Journal of Nuclear Medicine Vol. 48 No. 1 (Suppl) 4S-18S
© 2007 by Society of Nuclear Medicine
Screening for Cancer with PET and PET/CT: Potential and Limitations
Heiko Schöder1 and
Mithat Gönen2
1 Department of Radiology/Nuclear Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York; and 2 Department of Biostatistics and Epidemiology, Memorial Sloan-Kettering Cancer Center, New York, New York
Correspondence: For correspondence or reprints contact: Heiko Schöder, MD, Department of Radiology/Nuclear Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., Box 77, New York, NY 10021. E-mail: schoderh{at}mskcc.org
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ABSTRACT
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Screening for cancer remains a very emotional and hotly debated issue in contemporary medical practice. An analysis of published data reveals a multitude of opinions based on a limited amount of reliable data. Even for breast cancer screening, which is now widely practiced in the United States and many European countries, there is continuing controversy regarding the appropriate age limits for screening mammography and, in fact, concerning the value of mammography itself. Similarly, there is no agreement as to whether screening for lung or prostate cancer is meaningful as currently practiced. Recommendations and decisions regarding cancer screening should be based on reliable data, not good intention, assumptions, or speculation. Therefore, we first explain the underlying principles and premises of screening and then briefly discuss current controversies regarding screening for breast, prostate, and lung cancers. Recently, some authors advocated CT, PET, or PET/CT for whole-body screening without support from reliable data. We discuss the potential financial, legal, and radiation safety implications associated with whole-body CT or PET cancer screening. We conclude from the available data that neither CT nor PET/CT cancer screening is currently warranted. Far from providing a desirable binary answer (presence of absence of cancer), in nonselected populations the procedures frequently yield equivocal or indeterminate findings that require further evaluation, with associated costs and potential complications. The clinical and statistical relevance of occasionally detected cancers is likely too low to justify population-wide screening efforts with these 2 imaging modalities. Ultimately, the true utility, or lack thereof, of PET and PET/CT for cancer screening can be assessed only in a prospective randomized trial. Because of prohibitive costs and the required length of follow-up, it is unlikely that such a trial will ever be conducted. Rather than spending time and resources on screening studies, medical practitioners should continue using whole-body PET/CT for diagnosing, staging, and restaging cancer and for monitoring treatment effects. Researchers should also investigate the utility of whole-body PET/CT for the surveillance of selected groups of patients who have cancer, who have completed curative treatment, but who remain at high risk for recurrent disease.
Key Words: cancer screening • PET • PET/CT
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INTRODUCTION
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Certainty? In this world nothing is certain but death and taxes.
Benjamin Franklin
In 2005, an estimated 1,373,000 people in the United States were diagnosed with cancer, and about 570,000 died of cancer (1). Over the years, there has been considerable interest in screening as a means for reducing cancer-related mortality for a number of malignancies, including cancers of the breasts, colon, prostate, lungs, uterine cervix, and ovaries. In fact, screening has become popular in the United States. Recent statistics from the National Cancer Institute (NCI) demonstrated that about 70% of women aged 40 y or older in the United States had had a mammogram in the last year, more than 80% of women aged 18 y or older had had at least 1 Papanicolaou smear during the last 3 y, and 58% of men aged 50 y or older had had a prostate-specific antigen (PSA) test in the last year (2). The NCI estimates that 3%–35% of premature deaths from cancer could be avoided through appropriate screening (3). The NCI also suggests that screening might reduce cancer morbidity because treatment for earlier-stage cancers is often less aggressive than that for more advanced cancers. Nevertheless, there is as yet no convincing evidence that screening for lung, ovarian, colon, and prostate cancers translates into a reduction in mortality from these diseases.
Because screening, by definition, is undertaken in an apparently healthy population and because the fraction of cancers detected by screening is often in the range of 2%–5% (4–6), the vast majority of participants in screening tests derives no clear benefit from the tests, other than peace of mind. Peace of mind, however, may be misleading when the sensitivity of the test used for cancer detection is too low. At the same time, individuals who receive a false-positive diagnosis because the specificity of the test is too low may be subject to unnecessary worry and emotional trauma.
The use of CT for cancer screening (directed either at a single organ or at the entire body) has been debated among radiologists for at least the last 5 y. It is also the subject of passionate and apparently never-ending controversies. 18F-FDG PET or PET/CT has also been proposed for screening. Many imaging specialists can quote examples from their daily practice in which imaging studies conducted for 1 purpose detected other, unexpected, abnormalities. With CT, lung lesions can be discovered during screening for coronary calcification (7,8), or extracolonic lesions in the abdomen can be identified in subjects undergoing CT screening for colon cancer (9,10). Whole-body PET may detect an unexpected second primary cancer or premalignant lesions (11). However, in contrast to what common sense might suggest, these incidental findings do not prove that the screening of nonselected groups of individuals is reasonable. We have tried to weigh the available evidence for and against whole-body screening studies. Findings and conclusions are presented against the background of ongoing debates regarding the usefulness of cancer screening programs.
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SCREENING: DEFINITION AND PURPOSE
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Screening is defined as the investigation of a group of usually asymptomatic individuals to detect those with a high probability of having or developing a given disease (12). To be suitable as a target disease for screening, a disease should represent a significant health problem, have a long asymptomatic natural history, and have an effective intervention that favorably influences the outcome of the disease. The disease should have a relatively high prevalence to justify the cost of the screening program. Screening should identify all or most people with the index complaint (true-positive results), identify few people without the disease as having the disease (false-positive results), and be inexpensive, safe, effective, and easy to apply to a target high-risk population (13–16). The potential benefit to individuals identified as having the disease by screening should offset the cost for the test as well as the inconvenience and potential harms incurred by the many participating individuals who do not have the disease. The aim of screening is to eliminate, or at least significantly delay, death from that disease. Therefore, any cancer screening technique should focus on malignancies for which earlier detection will reduce mortality or morbidity. This notion is based on the premise that cancer at an earlier stage (smaller size) is more likely to be amenable to curative treatment. Accordingly, the goal is a reduction in the absolute number of advanced (nonresectable) cancers, which should translate into a decrease in disease-specific mortality.
In the assessment of the quality of any diagnostic test, including a screening test, 3 pertinent questions arise. Does the test accurately and reproducibly detect or measure the disease? Does a new test improve on existing methods for detecting the disease and predicting mortality or other clinically relevant events? Does the test reduce mortality, improve quality of life, or lower costs without subjecting patients to unnecessary risk? However, screening is different from diagnostic or therapeutic interventions because the majority of individuals who undergo a screening test do not have the disease in question. Therefore, the costs and potential risks associated with the test are spread across a wider group of individuals. In addition, the costs and potential harms of screening generally occur in the short term, whereas any benefits are typically realized only in the long term.
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STATISTICAL CONSIDERATIONS
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The quality of a diagnostic test is judged by sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Sensitivity and specificity are characteristics of the test itself and are not related to the population being tested. In contrast, the predictive value of a given test is closely related to the prevalence of the disease in the population under study. Therefore, PPV and NPV should always be interpreted in the context of the disease prevalence in the study group (Bayes' theorem). For instance, when a hypothetical test with a sensitivity of 90% and a specificity of 80% is applied in a population with a disease prevalence of 5%, the PPV will be only 19%, whereas the NPV will be 99%. When the same test is applied in a population with a disease prevalence of 95%, the PPV will be 99%, and the NPV will be 30%. Accordingly, in a population with a low prevalence of disease (the usual setting for any cancer screening program), the predictive value of a positive test result will remain relatively low, and in a population with a high prevalence of disease, the predictive value of a negative test result will again be relatively low.
Given that the prevalence of individuals with cancer is generally below 5% in many screening programs (5,14,17), the PPV of a positive screening test result is bound to be low, even if the test is highly sensitive and specific for that disease. To detect more true-positive cases than false-positive cases in a cohort with a 5% disease prevalence, a screening test must have an exceedingly high sensitivity—greater than 95%—if the specificity is slightly below 95% and vice versa. Although desirable, in reality, most screening tests do not meet this high standard, which means that the screening program must absorb the cost of many false-positive results. It might be argued that, most importantly, a screening test should have high sensitivity. However, high sensitivity at the expense of lower specificity will cause a high rate of false-positive cases (e.g., granulomatous disease instead of cancer in a lung nodule) as well as an increased detection of "pseudodisease," that is, overdiagnosis of disease that would not have affected survival or quality of life for the affected individual (see later discussion). Conversely, a test with a high specificity will ensure the cost-effectiveness (cost per year of life saved) of the screening program. Because of referral bias (only individuals with suspected disease are referred for further evaluation), it is difficult to determine the true accuracy of a screening test. In fact, accuracy could be determined only by monitoring all screened individuals for an appropriately long period of time. If the follow-up is too short, then some disease might be missed, and the test sensitivity might appear to be artificially high. If the follow-up is too long, then new disease might develop in the interim, and the test sensitivity might appear to be artificially low.
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BIASES ASSOCIATED WITH SCREENING TESTS
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Because of space limitation, we only briefly describe some potential pitfalls in designing or analyzing screening studies. Good reviews of this matter are available elsewhere (16–18).
Lead-time bias refers to the apparent differences in disease-specific survival (time from cancer diagnosis to death): In individuals with disease detected by screening, the time frame spans from the date of screening to death, whereas for nonscreened individuals, the time frame spans from the clinical presentation of disease to death. Because screening detects cancer in asymptomatic individuals, their survival will always be longer than that of nonscreened individuals because disease was detected at an earlier point in time. This situation remains true even if screening does not delay the ultimate time of death and if earlier treatment has no benefit.
Length bias occurs because a given disease may progress at various rates in different patients. Tumors that grow more slowly have a longer detectable preclinical phase than rapidly progressing cancers. Tumors that grow more slowly are easier to detect and more likely to be detected by screening (rapidly growing tumors may develop and appear clinically in the interim between 2 consecutive screening tests). Therefore, screening generally detects cancer with a better prognosis.
Overdiagnosis bias occurs when screening detects tumors that would otherwise have remained occult during the lifetime of that individual: the individual would have died with, rather than from, the disease. There are 2 possible scenarios: An individual may be bound to die from other diseases before the cancer becomes lethal, or screening detects a less aggressive malignancy that is not life threatening or that does not interfere seriously with the quality of life before the individual dies from other conditions (e.g., slowly growing prostate cancers in older men).
Stage shift and selection bias are other potential pitfalls in screening studies (16). The impact of bias on the results of a screening trial can be reduced through proper study design; a randomized controlled trial, in which study participants are randomized to a given test versus observation, generally provides data that are more stable and resistant to criticism than case–control or cohort studies. Further, mortality, rather than survival, should be recorded as the outcome measure.
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CANCER SCREENING TRIAL DESIGNS
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There are 5 study designs that are generally used in judging the evidence from a clinical trial, including screening studies (3). The highest level of statistical evidence is derived from randomized controlled trials. However, these trials are very expensive, require tens of thousands of participants, are affected by noncompliance, and take many years to complete. In imaging trials, the technology under investigation could have advanced by the time the trial is concluded (e.g., multidetector [64 or more rows] CT with true isotropic resolution instead of simple helical CT and PET/CT instead of PET alone). If a large randomized controlled trial is not feasible for financial or logistic reasons, then one has to rely on other trial designs, such as cohort studies, and indirect outcome measures, such as the earlier detection of cancer (19,20). In addition, one might investigate whether the test leads to a reduction in the number of interval cancers that become clinically apparent between 2 consecutive screening sessions (21,22). A reduction in the number of interval cancers would suggest that the time interval between sessions is appropriate and that the test itself is sufficiently sensitive for detecting rapidly growing cancers, thereby excluding length bias.
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APPROPRIATE OUTCOME MEASURES
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The terms "mortality" and "survival" are frequently used when reporting the outcome of screening studies. Unfortunately, both terms are oftentimes, and incorrectly, used synonymously. Survival is a case-based measure; it shows the percentage of individuals diagnosed with cancer who are still alive at a certain time point (usually 5 y) after the time of diagnosis. In this case, the denominator includes only individuals diagnosed with cancer. In contrast, mortality is a population-based measure; it shows how many people are dying of cancer within a given population (usually quoted as per 100,000 individuals). In this case, the denominator includes individuals diagnosed with cancer and all healthy individuals.
Because of lead-time bias, the 5-y survival for a given cancer will almost always improve with the introduction of a cancer screening test. However, because the incidence of cancer (number of new cases detected per 100,000 individuals) will almost always increase with screening, the following 2 prerequisites must be met for cancer mortality to decline as well: (a) more cancers must be detected at an earlier stage with screening than without, and these cases must be curable; and (b) the vast majority of screen-detected cancers must be clinically relevant (if screening only leads to overdiagnosis of cancer, this could actually increase cancer mortality if the cause of death in individuals so diagnosed were to be coded as "died of cancer," whereas another medical condition would have been assumed to be the cause of death if that individual had never undergone screening).
The gold standard parameter by which to measure the efficacy of a cancer screening test is a reduction in mortality. Disease-specific mortality has been the most widely accepted end point in randomized clinical trials. It requires that the cause of death be determined accurately and that screening and subsequent treatment have negligible effects on other causes of death. However, some recent reviews of randomized cancer screening trials suggested that misclassification of the cause of death is a common problem, leading to an overestimation of the effectiveness (or an underestimation of the harms) of screening (23–25). Therefore, all-cause mortality may be a more accurate end point for screening trials (23–25). This parameter depends only on the accurate documentation of deaths and when they occur; that is, it is not affected by misclassification of the cause of death. Therefore, it unequivocally accounts for complications of the screening process itself and related procedures attributable to false-positive screening test results. Unfortunately, a screening trial with all-cause mortality as the sole end point would require a prohibitively large number of individuals to be enrolled (most screening participants might not die during the trial) (26).
If data from a randomized controlled trial are not available, then evidence obtained by other trial designs, such as stage shift or improved survival rates, compared with those of historical controls, is sometimes used to demonstrate the effectiveness of a screening program (19). However, these parameters are not very reliable or accurate. It is also sometimes naively assumed that current improved survival rates for patients with cancer, compared with those for historical controls, are attributable to mass screening efforts, although such improvements may reflect only improved treatment, lead-time bias, or overdiagnosis. Indeed, in a recent analysis researchers found that for many cancers, changes in 5-y survival rates are essentially unrelated to trends in disease-specific mortality, suggesting that improvements in survival were largely attributable to earlier diagnosis and detection of subclinical cases that might never have appeared clinically (27).
Although there is currently no universally accepted cancer screening trial design or outcome parameter, most authors would agree that the highest level of statistical evidence and the greatest benefit for screening program participants is related to mortality reduction in a randomized controlled trial. Eventually, however, the true efficacy (or lack thereof) of a screening test will be shown only once the test is applied in general practice.
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CURRENT CONTROVERSIES IN CANCER SCREENING
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Screening for prostate and breast cancer is widely practiced in the United States, in accordance with recommendations issued by various committees and task forces. Proponents of screening with CT or PET like to quote the apparent success of breast and prostate cancer screening programs to lend credence to their attempts to introduce CT or PET as a new screening technique for lung cancer or whole-body assessment. However, contrary to expectation, our attempt to gather data to confirm the efficacy of current cancer screening programs proved to be a sobering experience. Neither breast cancer nor prostate cancer screening is without controversy; in fact, in the eyes of some critics, both tests fail to show any benefit in terms of mortality reduction at all. Regardless of various recommendations for prostate cancer screening with PSA testing and digital rectal examination (28–30), it is now widely acknowledged that the effectiveness of this approach remains unproven. A recent case–control study found no evidence for a survival benefit associated with PSA testing and digital rectal examination (31). It is hoped that ongoing trials, such as the European Randomized Study of Screening for Prostate Cancer (32) and the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial (33), will provide more definitive answers regarding the benefits of prostate cancer screening. However, conclusive data regarding the effects of screening on prostate cancer mortality are not expected until 2008–2010. The ultimate value of lung cancer screening with CT is also uncertain at present. Here we present a summary of the current controversies in breast and lung cancer screening in the hope that it will further a realistic, evidence-based reassessment of current efforts to institute cancer screening programs with PET or PET/CT.
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BREAST CANCER
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About 211,000 new cases of breast cancer were diagnosed in 2005, and 40,400 patients died of this disease (1). Breast cancer screening has been proposed as a means of reducing mortality from breast cancer and has been practiced for more than 30 y in many developed countries. It has been estimated that cancer is detected in 5–7 of every 1,000 women on the first screening mammogram (prevalence) and in 2 or 3 of every 1,000 women who undergo regular screening mammography (incidence) (5). Over the years, thousands of women have been enrolled in breast cancer screening trials worldwide, but controversy on the efficacy of screening mammography continues to date. Proponents and opponents of breast cancer screening (including physicians and biostatisticians) differ in their assessment of the quality of past mammography screening trials, in the interpretation of the trial results, and in their preference for the appropriate end point (26). Disagreement remains regarding whether past trials proved that breast cancer screening is meaningful. For instance, Fletcher and Elmore (34) estimated that 4–6 lives could be saved if 1,000 women aged 50–69 y underwent yearly screening mammograms for a total of 10 y. On the basis of the average cure rate for non-screening-detected breast cancer, they calculated that screening mammograms can reduce breast cancer mortality by about 30%. In contrast, a meta-analysis of 8 randomized trials conducted by the U.S. Preventive Services Task Force in 2002 (35) concluded that screening mammography leads to a 16% reduction in breast cancer mortality in women aged 50 y and older. It was estimated that 1,224 women would have to undergo yearly screening mammograms over a 14-y period to save 1 life. Gotzsche and Olsen (36) reviewed the same 8 screening mammography trials and arrived at a very different conclusion. These authors particularly focused on the methodological quality of the screening studies and found baseline imbalances between screening and control groups in 6 of the 8 trials and inconsistencies in the number of women randomized in 4 trials. Only in these methodologically inferior trials did mammography appear to "save lives" (the pooled relative risk for breast cancer mortality was 0.75, and the 95% confidence interval [CI] was 0.67–0.83). In contrast, the meta-analysis of the 2 trials that were considered of sufficient quality found no effect of screening on breast cancer mortality (pooled relative risk: 1.04; 95% CI: 0.84–1.27), nor was there any positive effect on all-cause mortality (pooled relative risk: 0.99; 95% CI: 0.94–1.05). These authors concluded that "screening for breast cancer with mammography is unjustified." In a subsequent analysis (25), the authors confirmed these findings and emphasized that screening leads to more aggressive treatment without proven benefit.
In 2003, a Swedish cohort study reported that screening reduced breast cancer mortality on the basis of lower mortality in women who had their breast cancer diagnosed during the screening period (1978–1997) than in women diagnosed with breast cancer before the introduction of mammography screening (1958–1977). More cancers were detected and treated in the screening group, leading to better survival (37). Others have classified the results of this trial as uninterpretable because of length and lead-time biases (38). Another recent study (39) estimated that screening reduced the mortality from breast cancer in the United States by 15% over the last 2 decades, but critics note that similar declines in breast cancer mortality have also been reported from countries without a national screening program (40). On March 25, 2006, the British Medical Journal (41) published a series of articles on screening mammography in which the rate of overdiagnosis of breast cancer was estimated to be 10%–30%.
Partly in recognition of the above-described controversy and trial limitations, some authors have suggested that it may be more appropriate to stream women into different screening regimens on the basis of breast characteristics or risk factors (22). Finally, it should be noted that the cumulative risk for having a false-positive mammogram result can approach 50% over a 10-y interval with yearly screening studies. This means that after 10 y of annual screening in the United States, 1 in 2 women will have at least 1 false-positive mammogram result (42).
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LUNG CANCER SCREENING TRIALS
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About 172,600 new cases of lung cancer were expected in 2005, and 163,500 patients were projected to die from this disease (1). Screening for lung cancer, originally with sputum cytology analysis and chest radiography and more recently with CT, has been proposed as a means to reduce mortality from this disease, but study results have created considerable controversy (4,43–47). Earlier trials showed no significant differences in lung cancer mortality between screened and control groups (17,48). Patients with lung cancer in the screened group were more likely to undergo surgical resection and lived longer than individuals in the control group, but equal numbers of individuals in both groups ultimately died from the disease. Thus, the apparent improvement in lung cancer survival was largely attributable to various biases (see earlier discussion), but screening did not affect the ultimate outcome of the disease.
Over the last 6 y, the controversy has focused on the role of screening CT (14,17,49–51). In several cohort studies (without control groups) from the United States, Europe, and Japan (4,6,43–46,52), low-dose CT imaging was performed for screening and was followed by immediate biopsy for suspicious lesions or high-resolution CT for further characterization of indeterminate nodules. Individuals were monitored at 1-y intervals with low-dose CT and similar management. This approach allowed for the detection of many early-stage lung cancers (4,43–46). At baseline scanning in these studies, lung cancer was detected with prevalences of 1.1% (46) to 2.7% (4); differences may be related to the age and risk of the screened populations. The rate of detection of lung cancer on annual follow-up scans (incidence) was about 1% (6,43,46). About 58%–100% of cancers on baseline CT scans and 67%–100% of cancers during follow-up scans were stage I disease. For instance, in the Early Lung Cancer Action Project study (21), lung cancer was diagnosed in 27 of 1,000 individuals during baseline CT (prevalence: 2.7%), and 23 of 27 cases were stage I malignancies. In the follow-up of this cohort, 1,184 CT scans were obtained and revealed a total of 30 new lung nodules, of which 7 were cancers (incidence: 0.7%). The median size of these lesions was 8 mm.
Although intuitively favorable, these results do not prove that a reduction in lung cancer mortality will occur with CT screening. Although it is better to detect lung cancer earlier than later, there may not be a linear relationship between tumor size and likelihood for metastasis (53) and, thus, likelihood for cure with early intervention. In fact, there is no clear cutoff in primary tumor size to predict when metastasis occurs. Otherwise, treatment with curative intent should render a patient with early lung cancer disease free for the rest of his or her life. However, even with stage I lung cancer, the average 5-y survival rate is only 47%, not 100%. Quite likely, many other biologic factors (e.g., histology, degree of neovascularity, and genetic alterations) and perhaps even random variability among primary tumors (54) may determine metastatic potential. Opponents of screening CT, therefore, contend that it remains unclear whether the detection of early-stage disease represents a true stage shift (earlier detection of clinically relevant disease associated with a decrease in the number of advanced lung cancers) or overdiagnosis (no decrease in lung cancer mortality; instead, only an increase in the number of detected lung cancers chiefly because of sophisticated technology, but no change in the rate of advanced cancers, i.e., no decrease in the number of cancers that are not amenable to treatment or that are likely to fail treatment with curative intent) (52,55).
Because of these concerns, many epidemiologists and physicians involved in the diagnosis and treatment of lung cancer have argued that the benefits of CT screening can be proven only in a large randomized controlled trial (17). Indeed, several such trials are now under way in the United States, Japan, and Europe. In the meantime, the U.S. Preventive Services Task Force (56) has concluded that it is not possible to assess the efficacy of lung cancer screening with CT on the basis of currently available data. The American Cancer Society currently suggests that patients discuss with their physicians the potential costs and benefits of lung cancer screening with CT (28). At the end of 2005, a consensus statement made by the Society of Thoracic Imaging concluded that there is currently insufficient evidence to justify recommending CT screening for lung cancer to patients, including those at high risk for lung cancer (55).
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WHOLE-BODY SCREENING WITH CT
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For a while, whole-body CT was marketed aggressively as the "one-stop shop" for detecting occult cancer and cardiovascular diseases. Although malignancies and coronary artery disease were in fact detected in many participants, the overall results were disappointing. Many self-declared CT screening practices have closed their doors, sometimes ending mired in financial distress and in lawsuits. A large study conducted at the University of California, San Diego, highlighted the logistical challenges and other problems associated with whole-body screening CT (57). Between January and June 2000, screening CT was performed for 1,192 individuals. A total of 76% (902/1,192) of these subjects were self-referred; the others were referred by a physician for a whole-body screening test. Participants were charged $1,000 for the screening CT. A total of 3,361 findings were detected in 1,030 of the 1,192 individuals (mean of 2.8 per individual). The proportion of individuals with abnormal findings increased with age (43% if <40 y and 99% if >70 y). Most of the "abnormalities" were benign and likely without clinical consequence (e.g., parenchymal scars in the lungs, vascular calcifications, calcified mediastinal lymph nodes, and simple cysts of the liver and kidneys). CT-detected abnormalities led to recommendations for the individual or referring physician in 37% of cases; of note, the most common recommendation (69%) was that for a follow-up imaging study. It was concluded that the low prevalence of abnormal findings in individuals younger than 40 y would not justify screening CT. At the other extreme of the spectrum, screening CT may not be meaningful in individuals older than 70 y. Although the expected prevalence of cancer increases with age, the 99% prevalence of CT-detected abnormalities in older people, combined with the frequent need for further evaluation, also limits its application in this age group. Thus, screening CT may be beneficial, if at all, only in well-defined age and risk groups.
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18F-FDG PET FOR CANCER SCREENING
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There is limited information about the true performance of whole-body PET for cancer screening. Data that might help to investigate this issue are derived from few case series analyzing the frequencies of malignancies incidentally detected during whole-body PET imaging and from PET screening studies conducted in Asian countries. These data are discussed in the following sections.
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INCIDENTAL ABNORMAL 18F-FDG UPTAKE DURING WHOLE-BODY PET
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18F-FDG PET occasionally detects previously unknown malignant or premalignant lesions that are unrelated to the disease for which the scan was performed. Although most clinicians can readily provide anecdotal evidence for this finding, Agress and Cooper (11) published their findings from a large study of 1,750 patients with cancer. 18F-FDG PET was performed for the evaluation of a variety of malignancies, and 58 foci of abnormal but unexpected 18F-FDG uptake were identified in 53 patients, that is, a frequency of 3.3%. Follow-up, available for 42 individuals, proved a malignant or premalignant condition for 30 individuals (1.7% of the entire study population). Further, 3 of 9 nonmalignant lesions were considered clinically important and required surgical or medical intervention. Although this study highlights the value of whole-body PET for the evaluation of patients with cancer, it does not provide a true estimate of the rate of detection of clinically occult malignancies, because dedicated follow-up was available only for individuals with abnormal 18F-FDG uptake and because non–18F-FDG-avid disease could have been missed in other individuals.
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THYROID AND INTESTINAL LESIONS FOUND POSITIVE BY PET
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Palpable thyroid nodules are detected in 4%–7% of the general population in the United States and at somewhat higher frequencies in areas or countries affected by iodine deficiency. With the increasing use of ultrasound and other imaging techniques, thyroid nodules are now discovered in 30%–60% of the general adult population (58–61). The vast majority of these nodules are benign; only 2%–5% of all thyroid nodules (60), 6%–9% of nonpalpable nodules (62), and 9%–13% of nodules selected for fine-needle aspiration represent cancer (61). With PET or PET/CT, the rate of such incidentally detected (hypermetabolic) thyroid nodules is 1%–3% (63–65). Cumulative experience in more than 20,000 PET studies has been reported. In a study by Kang et al. (63), 29 of 1,340 individuals (2%) showed either diffuse (n = 8) or focal (n = 21) 18F-FDG uptake in the thyroid gland. Histologic analysis was available for 15 of the 21 hypermetabolic nodules and revealed papillary carcinoma in 4 (27%). In a study of 8,800 patients with cancer, incidental focal 18F-FDG uptake was noted in 101 individuals, and diffuse uptake was noted in 162 individuals. Tissue diagnosis, obtained predominantly for focal lesions, proved cancer in 24 instances (66). Other authors (64,65) have reported that up to 50% of hypermetabolic thyroid nodules are malignant. All of these studies were limited by the fact that cytologic verification was available for only two thirds of the findings or fewer. The true prevalence of cancer in hypermetabolic thyroid nodules is therefore still somewhat unclear.
Unexpected abnormal 18F-FDG uptake in the abdomen has been the subject of several reports and often can be attributed to colon adenomas, which may be precursors for colon cancer, or frank malignancies. Yasuda et al. (67) reported abnormal focal 18F-FDG uptake in 24% of 59 adenomas found at endoscopy and in 90% of all adenomas that were 
1.3 cm. Pandit-Taskar et al. (68) observed focal 18F-FDG uptake in the abdomen, unrelated to the disease for which the PET had been ordered, in 16 of 1,000 patients with cancer. A definitive diagnosis could be rendered for 14 lesions, and 12 of them were malignant or premalignant. Using PET/CT, Israel et al. (69) reported incidental abnormal 18F-FDG uptake in the abdomen in 58 of 4,390 patients with cancer (1.3%). Follow-up was available for 34 patients and showed malignant or premalignant conditions for 20 (58% of verified lesions; 0.5% of the entire study population). Kamel et al. (70) reported abnormal abdominal 18F-FDG uptake with a frequency of 3% in 98 of 3,281 patients. Follow-up was available for 69 of these 98 patients (70%); cancer was detected in 13 individuals (19%), and another 29 (42%) had precancerous lesions. Eight of the 13 patients (62%) with incidentally detected colon or esophageal carcinoma were eligible for curative surgical resection.
In conclusion, abnormal focal 18F-FDG uptake in the thyroid gland or abdomen is a rare finding but, when it occurs, requires further evaluation because a significant fraction of such lesions represent either malignant or premalignant conditions, usually at a state when curative treatment is likely to succeed. It should be noted that these PET scans were performed for patients with cancer, many of whom may have an increased likelihood for developing second primary malignancies (e.g., because of the presence of certain mutations in tumor suppressor genes in patients with cancer). Therefore, it is possible that the frequency with which focal 18F-FDG uptake indicates cancer is lower among healthy individuals participating in screening studies. Nevertheless, in current clinical practice, in which whole-body PET is essentially used only in the evaluation of patients with cancer, one must conclude that incidental focal 18F-FDG uptake will require further evaluation.
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LUNG CANCER SCREENING WITH 18F-FDG PET
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In 3 recent studies, the sensitivity of 18F-FDG PET for the detection of T1 lung cancers ranged between 68% and 95% (46,71,72). Marom et al. (72) determined the sensitivity of 18F-FDG PET in 185 patients with T1 lung cancer (192 lesions; mean size: 2.0 cm; range: 0.5–3.0 cm). A total of 95% (183/192) of all lesions showed increased 18F-FDG uptake (greater than mediastinal blood-pool activity), whereas the PET findings for the remaining 9 lesions (size: 0.3–2.5 cm; mean, 1.3 cm) were negative. The rate of detection tended to be lower for carcinoid tumors and bronchoalveolar cell carcinomas (BAC; the PET findings for 5/6 and 7/11 tumors were positive, respectively). The data appeared encouraging because the sizes of the lesions studi
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ABSTRACT
INTRODUCTION
