 Patient Preparation 12 CLINICAL PHARMACOLOGY
2.4 Radiation Dosimetry 12.1 Mechanism of Action
2.5 Radiation Safety – Drug Handling 12.2 Pharmacodynamics
2.6 Drug Preparation and Administration 12.3 Pharmacokinetics
2.7 Imaging Guidelines 13 NONCLINICAL TOXICOLOGY
3 DOSAGE FORMS AND STRENGTHS 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
4 CONTRAINDICATIONS 14 CLINICAL STUDIES
5 WARNINGS AND PRECAUTIONS 14.1 Oncology
5.1 Radiation Risks 14.2 Cardiology
5.2 Blood Glucose Abnormalities 14.3 Neurology
6 ADVERSE REACTIONS 15 REFERENCES
7 DRUG INTERACTIONS 16 HOW SUPPLIED/STORAGE AND DRUG HANDLING
17 PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing
information are not listed.

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE 2.1 Recommended Dose for Adults

Fludeoxyglucose F18 Injection is indicated for positron Within the oncology, cardiology and neurology settings, the
emission tomography (PET) imaging in the following recommended dose for adults is 5 to 10 mCi (185 to 370
settings: MBq) as an intravenous injection.

1.1 Oncology 2.2 Recommended Dose for Pediatric Patients

For assessment of abnormal glucose metabolism to assist
in the evaluation of malignancy in patients with known or
suspected abnormalities found by other testing modalities,
or in patients with an existing diagnosis of cancer.
1.2 Cardiology
For the identification of left ventricular myocardium with
residual glucose metabolism and reversible loss of systolic
function in patients with coronary artery disease and left
ventricular dysfunction, when used together with myocar-
dial perfusion imaging.
1.3 Neurology
For the identification of regions of abnormal glucose
metabolism associated with foci of epileptic seizures.
2 DOSAGE AND ADMINISTRATION
Fludeoxyglucose F18 Injection emits radiation. Use proce-
dures to minimize radiation exposure. Calculate the final
dose from the end of synthesis (EOS) time using proper
radioactive decay factors. Assay the final dose in a prop-
erly calibrated dose calibrator before administration to the
patient [see Description (11.2)].
Within the neurology setting, the recommended dose for
pediatric patients is 2.6 mCi, as an intravenous injection.
The optimal dose adjustment on the basis of body size or
weight has not been determined [see Use in Special Popula-
tions (8.4)].
2.3 Patient Preparation
• To minimize the radiation absorbed dose to the bladder,
encourage adequate hydration. Encourage the patient to
drink water or other fluids (as tolerated) in the 4 hours
before their PET study.
• E ncourage the patient to void as soon as the imaging
study is completed and as often as possible thereafter for
at least one hour.
• S creen patients for clinically significant blood glucose
abnormalities by obtaining a history and/or laboratory
tests [see Warnings and Precautions (5.2)]. Prior to
Fludeoxyglucose F 18 PET imaging in the oncology and
neurology settings, instruct patient to fast for 4 to 6 hours
prior to the drug’s injection.
• I n the cardiology setting, administration of glucose-
containing food or liquids (e.g., 50 to 75 grams) prior to
Fludeoxyglucose F 18 Injection facilitates localization of
cardiac ischemia

19
2.4 Radiation Dosimetry
The estimated human absorbed radiation doses (rem/mCi)
to a newborn (3.4 kg), 1-year old (9.8 kg), 5-year old (19
kg), 10-year old (32 kg), 15-year old (57 kg), and adult (70
kg) from intravenous administration of Fludeoxyglucose F
18 Injection are shown in Table 1. These estimates were
calculated based on human 2 data and using the data
published by the International Commission on Radiological
Protection 4 for Fludeoxyglucose 18F. The dosimetry data
show that there are slight variations in absorbed radiation
dose for various organs in each of the age groups. These
dissimilarities in absorbed radiation dose are due to devel-
opmental age variations (e.g., organ size, location, and
overall metabolic rate for each age group). The identified
critical organs (in descending order) across all age groups
evaluated are the urinary bladder, heart, pancreas, spleen,
and lungs.

Table 1. Estimated Absorbed Radiation Doses (rem/mCi) After

Intravenous Administration of Fludeoxyglucose F 18 Injectiona

Newborn 1-year old 5-year old 10-year old 15-year old Adult
Organ
(3.4 kg) (9.8 kg) (19 kg) (32 kg) (57 kg) (70 kg)

Bladder wallb 4.3 1.7 0.93 0.60 0.40 0.32

Heart wall 2.4 1.2 0.70 0.44 0.29 0.22
Pancreas 2.2 0.68 0.33 0.25 0.13 0.096
Spleen 2.2 0.84 0.46 0.29 0.19 0.14
Lungs 0.96 0.38 0.20 0.13 0.092 0.064
Kidneys 0.81 0.34 0.19 0.13 0.089 0.074
Ovaries 0.80 0.8 0.19 0.11 0.058 0.053
Uterus 0.79 0.35 0.19 0.12 0.076 0.062
LLI wall* 0.69 0.28 0.15 0.097 0.060 0.051
Liver 0.69 0.31 0.17 0.11 0.076 0.058
Gallbladder wall 0.69 0.26 0.14 0.093 0.059 0.049
Small intestine 0.68 0.29 0.15 0.096 0.060 0.047
ULI wall** 0.67 0.27 0.15 0.090 0.057 0.046
Stomach wall 0.65 0.27 0.14 0.089 0.057 0.047
Adrenals 0.65 0.28 0.15 0.095 0.061 0.048
Testes 0.64 0.27 0.14 0.085 0.052 0.041
Red marrow 0.62 0.26 0.14 0.089 0.057 0.047
Thymus 0.61 0.26 0.14 0.086 0.056 0.044
Thyroid 0.61 0.26 0.13 0.080 0.049 0.039
Muscle 0.58 0.25 0.13 0.078 0.049 0.039
Bone surface 0.57 0.24 0.12 0.079 0.052 0.041
Breast 0.54 0.22 0.11 0.068 0.043 0.034
Skin 0.49 0.20 0.10 0.060 0.037 0.030
Brain 0.29 0.13 0.09 0.078 0.072 0.070
Other tissues 0.59 0.25 0.13 0.083 0.052 0.042

a MIRDOSE 2 software was used to calculate the radiation absorbed dose. Assumptions on the biodistribution based on data from Gallagher et al.1 and
Jones et al.2

b The dynamic bladder model with a uniform voiding frequency of 1.5 hours was used. *LLI = lower large intestine; **ULI = upper large intestine

20
2.5 Radiation Safety – Drug Handling
• U se waterproof gloves, effective radiation shielding,
and appropriate safety measures when handling Flude-
oxyglucose F18 Injection to avoid unnecessary radiation
exposure to the patient, occupational workers, clinical
personnel and other persons.
• R adiopharmaceuticals should be used by or under the
control of physicians who are qualified by specific training
and experience in the safe use and handling of radio-
nuclides, and whose experience and training have been
approved by the appropriate governmental agency autho-
rized to license the use of radionuclides.
• Calculate the final dose from the end of synthesis (EOS)
time using proper radioactive decay factors. Assay the
final dose in a properly calibrated dose calibrator before
administration to the patient [see Description (11.2)].
• The dose of Fludeoxyglucose F18 used in a given patient
should be minimized consistent with the objectives of
the procedure, and the nature of the radiation detection
devices employed.
2.6 Drug Preparation and Administration
• Calculate the necessary volume to administer based on
calibration time and dose.
• Aseptically withdraw Fludeoxyglucose F18 Injection from
its container.
• Inspect Fludeoxyglucose F18 Injection visually for particu-
late matter and discoloration before administration,
whenever solution and container permit.
• Do not administer the drug if it contains particulate matter
or discoloration; dispose of these unacceptable or unused
preparations in a safe manner, in compliance with appli-
cable regulations.
• Use Fludeoxyglucose F 18 Injection within 12 hours from
the EOS.
2.7 Imaging Guidelines
• Initiate imaging within 40 minutes following Fludeoxyglu-
cose F 18 Injection administration.
• Acquire static emission images 30 to 100 minutes from
the time of injection.
3 DOSAGE FORMS AND STRENGTHS
Multiple-dose 30mL and 50mL glass vial containing 0.74
to 7.40 GBq/mL (20 to 200 mCi/mL) of Fludeoxyglucose
F 18 Injection and 4.5 mg of sodium chloride with 0.1 to
0.5% w/w ethanol as a stabilizer (approximately 15 to 50
mL volume) for intravenous administration.
4 CONTRAINDICATIONS
None
5 WARNINGS AND PRECAUTIONS
5.1 Radiation Risks
Radiation-emitting products, including Fludeoxyglucose F
18 Injection, may increase the risk for cancer, especially
in pediatric patients. Use the smallest dose necessary for
imaging and ensure safe handling to protect the patient
and health care worker [see Dosage and Administration
(2.5)].
5.2 Blood Glucose Abnormalities
In the oncology and neurology setting, suboptimal imaging
may occur in patients with inadequately regulated blood
glucose levels. In these patients, consider medical therapy
and laboratory testing to assure at least two days of normo-
glycemia prior to Fludeoxyglucose F 18 Injection adminis-
tration.
6 ADVERSE REACTIONS
Hypersensitivity reactions with pruritus, edema and rash
have been reported in the post-marketing setting. Have
emergency resuscitation equipment and personnel imme-
diately available.
7 DRUG INTERACTIONS
The possibility of interactions of Fludeoxyglucose F 18
Injection with other drugs taken by patients undergoing
PET imaging has not been studied.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C
Animal reproduction studies have not been conducted
with Fludeoxyglucose F 18 Injection. It is also not known
whether Fludeoxyglucose F 18 Injection can cause fetal
harm when administered to a pregnant woman or can
affect reproduction capacity. Consider alternative diag-
nostic tests in a pregnant woman; administer Fludeoxyglu-
cose F 18 Injection only if clearly needed.
8.3 Nursing Mothers
It is not known whether Fludeoxyglucose F 18 Injection is
excreted in human milk. Consider alternative diagnostic
tests in women who are breast-feeding. Use alternatives to
breast feeding (e.g., stored breast milk or infant formula)
for at least 10 half-lives of radioactive decay, if Fludeoxy-
glucose F 18 Injection is administered to a woman who is
breast-feeding.
8.4 Pediatric Use
The safety and effectiveness of Fludeoxyglucose F 18 Injec-
tion in pediatric patients with epilepsy is established on the
basis of studies in adult and pediatric patients. In pediatric
patients with epilepsy, the recommended dose is 2.6 mCi.
The optimal dose adjustment on the basis of body size or
weight has not been determined. In the oncology or cardi-
ology settings, the safety and effectiveness of Fludeoxyglu-
cose F 18 Injection have not been established in pediatric
patients.
21
11 DESCRIPTION Table 3. Radiation Attenuation of 511
keV Photons by lead (Pb) shielding
11.1 Chemical Characteristics
Fludeoxyglucose F 18 Injection is a positron emitting Shield thickness Coefficient of
radiopharmaceutical that is used for diagnostic purposes (Pb) mm attenuation
in conjunction with positron emission tomography (PET) 0 0.00
imaging. The active ingredient 2-deoxy-2-[ 18F]fluoro-D- 4 0.50
glucose has the molecular formula of C6H1118FO5 with
a molecular weight of 181.26, and has the following 8 0.25
chemical structure: 13 0.10
26 0.01
39 0.001
52 0.0001

For use in correcting for physical decay of this radionuclide,

the fractions remaining at selected intervals after calibra-
tion are shown in Table 4.

Table 4. Physical Decay Chart for

Fludeoxyglucose F 18 Injection is provided as a ready to
use sterile, pyrogen free, clear, colorless solution. Each
mL contains between 0.740 to 7.40GBq (20.0 to 200 mCi)
of 2-deoxy-2-[18F]fluoro-D-glucose at the EOS, 4.5 mg of
sodium chloride and 0.1 to 0.5% w/w ethanol as a stabilizer.
The pH of the solution is between 4.5 and 7.5. The solu-
tion is packaged in a multiple-dose glass vial and does not
contain any preservative.
11.2 Physical Characteristics
Fluorine F 18 decays by emitting positron to Oxygen O 16
(stable) and has a physical half-life of 109.7 minutes. The
principal photons useful for imaging are the dual 511 keV
gamma photons, that are produced and emitted simultane-
ously in opposite direction when the positron interacts with
an electron (Table 2).
Table 2. Principal Radiation Emission
Data for Fluorine F 18
Radiation/Emission % Per Disintegration Mean Energy
Positron(ß+) 96.73 249.8 keV
Gamma(±)* 193.46 511.0 keV
*Produced by positron annihilation
From: Kocher, D.C. Radioactive Decay Tables DOE/TIC-I 1026,
89 (1981)
The specific gamma ray constant (point source air kerma
coefficient) for fluorine F 18 is 5.7 R/hr/mCi (1.35 x 10 -6
Gy/hr/kBq) at 1 cm. The half-value layer (HVL) for the 511
keV photons is 4 mm lead (Pb). The range of attenuation
coefficients for this radionuclide as a function of lead
shield thickness is shown in Table 3. For example, the
interposition of an 8 mm thickness of Pb, with a coef-
ficient of attenuation of 0.25, will decrease the external
radiation by 75 percent.
22
Fluorine F 18
Minutes Fraction Remaining
0* 1.000
15 0.909
30 0.826
60 0.683
110 0.500
220 0.250
*calibration time
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Fludeoxyglucose F 18 is a glucose analog that concentrates
in cells that rely upon glucose as an energy source, or in
cells whose dependence on glucose increases under patho-
physiological conditions. Fludeoxyglucose F 18 is trans-
ported through the cell membrane by facilitative glucose
transporter proteins and is phosphorylated within the cell
to [18F] FDG-6-phosphate by the enzyme hexokinase. Once
phosphorylated it cannot exit until it is dephosphorylated
by glucose-6-phosphatase. Therefore, within a given tissue
or pathophysiological process, the retention and clearance
of Fludeoxyglucose F 18 reflect a balance involving glucose
transporter, hexokinase and glucose-6-phosphatase activi-
ties. When allowance is made for the kinetic differences
between glucose and Fludeoxyglucose F 18 transport and
phosphorylation (expressed as the “lumped constant” ratio),
Fludeoxyglucose F 18 is used to assess glucose metabolism.
In comparison to background activity of the specific organ
or tissue type, regions of decreased or absent uptake of
Fludeoxyglucose F 18 reflect the decrease or absence of
glucose metabolism. Regions of increased uptake of Flude-
oxyglucose F 18 reflect greater than normal rates of glucose
metabolism.
12.2 Pharmacodynamics
Fludeoxyglucose F 18 Injection is rapidly distributed to all
organs of the body after intravenous administration. After
background clearance of Fludeoxyglucose F 18 Injection,
optimal PET imaging is generally achieved between 30 to 40
minutes after administration.
In cancer, the cells are generally characterized by enhanced
glucose metabolism partially due to (1) an increase in activity
of glucose transporters, (2) an increased rate of phosphoryla-
tion activity, (3) a reduction of phosphatase activity or, (4) a
dynamic alteration in the balance among all these processes.
However, glucose metabolism of cancer as reflected by
Fludeoxyglucose F 18 accumulation shows considerable
variability. Depending on tumor type, stage, and location,
Fludeoxyglucose F 18 accumulation may be increased,
normal, or decreased. Also, inflammatory cells can have the
same variability of uptake of Fludeoxyglucose F 18.
In the heart, under normal aerobic conditions, the myocar-
dium meets the bulk of its energy requirements by oxidizing
free fatty acids. Most of the exogenous glucose taken
up by the myocyte is converted into glycogen. However,
under ischemic conditions, the oxidation of free fatty acids
decreases, exogenous glucose becomes the preferred
myocardial substrate, glycolysis is stimulated, and glucose
taken up by the myocyte is metabolized immediately instead
of being converted into glycogen. Under these conditions,
phosphorylated Fludeoxyglucose F 18 accumulates in the
myocyte and can be detected with PET imaging.
In the brain, cells normally rely on aerobic metabolism. In
epilepsy, the glucose metabolism varies. Generally, during
a seizure, glucose metabolism increases. Interictally, the
seizure focus tends to be hypometabolic.
12.3 Pharmacokinetics
Distribution: In four healthy male volunteers, receiving an
intravenous administration of 30 seconds in duration, the
arterial blood level profile for Fludeoxyglucose F 18 decayed
triexponentially. The effective half-life ranges of the three
phases were 0.2 to 0.3 minutes, 10 to 13 minutes with a
mean and standard deviation (STD) of 11.6 (±) 1.1 min,
and 80 to 95 minutes with a mean and STD of 88 (±) 4 min.
Plasma protein binding of Fludeoxyglucose F 18 has not
been studied.
Metabolism: Fludeoxyglucose F 18 is transported into cells
and phosphorylated to [ 18F]FDG-6- phosphate at a rate
proportional to the rate of glucose utilization within that
tissue. [F 18]-FDG-6-phosphate presumably is metabolized
to 2-deoxy-2-[F 18]fluoro-6-phospho-D-mannose([F 18]
FDM-6-phosphate).
Fludeoxyglucose F 18 Injection may contain several impuri-
ties (e.g., 2-deoxy-2-chloro-D-glucose (ClDG)). Biodistribu-
tion and metabolism of ClDG are presumed to be similar
to Fludeoxyglucose F 18 and would be expected to result
in intracellular formation of 2-deoxy-2-chloro-6-phospho-
D-glucose (ClDG-6-phosphate) and 2-deoxy-2-chloro-
6phospho-D-mannose (ClDM-6-phosphate). The phos-
phorylated deoxyglucose compounds are dephosphorylated
and the resulting compounds (FDG, FDM, ClDG, and ClDM)
presumably leave cells by passive diffusion. Fludeoxyglu-
cose F 18 and related compounds are cleared from non-
cardiac tissues within 3 to 24 hours after administration.
Clearance from the cardiac tissue may require more than 96
hours. Fludeoxyglucose F 18 that is not involved in glucose
metabolism in any tissue is then excreted in the urine.
Elimination: Fludeoxyglucose F 18 is cleared from most
tissues within 24 hours and can be eliminated from the
body unchanged in the urine. Three elimination phases
have been identified in the reviewed literature. Within 33
minutes, a mean of 3.9% of the administrated radioactive
dose was measured in the urine. The amount of radiation
exposure of the urinary bladder at two hours post-adminis-
tration suggests that 20.6% (mean) of the radioactive dose
was present in the bladder.
Special Populations: The pharmacokinetics of Fludeoxy-
glucose F 18 Injection have not been studied in renally-
impaired, hepatically impaired or pediatric patients. Flude-
oxyglucose F 18 is eliminated through the renal system.
Avoid excessive radiation exposure to this organ system and
adjacent tissues.
The effects of fasting, varying blood sugar levels, condi-
tions of glucose intolerance, and diabetes mellitus on
Fludeoxyglucose F 18 distribution in humans have not been
ascertained [see Warnings and Precautions (5.2)].
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Animal studies have not been performed to evaluate the
Fludeoxyglucose F 18 Injection carcinogenic potential,
mutagenic potential or effects on fertility.
14 CLINICAL STUDIES
14.1 Oncology
The efficacy of Fludeoxyglucose F 18 Injection in positron
emission tomography cancer imaging was demonstrated
in 16 independent studies. These studies prospectively
evaluated the use of Fludeoxyglucose F 18 in patients with
suspected or known malignancies, including non-small
cell lung cancer, colo-rectal, pancreatic, breast, thyroid,
melanoma, Hodgkin’s and non-Hodgkin’s lymphoma, and
various types of metastatic cancers to lung, liver, bone, and
axillary nodes. All these studies had at least 50 patients and
used pathology as a standard of truth. The Fludeoxyglucose
F 18 Injection doses in the studies ranged from 200 MBq to
740 MBq with a median and mean dose of 370 MBq.
23
 In the studies, the diagnostic performance of Fludeoxyglu-
cose F 18 Injection varied with the type of cancer, size of
cancer, and other clinical conditions. False negative and
false positive scans were observed. Negative Fludeoxyglu-
cose F 18 Injection PET scans do not exclude the diagnosis
of cancer. Positive Fludeoxyglucose F 18 Injection PET
scans can not replace pathology to establish a diagnosis of
cancer. Non-malignant conditions such as fungal infections,
inflammatory processes and benign tumors have patterns
of increased glucose metabolism that may give rise to
false-positive scans. The efficacy of Fludeoxyglucose F 18
Injection PET imaging in cancer screening was not studied.
14.2 Cardiology
The efficacy of Fludeoxyglucose F 18 Injection for cardiac
use was demonstrated in ten independent, prospective
studies of patients with coronary artery disease and chronic
left ventricular systolic dysfunction who were scheduled to
undergo coronary revascularization. Before revasculariza-
tion, patients underwent PET imaging with Fludeoxyglucose
F 18 Injection (74 to 370 MBq, 2 to 10 mCi) and perfusion
imaging with other diagnostic radiopharmaceuticals. Doses
of Fludeoxyglucose F 18 Injection ranged from 74 to 370
MBq (2 to 10 mCi). Segmental, left ventricular, wall-motion
assessments of asynergic areas made before revasculariza-
tion were compared in a blinded manner to assessments
made after successful revascularization to identify myocar-
dial segments with functional recovery.
15 REFERENCES
Left ventricular myocardial segments were predicted to
have reversible loss of systolic function if they showed
Fludeoxyglucose F 18 accumulation and reduced perfusion
(i.e., flow-metabolism mismatch). Conversely, myocardial
segments were predicted to have irreversible loss of systolic
function if they showed reductions in both Fludeoxyglucose
F 18 accumulation and perfusion (i.e., matched defects).
Findings of flow-metabolism mismatch in a myocardial
segment may suggest that successful revascularization
will restore myocardial function in that segment. However,
false-positive tests occur regularly, and the decision to have
a patient undergo revascularization should not be based
on PET findings alone. Similarly, findings of a matched
defect in a myocardial segment may suggest that myocar-
dial function will not recover in that segment, even if it is
successfully revascularized. However, false-negative tests
occur regularly, and the decision to recommend against
coronary revascularization, or to recommend a cardiac
transplant, should not be based on PET findings alone. The
reversibility of segmental dysfunction as predicted with
Fludeoxyglucose F 18 PET imaging depends on successful
coronary revascularization. Therefore, in patients with a
low likelihood of successful revascularization, the diag-
nostic usefulness of PET imaging with Fludeoxyglucose F
18 Injection is more limited.
24
14.3 Neurology
In a prospective, open label trial, Fludeoxyglucose F 18
Injection was evaluated in 86 patients with epilepsy. Each
patient received a dose of Fludeoxyglucose F 18 Injec-
tion in the range of 185 to 370 MBq (5 to 10 mCi). The
mean age was 16.4 years (range: 4 months to 58 years;
of these, 42 patients were less than 12 years and 16
patients were less than 2 years old). Patients had a known
diagnosis of complex partial epilepsy and were under
evaluation for surgical treatment of their seizure disorder.
Seizure foci had been previously identified on ictal EEGs
and sphenoidal EEGs. Fludeoxyglucose F 18 Injection PET
imaging confirmed previous diagnostic findings in 16%
(14/87) of the patients; in 34% (30/87) of the patients,
Fludeoxyglucose F 18 Injection PET images provided new
findings. In 32% (27/87), imaging with Fludeoxyglucose
F 18 Injection was inconclusive. The impact of these
imaging findings on clinical outcomes is not known.
Several other studies comparing imaging with Flude-
oxyglucose F 18 Injection results to subsphenoidal EEG,
MRI and/or surgical findings supported the concept that
the degree of hypometabolism corresponds to areas of
confirmed epileptogenic foci. The safety and effectiveness
of Fludeoxyglucose F 18 Injection to distinguish idiopathic
epileptogenic foci from tumors or other brain lesions that
may cause seizures have not been established.
1. G allagher B.M., Ansari A., Atkins H., Casella V.,
Christman D.R., Fowler J.S., Ido T., MacGregor R.R.,
Som P., Wan C.N., Wolf A.P., Kuhl D.E., and Reivich M.
“Radiopharmaceuticals XXVII. 18F-labeled 2-deoxy-
2-fluoro-d-glucose as a radiopharmaceutical for
measuring regional myocardial glucose metabolism
in vivo: tissue distribution and imaging studies in
animals,” J Nucl Med, 1977; 18, 990-6.
2. Jones S.C., Alavi, A., Christman D., Montanez, I., Wolf,
A.P., and Reivich M. “The radiation dosimetry of 2
[F-18] fluoro-2-deoxy-D-glucose in man,” J Nucl Med,
1982; 23, 613-617.
3. Kocher, D.C. “Radioactive Decay Tables: A handbook of
decay data for application to radiation dosimetry and
radiological assessments,” 1981, DOE/TIC-I 1026, 89.
4. ICRP Publication 53, Volume 18, No. l-4,1987, pages
75-76.
16 HOW SUPPLIED/STORAGE AND DRUG HANDLING

Fludeoxyglucose F 18 Injection is supplied in a multi-dose,

capped 30 mL and 50 mL glass vial containing between
0.740 to 7.40GBq/mL (20 to 200 mCi/mL), of no carrier
added 2deoxy-2-[F 18] fluoro-D-glucose, at end of synthesis,
in approximately 15 to 50 mL. The contents of each vial are
sterile, pyrogen-free and preservative-free.

NDC 40028-511-30; 40028-511-50

Receipt, transfer, handling, possession, or use of this

product is subject to the radioactive material regulations
and licensing requirements of the U.S. Nuclear Regula-
tory Commission, Agreement States or Licensing States as
appropriate.

Store the Fludeoxyglucose F 18 Injection vial upright

in a lead shielded container at 25°C (77°F); excursions
permitted to 15-30°C (59-86°F).

Store and dispose of Fludeoxyglucose F 18 Injection in

accordance with the regulations and a general license, or
its equivalent, of an Agreement State or a Licensing State.

The expiration date and time are provided on the container

label. Use Fludeoxyglucose F 18 Injection within 12 hours
from the EOS time.

17 PATIENT COUNSELING INFORMATION

Instruct patients in procedures that increase renal clearance

of radioactivity. Encourage patients to:
• drink water or other fluids (as tolerated) in the 4 hours
before their PET study.
• void as soon as the imaging study is completed and as
often as possible thereafter for at least one hour.

Manufactured by: PETNET Solutions Inc.

810 Innovation Drive
Knoxville, TN 37932

Distributed by: PETNET Solutions Inc.

810 Innovation Drive
Knoxville, TN 37932

PN0002262 Rev. A
March 1, 2011

25
Trademarks and service marks used in this
material are property of Siemens Medical
Solutions USA or Siemens AG.

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© 2012 Siemens Medical Solutions USA, Inc.
All rights reserved. Siemens Medical Solutions USA, Inc.
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All photographs © 2012 Siemens Medical 2501 N. Barrington Road
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