Annals of Internal Medicine
The PET and the Pendulum
W e live in an era in which new medical procedures,
diagnostic tests, and treatments are being intro-
duced at a rapid pace. Some important new technologies
were widely adopted without rigorous initial outcomes
testing, with subsequent reconsideration and reduction in
use, as exemplified by the pulmonary artery catheter in
critically ill patients (1). Other procedures, such as lung
volume reduction surgery for severe chronic obstructive
pulmonary disease, underwent careful evaluation relatively
early on (after a modern reintroduction in the case of lung
volume reduction surgery), which strongly influenced their
role in current practice (2). These well-studied procedures
must be reexamined in light of newer refinements, such as
bronchoscopic lung volume reduction (3).
Somewhere between these extremes is the ongoing
evolution of positron emission tomography (PET), which
has engendered enormous interest since its introduction
into clinical oncology in the late 1980s. This technique has
a very wide range of potential applications in diagnosis,
staging, guiding biopsies, assessment of response to ther-
apy, and identification of recurrent disease, as reflected in a
burgeoning literature. In lung cancer, PET considerations
are particularly complex—and promising— because the
technique provides information about the primary lesion,
mediastinum, and distant metastases.
The stakes in this very common form of cancer are
enormous for individual patients, physicians, and a health
care system struggling mightily to control costs, because
lung cancer staging is the foundation for most treatment
decisions. The staging system, which grows more complex
with each iteration, serves to triage individual patients via
the TNM system (tumor, node, metastasis) to a wide range
of treatments based on the extent of disease and prognosis.
So a single test— especially a noninvasive one—that could
accurately stage lung cancer at a reasonable cost would be a
major step in avoiding futile surgery and inappropriate
undertreatment.
For many, the proverbial pendulum has already swung
to PET, especially when integrated with computed tomog-
raphy (CT), as an indispensable test for noninvasive detec-
tion of distant metastatic disease in lung cancer. Fortu-
nately, acceptance by clinicians has been increasingly
validated by many detailed studies that have served to clar-
ify its clinical role; an example is the admirable study by
Maziak and colleagues (4) in this issue. In this study, de-
rived from 5 Canadian academic institutions, Maziak and
colleagues randomly assigned 337 patients with non–small
cell lung cancer—thought to be stage I, II, or IIIA on the
basis of initial chest radiography and CT—to staging with
PET-CT or a combination of abdominal CT and radio-
nuclide bone scanning (conventional staging). Three statis-
tically and clinically significant findings emerged. First,
PET-CT correctly upstaged disease to unresectable stage
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Editorial
IIIB and IV in 13.8% of patients; conventional staging
correctly upstaged disease in only 6.8%. Therefore,
PET-CT staging resulted in proportionately fewer inappro-
priate attempts at surgical cure. Second, false-positive
PET-CT findings incorrectly upstaged disease in 4.8% of
patients, versus 0.6% in the conventionally staged group.
In the latter patients, disease was eventually correctly
staged by using additional diagnostic procedures (including
biopsy when necessary), then treated appropriately. Maziak
and colleagues note that subsequent clarifying tests were
performed more frequently in the conventionally staged
group. Finally, PET-CT incorrectly downstaged disease
in fewer patients (15%) than did conventional staging
(29.6%), which also helped avoid futile thoracotomies
and allowed more stage-appropriate chemotherapy plus
radiation.
Maziak and colleagues’ study (4) certainly has some
notable limitations, many of which the authors mention.
The sample sizes were small, especially for some of the
subgroup analyses; for example, only 1 patient in the con-
ventional staging group had incorrect upstaging. Small
sample sizes mean wide confidence intervals and consider-
able uncertainty about the true rates. Generalizability is
unknown because PET-CT was performed on only 5 ma-
chines at top referral centers with strict quality control
guidelines. The patients’ true state—the presence or ab-
sence of metastatic disease—was ascertained through clin-
ical judgment, with concurrence of an adjudication com-
mittee. This diagnostic reference standard is imperfect but
necessary for a study of this type because it avoids unnec-
essarily subjecting patients to biopsy of every suspicious
abnormality on scans. The authors did not report the costs
of care in the 2 groups, so they do not advance our limited
understanding of the economic implications of PET-CT.
Finally, because the authors did not provide information
on long-term survival, we do not know whether ordering
PET-CT for lung cancer staging ultimately helps patients
live longer. Nevertheless, Maziak and colleagues are among
the first to specifically compare PET-CT with conventional
staging, and the results certainly suggest that PET-CT has
important advantages. The head-to-head comparative
study design also distinguishes the current study from
other studies that focused on the addition of PET to con-
ventional staging and evaluated PET rather than PET-CT
(5–7).
Many issues remain, and it is particularly difficult to
formulate recommendations for optimal preoperative as-
sessment when the number of possible tests is increasing,
along with important technical refinements in individual
tests. For example, is integrated PET-CT so superior that
CT or PET alone is now obsolete for staging lung cancer
(8 –13)? Are the putative advantages worth the increased
cost (current charges at my university hospital are $3060
18 August 2009 Annals of Internal Medicine Volume 151 • Number 4 279
Editorial The PET and the Pendulum
for chest CT, $3680 for PET, and $4180 for PET-CT)?
How shall we incorporate new refinements in PET tech-
nology, such as dual–time-point imaging (14), into our
judgments about when to test and how to interpret the
results? Should we routinely do endoscopic ultrasonic
biopsy—in addition to or instead of imaging— even if
mediastinal nodes are small and PET results are negative,
in an attempt to stage the mediastinum histologically (15)?
What level of evidence is necessary to establish a clear
preference for one of several tests, especially given the
many available tests that we could compare in various
combinations?
In interpreting PET-CT results, one must be particu-
larly mindful of false-negative and false-positive results (16,
17), identifying them with additional imaging studies and
even biopsy if necessary for key management decisions.
Clearly, decisions to do additional testing must be individ-
ualized. A PET-CT finding that is discordant with the
pretest probability of neoplastic involvement is a key clue
to a false-negative or a false-positive PET-CT result. In
other words, a surprising PET-CT result (for example, a
negative PET-CT result when the probability of metastases
is high) is a good indication for further testing.
At this point in an evolving saga, it is reasonable to
order PET-CT for lung cancer staging, especially for pa-
tients who seem to be candidates for curative therapy. A
recommendation to use PET-CT does not imply that other
means of preoperative assessment are invalid or unaccept-
able; preferences among imperfect tests always depend on
local expertise and test availability. We will need additional
comparisons between PET-CT and other staging tests—
preferably studies that measure clinical outcomes and in-
clude cost analyses—as lung cancer staging continues to
transform and improve.
Mitchell L. Margolis, MD
Philadelphia Veterans Affairs Medical Center and University
of Pennsylvania
Philadelphia, PA 19104
Potential Financial Conflicts of Interest: None disclosed.
Corresponding Author: Mitchell L. Margolis, MD, Room 8A112 Clin-
ical Addition, Philadelphia Veterans Affairs Medical Center, Philadel-
phia, PA 19104; e-mail, mitchell.margolis@med.va.gov.
This article was published at www.annals.org on 7 July 2009.
Ann Intern Med. 2009;151:279-280.
280 18 August 2009 Annals of Internal Medicine Volume 151 • Number 4
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