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Integrated PET-CT: Evidence-Based Review of Oncology Indications

Integrated PET-CT: Evidence-Based Review of Oncology Indications

Combined-modality positronemission
tomography (PET)-
computed tomography (CT) is
becoming the imaging method of
choice for an increasing number of
oncology indications. The goal of this
paper is to review the evidence-based
literature justifying PET-CT fusion.
The best evidence comes from prospective
studies of integrated PETCT
scans compared to other methods
of acquiring images, with histopathologic
confirmation of disease presence
or absence. Unfortunately, very
few studies provide this kind of data.
Retrospective studies with similar
comparisons can be used to provide
evidence favoring the use of integrated
PET-CT scans in specific clinical
situations. Also, inferential conclusions
can be drawn from studies where
clinical rather than pathologic data
are used to establish disease presence
or absence.

PET is a diagnostic examination
from the acquisition of physiologic
images based on the detection of
positrons emitted by a glucose analog,
fluorine-18 (18F)-fluorodeoxyglucose
(FDG). Due to increased glucose
transport and increased glycolysis in
the malignant cells, 18F-FDG is accumulated
and subsequently trapped
within malignant cells to a greater
extent than normal cells. However,
FDG is not tumor-specific, as it can
also accumulate in benign and inflammatory
lesions.

Integrated PET-CT

PET imaging is based on the physiologic
distribution of the tracer and,
therefore, has poor spatial localization
compared to conventional x-rays,
CT, or MRI. As an alternative to PET
scans, fusion of PET with CT images
has been developed in order to improve
the accuracy of PET and provide both functional and anatomic information.
Image fusion can be
achieved as a visual, software-based,
or hardware-based process.

In visual image fusion, PET and
CT images obtained separately are
viewed next to each other and the
visual fusion occurs in the reader's
mind. In software fusion, PET and
CT images obtained separately are
coregistered with the help of special
software, but this is difficult and timeconsuming.
Software fusion works
well for brain studies, as brain is covered
by rigid skull, which provides
ample landmarks for fusion, and there
is no organ motion during acquisition
of functional and anatomic studies.
In contrast, such software fusion
is less successful in body imaging,
because cardiac and respiratory motions
can secondarily affect the accuracy
of anatomic and functional
studies of various organs in the chest
and abdomen.

Recently, integrated PET-CT scanners
(hardware fusion) have been developed,
consisting of a CT scanner
and a PET scanner assembled together
in one machine. Potential advantages
of integrated PET-CT scanners
are shorter image acquisition time (20-
40 vs 60-90 min), better anatomic
localization than achieved with PET
alone, and rapid staging of a malignancy
in a single study.

In preparation for an integrated
PET-CT study, the patient must be
fasting for at least 6 hours. Diabetics
should have a glucose level less than
200 mg/dL, as a high glucose level
may potentially produce false-negative
results. Patients need to lie still
for a total of 30 minutes-approximately
5 minutes for the CT scan followed
by 20 to 30 minutes for the
PET scan. A dose of 10 to 20 mCi
FDG is injected through a peripheral
intravenous (IV) line (not a central
line, as retained activity in the central
line may cause reconstruction streak
artifacts).

Use of Contrast Agents
The use of oral and IV CT contrast
agents for integrated PET-CT scans is
controversial. Usually, it is recommended
that the CT portion of PETCT
be performed without contrast, as
there is concern that contrast could
yield incorrect attenuation values in
the attenuation correction of PET images.
However, it is known that contrast-
enhanced CT scans are superior
to CT alone, especially for visualizing
perivascular structures, lymph
nodes, hepatic lesions, and so forth.
Oral contrast has been used with integrated
PET-CT scans with minimal
effect on the CT attenuation correction
of PET images (slight increase of
FDG uptake in the sigmoid colon)
and with higher-quality CT images.
Antoch et al used IV and oral contrast
in the CT scanning of integrated PETCT
and reported a significant improvement
of CT reading without compromising
PET quality.[1]

We administer IV contrast to all
patients, unless there is a contraindication
such as previous allergic reaction
or impaired renal function. We
have found that IV contrast does not
significantly affect the PET images.
The major artifact on the PET images
is found in the venous vessels carrying
the undiluted contrast to the heart.
The non-attenuation-corrected images
can be used if there is a question of
a contrast artifact, as the contrast artifact
will only appear on the CT-based
attenuation-corrected images and not
the non-attenuation-corrected images.
We use oral contrast for all patients
with suspected malignancies in
the abdomen and pelvis and also found
that PET images are not significantly
affected.

As of May 2004, Medicare approved
reimbursements for PET in
the evaluation of non-small-cell lung,
colorectal, head and neck (including
thyroid), melanoma, lymphoma,
esophageal, and breast cancers.

Data Reviewed
Data from disease-specific studies
using integrated PET-CT or PET-CT
with visual or software fusion will be
reviewed for initial diagnosis, staging,
detection of recurrence, radiation
treatment planning, and response to
treatment. When available, comparative
data will be reviewed for sensitivity,
specificity, and accuracy. The
greater the sensitivity of the imaging
study, the greater the likelihood that
the image will be positive where there
is disease present (ie, the less likely
there will be a falsely negative scan).
The greater the specificity of the imaging
study, the greater the likelihood
that the image will be negative when
there is no disease present (ie, the
lower the chance that there will be a
falsely positive scan). The greater the
accuracy of the scan, the higher the
probability of both true-positive and
true-negative images. Table 1 summarizes
the sensitivity, specificity, and
accuracy of PET-CT in different malignancies
as determined from our literature
search.

Lung Cancer

The literature has more evidence
supporting the use of PET in lung
cancer than in any other malignancy.
Integrated PET-CT significantly increases
the number of patients with
correctly staged non-small-cell lung
cancer (NSCLC) and guides treatment.

In a landmark prospective study,
Lardinois et al compared the accuracies
of integrated PET-CT, CT alone,
PET alone, and visual correlation of
PET and CT scans in the staging of 50
patients with NSCLC. As a reference,
the investigators used histopathologic
assessment or at least one other
imaging method. Compared with visual
correlation, integrated PET-CT
provided 24 items of additional information
in 41% of patients. Integrated
PET-CT was found to be more accurate
than PET alone in nodal staging.
Moreover, tumor staging was significantly
more accurate with integrated
PET-CT than with CT alone, PET
alone, or visual correlation of PET
and CT.[2] A subsequent study by
Lardinois et al found that of the 300
NSCLC patients staged with integrated
PET-CT, approximately one-third
had unsuspected extrathoracic lesions,
and only 63% of these lesions were
NSCLC metastases, suggesting the
caveat that PET-positive extrathoracic
lesions may mimic metastases of
NSCLC.[3]

Buck et al prospectively evaluated
128 patients with lung lesions (100
malignant and 28 benign tumors).
Integrated PET-CT compared to
PET for tumor staging had similar
sensitivity (99% vs 98%), greater
specificity (75% vs 46%), and
better accuracy (94% vs 87%). Integrated
PET-CT was similar to
PET for nodal involvement (74%
sensitivity, 92% specificity, and
86% accuracy). For differentiation
of operable (N0-N2) vs inoperable
(N3) patients, the accuracy of PETCT
was 96%, compared with 91% for
PET.[4]

In another study of 27 NSCLC patients,
Antoch et al found integrated
PET-CT to be more accurate in overall
tumor staging than PET or CT
alone. Primary tumor stage was correctly
determined in more patients by
integrated PET-CT than by PET or
CT alone.

In detecting metastasis to lymph
nodes, PET-CT was similar to PET
and better than CT, with a sensitivity
of 89% vs 89% vs 70%, specificity of
94% vs 89% vs 59%, and accuracy of
93% vs 89% vs 63%. Also, more distant
metastases were detected with integrated
PET-CT scan, than with PET
or CT alone.[5]

Schaffler et al studied 92 NSCLC
patients with pleural abnormalities on
CT. Their findings suggest that a
negative PET scan for indeterminate
pleural abnormalities on CT indicates
a benign character, whereas positive
findings on PET scan are sensitive
for malignancy. Visual fusion PETCT
was similar to PET in detection of
pleural malignancies.[6]

Other than the role in lung cancer
staging, coregistered PET-CT has a
very important role in radiotherapy
planning in these patients. The addition
of PET to CT imaging produced
changes of 22% to 64% in the treatment
volume in 22% to 100% of patients
studied.[7,8]

Studies have also shown that PET
is a useful test for staging small-cell
lung cancer (SCLC), potentially
modifying both the stage and management
of these patients. In our literature
search, we could not find any
studies of integrated PET-CT in staging
SCLC.

Breast CancerInitial Staging
At present, PET is not indicated
for breast cancer screening and diagnosis
of primary tumor. PET sensitivity
is low for breast tumors less
than 1 cm in diameter and for certain
tumor types such as lobular carcinoma
and in situ carcinoma, which are
less FDG-avid. In addition, PET is
not sufficiently accurate in axillary
lymph node staging, as small axillary
metastases are frequently missed by
the procedure. Therefore, mammography
remains the imaging modality
of choice for screening of breast cancer
and evaluation of breast lesions,
and lymph node dissection or sentinel
node biopsy the most reliable techniques
in staging the axilla.

Wang et al used PET-CT for initial
staging of 15 patients with breast
lesions ranging from 3 to 8 cm.
Sensitivity, specificity, and accuracy
were 93%, 91%, and 100% for the
diagnosis of the primary tumor and
80%, 90%, and 87% for the detection
of lymph node metastases, suggesting
that PET-CT has higher accuracy
than mammography, ultrasound, or
PET alone in the initial staging of
patients with breast tumors larger than
3 cm.[9]

Restaging and Follow-up
The main applications of PET in
breast cancer are in restaging and treatment
monitoring, as PET has a high
sensitivity, specificity, and accuracy
in diagnosing recurrent or metastatic
breast cancer (Figure 1).

A recent study compared PET,
PET-CT hardware fusion, and PETCT
software fusion in restaging 56
patients with breast cancer. Integrated
PET-CT and PET had similar sensitivity
(71% vs 66%), specificity
(68% vs 75%), and accuracy (70% vs
70%) in detecting residual/recurrent
breast cancer. Software fusion was
successful in almost 100% of patients
and yielded a similar accuracy when
compared to hardware fusion. The
lower-than-expected accuracy of both
PET and PET-CT was explained by
the high prevalence of lobular carcinoma
(16% of patients) in the study
population.[10]

Another retrospective study used
integrated PET-CT in 82 patients suspected
of having breast cancer recurrence
because of rising serum tumor
markers and/or equivocal imaging
findings. Sensitivity, specificity, and
accuracy of PET-CT were respectively
90%, 66%, and 85%. The study
revealed an impact on management
in 85% of patients.[11]

Buck et al found that integrated
PET-CT changed the management in
36% of 78 breast cancer patients with
rising tumor markers.[12] Similarly,
Tatsumi et al reported that integrated
PET-CT added incremental value to
PET alone in 40% of the 60 breast
cancer patients studied retrospectively
for initial tumor staging, recurrence,
and follow-up.[13]

Gastrointestinal MalignanciesEsophageal and Gastric Cancers
PET scanning detects unrecognized
metastatic disease and also predicts
response early in the course of therapy
for patients with esophageal cancer.
Very early studies revealed that
combining PET with CT improves the
diagnostic accuracy of CT.

One prospective study of 26 patients
with esophageal or gastroesophageal
junction cancers found that the
accuracy in determining resectability
was 65% for CT vs 88% for PET, and
92% for PET-CT. PET and CT together
would have decreased unnecessary
surgery by 90%.[14] In a recent
retrospective study of 43 patients with
newly diagnosed esophageal cancer,
staging accuracy improved from 83%
with PET to 93% with integrated PETCT.[
15] Bar-Shalom et al studied 18
esophageal cancer patients and found
that PET correctly diagnosed the status
of malignancy in 78% of patients.
Combined PET-CT improved detection
and characterization of suspicious
sites on PET or CT in 89% of patients
and affected management in 22%.[16]

Gastrointestinal Stromal Tumors
PET-CT has an important role in
the assessment of gastrointestinal stromal
tumor (GIST) response to imatinib
(Gleevec), as CT alone may not
reveal a response until several months
after the start of treatment. Antoch et
al studied the response to imatinib in
20 GIST patients, by performing PETCT
before and 1, 3, and 6 months
after starting treatment. PET-CT detected
more lesions than PET or CT
alone. Assessment of tumor response
at 1 month was accurate in 95% of
patients by integrated PET-CT, 90%
by visual fusion PET-CT, 85% by
PET, and 44% by CT. Integrated PETCT,
visual fusion PET-CT, and PET
alone accurately diagnosed tumor response
in 100% of patients at 3 and 6
months, whereas CT was found to be
accurate in only 60% at 3 months and
57% at 6 months. Thus, integrated
PET-CT is the imaging test of choice
for evaluation of GIST response to
imatinib.[17]

Colorectal Cancer
PET has a definite role in the early
detection of recurrent colorectal cancer
and a limited role in primary staging
of this cancer. Studies have shown
that PET has a higher accuracy than
CT in the diagnosis of recurrent colorectal
cancer (Figure 2). Newer studies
have assessed the role of PET-CT
in colorectal cancer.

Burger et al studied 65 patients
with recurrent colorectal carcinoma.
PET-CT was better than PET for diagnosing
local recurrence (sensitivity
of 96% vs 77% and specificity of 97%
vs 89%). PET-CT was also better than
PET for the detection of distant
metastases (sensitivity of 95% vs 66%
and specificity of 98% vs 79%). PETCT
also improved interobserver
agreement.[18]

In a retrospective study of 45 colorectal
cancer patients, staging and
restaging accuracy improved from
78% with PET to 89% with integrated
PET-CT.[19] Another retrospective
study comparing integrated PET-CT to
PET in the initial staging of 35 colorectal
cancer patients found that PET-CT
changed the stage in 20% of patients
and revealed additional findings not
seen on other imaging modalities in
17%. PET-CT also increased the reader's
confidence in localizing and characterizing
lesions.[20]

Integrated PET-CT is also an accurate
technique for the detection of
pelvic recurrence after surgical removal
of rectal cancer, as shown in a study
of 62 patients. Integrated PET-CT was
better than PET for differentiating
malignant from benign FDG uptake
in the pelvis, with a sensitivity of 98%
vs 82%, specificity of 96% vs 65%,
and accuracy of 93% vs 74%.[21]

Pancreatic Cancer
Initial studies showed that PET has
a higher sensitivity, specificity, and
accuracy than CT in diagnosing pancreatic
carcinomas. PET is also more
accurate than CT in identifying malignant
pancreatic cystic lesions. Newer
studies have compared PET-CT
with PET in pancreatic cancers.
Lemke et al studied 104 patients with
suspected pancreatic lesions. PET-CT
software fusion had a higher sensitivity
for malignancy detection than PET
or CT (89% vs 84% vs 77%), but did
not improve specificity (64%). All
image modalities failed to stage lymph
node involvement.[22] Another study
of 28 patients with pancreatic cancer
found that integrated PET-CT improved
diagnostic certainty on 20%
of sites in 42% of patients with positive
PET findings.[23]

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