This article reviews recent developments in the use of positron emission tomography (PET) in oncology with regard to technology, clinical experience, and reim-bursement policies. With proven cost-effectiveness and clinical impact, the authors expect that expanded use of PET will improve patient care and corresponding better reimbursement policy will follow.
Dr. Tan, Mr. Turner, and Dr. Forde are with the Molecular
Imaging Institute, Radiologic Associates of NW Indiana, Inc., Crown
Point, IN. They are also affiliated with the Department of
Radiology and Dr. Klein and Dr. Tabib are with the Department of
Oncology at Porter Memorial Hospital, Valparaiso, IN.
Since this article was written, Dr. Tan is now with the
Department of Radiology, St. Rita's Medical Center, Lima, OH.
Since our previous review of clinical applications of positron
emission tomography (PET) in this journal in 1995, there have been
many developments in PET technology, clinical experience, and
There are three major areas in which PET scanning has proven
useful: oncology, cardiology, and neurology.
The vast majority of PET scanning performed in the United States is
in oncology. There are two reasons for this trend: clinical impact
and reimbursement policy. In recent years, the results of large
clinic PET studies involving tumor detection and staging have
provided solid evidence of the cost-effectiveness of this modality.
This has a major impact on clinical decision-making, with the
effect of impacting patients' treatment plans.
This scenario, in turn, enhanced reimbursement policy dev-elopment
on indications for oncologic PET imaging.
In contrast, neurologic and cardiologic PET imaging has lagged
behind more than had been expected. For instance, one of the major
applications of neurologic PET imaging is the accurate diagnosis of
Alzheimer's disease. However, since no effective preventive nor
therapeutic measures are available for this disease, the use of PET
for diagnosis cannot have a clinical impact on patient outcome.
Cardiologic PET imaging is used almost exclusively for
myocardial viability assessment. This requires PET myocardial
perfusion with N-13 ammonia combined with PET metabolism with F-18
fluorodeoxyglucose (FDG) to detect mismatched perfusion-metabolism
(diminished myocardial perfusion with preserved metabolism). N-13
ammonia has a half-life of 10 minutes and requires an expensive
onsite cyclotron (at a cost of $2 to $2.5 million) to produce it.
Because of its short half-life, it is not commercially feasible to
distribute N-13 ammonia from a cyclotron center to PET centers.
Rb-82 PET imaging for myocardial perfusion is the first indication
for PET imaging that has been approved by the FDA and is reimbursed
by Medicare. However, Rb-82 generators are very expensive (mainly
due to very few centers using it) and published data demonstrate no
major advantage in sensitivity or accuracy compared with the widely
available stress thallium myocardial perfusion scintigraphy. Rb-82
PET imaging has fallen out of favor in recent years.
History and current reimbursement policy of PET
While PET scans emerged about the same time as computed
tomography (CT) scanners,
clinical use of PET imaging has been delayed compared with CT. The
main obstacle to its acceptance has been a lack of reimbursement
for PET scans, although this situation has improved recently. In
the early 1990s, some private insurance companies approved payment
for PET imaging on a case-by-case basis for certain brain tumors
and epilepsy focus localization. In March 1995, the Healthcare
Finance Administration (HCFA) finally approved the first indication
for PET imaging with Rb-82 for diagnostic imaging of patients with
coronary artery disease. Coverage for the use of FDG to evaluate
myocardial viability is still under review. In 1998, HCFA began
reimbursement for FDG-PET scanning for the evaluation of
indeterminate solitary pulmonary nodules and for initial staging of
non-small-cell lung cancer. In 1999, HCFA added three new
indications: detection and localization of colorectal cancer with
rising carcinoembyronic antigen (CEA), staging/restaging with
characterization of Hodgkin's disease and non-Hodgkin's lymphoma,
and identification of metastases in melanoma
(Table 1). These added indications have set the benchmark for
private insurance companies to follow.
Why HCFA has authorized Medicare to reimburse PET imaging for
some tumors and has excluded others is not clear. But the principle
mechanism of tumor detection with FDG-PET imaging is clear, which
is based on the fact that almost all malignant cells have increased
glucose metabolism, increased protein synthesis, and uncontrolled
cell proliferation. The most widely used radiopharmaceutical in
clinical PET is FDG, a glucose analog. It is transported into cells
like glucose and phosphorylated to FDG-6-phosphate by hexokinase as
glucose. However, FDG-6-phosphate is polar and does not cross cell
membranes, therefore it is trapped in cancer cells. FDG-6-phosphate
can be dephosphorylated to FDG by glucose-6-phosphatase, but this
process occurs very slowly in malignant cells because of a
deficiency or lack of glucose-6-phosphatase. Trapped FDG serves as
a tracer of glucose metabolism proportional to the rate of true
glucose metabolism. Primarily, FDG-PET images are interpreted by
visual analysis and/or semiquantitative analysis, such as
standardized uptake value (SUV), which is defined as the activity
in the region of interest (ROI) in uCi/mL divided by the patient's
weight in kilograms and injected dose of FDG in mCi. In some
scenarios, SUV is a very useful tool to discriminate benign from
This article addresses current oncologic indications covered by
HCFA to illustrate the usefulness of FDG-PET categories and
addresses its strengths and limitations.
Solitary pulmonary nodule
Each year, 150,000 new cases of solitary pulmonary nodule (SPN)
are diagnosed. Statistically, approximately 40% of these SPN cases
are malignant. FDG-PET imaging has been very useful in the
characterization of SPN, with an overall sensitivity of 95%,
specificity of 88% and accuracy of 94%.
Generally, malignant SPNs are hypermetabolic in utilizing glucose,
resulting in focally intense FDG uptake within the nodules (figure
1). In contrast, most benign nodules (calcified granulomas or
scars) are not highly FDG avid. Semiquantitative measurements are
helpful in some borderline cases. Currently the metabolic threshold
for pulmonary malignancy used by many experts is SUV 2.6 to 3.0.
Although the specificity of FDG-PET imaging is relatively high
(88%), false-negative results can occur, especially in
bronchiole-alveolar cell carcinoma.
Therefore, SPN, which is metabolically inactive, should be followed
up by a CT scan or chest radiograph. False-positive results may be
seen in granulomatous disease, such as tuberculosis or fungal
infection, and sarcoiclosis. Therefore, a hypermetabolic (hot) SPN
on FDG-PET scan should be followed by a tissue biopsy to confirm
the diagnosis; some investigators recommend proceeding directly to
a thoracotomy, as long as the patient's clinical presentation
permits. FDG-PET imaging is the single best modality for SPN
characterization compared with CT and commonly used Bayesian
Staging non-small-cell lung cancer
Lung cancer is the most common and deadly cancer in both men and
women. Non-small-cell lung cancer (NSmCLCa) accounts for 70% to 80%
of all cases of lung cancer. Successful surgical resection with
intent to cure NSmCLCa depends on the extent of the cancer.
Preoperative staging of mediastinum with CT is only 50% accurate.
Mediastinocopy has higher sensitivity than CT (approximately 85% to
90%), but is invasive and cannot access all thoracic station lymph
nodes. Furthermore, up to 25% to 33% patients with lung cancer
determined to be resectable by conventional imaging staging
criteria are found at surgery to have unresectable disease.
This underestimation of extended disease is due to the fact that
morphologic modalities are limitated in identifying metastatic
lesions and in characterizing borderline-sized lymph nodes.
Multicenter studies have shown that FDG-PET imaging has very
high sensitivity (88%) and specificity (93%) for staging NSmCLCa,
which is comparable to that of mediastinoscopy (90% to 95%).
FDG-PET imaging, however, has the advantages of lower cost, less
morbidity, and accessibility to all station lymph nodes. It is
particularly useful in high-risk surgical candidates, in whom there
has been non-yield of biopsy or difficult biopsy site, and patients
with bleeding disorders threatening biopsy attempts.
Small-cell lung cancer staging can be done equally well with
FDG-PET imaging, but it is not reimbursed by HCFA since the
majority of patients with small-cell lung cancer already have
distant metastases at the time of presentation. Chemo/radiation
therapy is the mainstream of the treatment. Staging small-cell lung
cancer with PET may not alter patients' treatment.
Recurrent colorectal cancer
Colorectal cancer is the second leading cancer death overall in
western industrialized countries. Primary treatment is surgical
resection with an approximate 50% 5-year survival rate. Reportedly,
2% to 50% of patients who have undergone surgical resection develop
local recurrence within the following 2 years. If recurrent cancer
is detected earlier, re-resection may still lead to a improved
survival rate. To detect recurrent colorectal cancer, the tumor
marker such as CEA is seen in only active disease, but in <50%
of cases. Also, elevated CEA does not help to localize the site of
recurrence. Because of postoperative changes and altered local
anatomic structures, morphologic modalities such as CT, MRI and
ultrasound cannot differentiate postoperative scar from tumor
recurrence until the lesion becomes obvious in late stages. A
negative biopsy result cannot exclude early recurrence due to
potential tissue sampling errors. Multiple reports
have shown that FDG-PET scanning is highly accurate in detecting
early localized tumor recurrence with about 95% sensitivity, 98%
specificity, and 96% accuracy, while CT provides only 65% accuracy.
FDG-PET scanning evaluates the chest, abdomen, and pelvis in one
examination setting, which permits identification of local
recurrence as well as distant metastases. FDG-PET is also highly
sensitive in detecting hepatic and extrahepatic metastases with 90%
sensitivity. In contrast, the immunoscinitgraphic imaging such as
Oncoscint is only about 50% sensitive.
PET imaging has made substantial impact on patient clinical
management. FDG-PET scanning can distinguish post-treatment
(operative/ radiation therapy) scar from recurrent tumor since
malignant tumors are metabolically active and FDG-avid on PET
imaging but scar tissue is not (figure 3). This high accuracy in
identifying early-stage recurrent tumors with FDG-PET is crucial
for surgical cure and improving patient outcome. Current literature
shows that PET scans often detect unsuspected metastases not seen
on morphologic imaging such as CT, MRI, and ultrasound. When PET
scanning is used as part of workup for suspected recurrent
colorectal cancer, the findings alter surgical planning in 27% to
63% (average 38%) of cases, which results in cost savings and
avoidance of unnecessary surgery.
In the past, CT scans and gallium scinitgraphy were the standard
modalities for accurate staging and follow-up for patients with
lymphoma (Hodgkin's disease and non-Hodgkin's lymphoma). However,
as in colorectal cancer, morphologic imaging modalities have
obvious limitations in differentiating post-treatment scar tissue
from residual or recurrent lymphoma. For instance, using CT
scanning to evaluate lymphoma requires size criteria and
enlargement of lymph nodes on serial CT scans to confirm malignant
disease, which increases costs and takes months, delaying the
initiation of potentially curative treatment. Gallium-67 has
limitations in resolving small or low-grade lesions and is
problematic in evaluating the abdomen, because physiologic uptakes
within the liver and spleen hinder detection of liver lesions. FDG-
PET can also replace bone scans in primary staging of malignant
have demonstrated that FDG-PET is ideal modality to stage lymphoma
and follow-up tumor treatment response, since hypermetabolic foci
indicate active disease in a treated site, while the absence of
intense of FDG uptake is typical of fibrosis. Several studies also
show FDG-PET is superior to gallium-67 scintigraphy, i.e. to detect
more non-Hodgkin's lesions than gallium-67 especially in low grade
neoplasms. Most clinic series and our experience show that PET
scans can detect nearly all untreated lymphomas. FDG uptake is
higher in untreated high-grade lymphomas than in low-grade
lymphomas; although there is some overlap in SUVs. Many centers use
FDG-PET to stage lymphoma and to determine if lymphadenopathy seen
on CT after treatment is metabolically active or inactive, and thus
whether additional chemotherapy is required. The current trend
confirms our previous statement:
"If PET is available, gallium scinitgraphy and lymphangiography
play little role in lymphoma evaluation." In some centers and in
our institute, FDG-PET has successfully replaced gallium
scintigraphy for evaluation of residual and recurrent lymphomas
The incidence of malignant melanoma is rapidly increasing and
its incidence has increased more than 5% per year since early
1970s, more than any other malignancy. Melanoma is curable only
when diagnosed early with complete resection from skin. Early
diagnosis depends on regular skin examination and excisional biopsy
of suspicious lesions. Malignant melanoma has a high mortality
secondary to nodal metastases and unpredictable metastatic
behavior. Melanoma is one of the most metabolically active tumors
and is FDG-avid, make it well suited for FDG-PET imaging. Several
have shown that FDG-PET scanning has an obvious advantage over
morphologic imaging modalities such as CT, MRI, and ultrasound in
the early staging of the disease and and is more accurate in
staging melanoma patients than conventional images. Steinert and
reported 33 cases of known melanoma scanned with FDG-PET with
overall sensitivity 93% and specificity 100%. The accuracy for
melanoma detection is 90% to 95% for FDG-PET versus 40% to 80% for
conventional workups. Actually, FDG-PET detects more unsuspected
lesions with one whole-body scan than multiple CTs, which reveals
unresectable disease and prevents unnecessary surgery on patients
who would not benefit from surgery due to extensive metastasis
(figure 5). A cost effectiveness analysis shows that 36% of cases
scheduled for surgical resection based on conventional images
changed into medical treatment based on FDG-PET findings of
previously unsuspected additional lesions. The cost saving was
$2200 per patient and considerable morbidity and mortality
associated with surgery were avoided.
Where do we go from here?
Because of the current relief of many regulatory challenges and
new PET reimbursement policies, the availability of FDG-PET
scanners has progressed rapidly nationwide. Currently, there are
approximately PET centers in the United States. The current cost of
a dedicated PET system ranges from $1 to $2.5 million dollars
without an onsite cyclotron, the latter costs an additional $2 to
$2.5 million dollars. New PET scanners have better spatial
resolution and more efficient counting capacity as well as two- and
three-dimensional acquisition modes. Mobile PET scanners are now
also available commercially. Several commercial radiopharmaceutical
companies have developed regional supply sites to distribute FDG to
PET centers that cannot afford a cyclotron. Each FDG dose (about 10
mCi) costs about $600 to $700 and is ordered the evening before the
imaging is performed and is delivered early the next morning.
Medicare reimbursement for approved indications of FDG-PET imaging
range from $1,700 to $2,500 depending on geographic regions, which
includes the cost of the radiopharmaceutical, technique fee, and
radiologists' professional fee.
Dual-head hybrid coincidence cameras (conventional dual
detectors cameras coupled with high-energy collimator and
coincidence detection circuitry) have gained popularity in recent
years because they are less expensive than dedicated PET scanners.
Although these cameras suffered originally from inferior count
sensitivity and spatial resolution compared with dedicated PET
scanners, their performance has continuously im-proved and they
provide a more accessible and less expensive alternative for small
hospitals/physician groups to offer metabolic imaging services.
Published data indicate that dual-head coincidence cameras are
significantly superior in tumor detection when compared with
conventional imaging modalities such as CT. Good agreement between
the results of a dual-head coincidence camera and dedicated PET
scanner has been reported in detecting hypermetabolic lesions more
than 10 to 15 mm in 70 patients with histologically proven
malignant tumors, or suspected recurrent or metastatic disease.
Other oncologic indications appear very promising. Currently,
the following indications for FDG-PET scanning are under HFCA
consideration: 1) detecting primary and recurring head and neck
2) differentiating residual and recurrent brain tumors from
3) detection and localization of intermediate breast lesions on
mammograms or in patients with breast implantation, as well as
evaluation of axillary lymph node metastases with sensitivity and
specificity ranging from 80% to 100%;
and 4) assessment of response to cancer treatment.
In the end of 19th century, Dr. Roentgen discovered X-ray, which
made medical imaging an exciting and challenging medical specialty.
In the past decade, FDG-PET imaging had revolutionized tumor
detection and characterization. At the dawn of the 21st century,
the human gene will be completely decoded and modern medicine will
focus on gene therapy,
which demands functional and molecular imaging--this is what PET
imaging is all about. Future wide utilization of FDG-PET imaging to
improve patient care and corresponding better reimbursement policy
are expected. Finally, we finally can say without hesitation,
clinical PET imaging's time has arrived!
The authors would like to thank Marcia K. Tan for typing the
manuscript, and Kiayona Torreu and Jim Doyle for their technical
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