Authorship and contributorship: CY Chang participated the design of the study and drafted the manuscript. SJ Chang participated in the design of the study and preformed the statistical analysis. SC Chang participated in the design of the study and revised the manuscript. MK Yuan participated in the design of the study and revised the manuscript. All authors read and approved the final manuscript.
The value of positron emission tomography in early detection of lung cancer in high-risk population: a systematic review
Version of Record online: 25 APR 2012
© 2012 Blackwell Publishing Ltd
The Clinical Respiratory Journal
Volume 7, Issue 1, pages 1–6, January 2013
How to Cite
Chang, C.-Y., Chang, S.-J., Chang, S.-C. and Yuan, M.-K. (2013), The value of positron emission tomography in early detection of lung cancer in high-risk population: a systematic review. The Clinical Respiratory Journal, 7: 1–6. doi: 10.1111/j.1752-699X.2012.00290.x
Conflict of interest: The authors have stated explicitly that there are no conflicts of interest in connection with this article.
Disclosure: The authors declare no conflicts of interest. This study had no specific funding source.
- Issue online: 26 MAR 2013
- Version of Record online: 25 APR 2012
- Accepted manuscript online: 8 MAR 2012 04:30AM EST
- Received: 24 November 2011; Revision requested: 27 January 2012; Accepted: 26 February 2012
- early lung cancer;
- positron emission tomography;
Background: Early detection trials with chest radiography and sputum cytology were ineffective in decreasing lung cancer mortality. The advent of low-dose spiral chest computed tomography (LDCT) provided clinicians with a new tool that could be with early diagnosis; however, this also raised significant concerns regarding the systematic use of LDCT with its high false-positive rate for benign nodules. At this time, there is limited information about the true role of PET (positron emission tomography) for early detection of lung cancer.
Methods: We used systematic methods, including Preferred Reporting Items for Systematic reviews and Meta-Analyses statement, to identify relevant studies, assess study eligibility, evaluate study methodological quality, and summarize findings regarding diagnostic accuracy and outcome.
Results: In total, only seven eligible studies were selected from 82 potentially relevant studies. The sensitivity of 18F-FDG-PET for the detection of T1 lung cancers ranged between 68% and 95%. The rate of detection tended to be lower for carcinoid tumors, adenocarcinoma and bronchoalveolar cell carcinomas. FDG-PET using SUV (standardized uptake value) level can predict the outcome of the screening detected lung cancer. A combination of FDG-PET and LDCT may improve screening for lung cancer in high-risk patients.
Conclusions: PET or PET/CT may be used as a useful tool for early detection of lung cancer in high-risk population based on the existing information. However, there is still limited information with regards to evidence of survival benefits from PET screening in high-risk patients.
Please cite this paper as: Chang C-Y, Chang S-J, Chang S-C and Yuan M-K. The value of positron emission tomography in early detection of lung cancer in high-risk population: a systematic review. Clin Respir J 2013; 7: 1–6.
Early detection trials with chest radiography (CXR) and sputum cytology, funded by the US National Cancer Institute in the 1970s, were ineffective in decreasing lung cancer mortality. The advent of low-dose spiral chest computed tomography (LDCT) established a new method to assist with early diagnosis, and initial studies conducted in Japan in the 1990s demonstrated the potential value of LDCT for lung cancer screening. However, the apparent improvement in lung cancer survival was largely attributable to various biases, but screening did not affect the ultimate outcome of the disease (1). Even with stage I lung cancer, the average 5-year survival rate is only 47%, not 100%. Many other biologic factors (e.g. histology, degree of neovascularity and genetic alterations), and perhaps even random variability among primary tumors, may determine metastatic potential (2). 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 (3). A major concern in systematic use of spiral CT is the high frequency of false-positive findings for benign nodules.
Positron emission tomography (PET) is a nuclear medicine imaging technique that produces a three-dimensional image of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide (tracer). If the biologically active molecule chosen for PET is FDG, an analogue of glucose, the concentrations of tracer imaged then give tissue metabolic activity, in terms of regional glucose uptake. There is limited information about the true performance of whole-body PET for screening or early detection of lung cancer. The aim of our review was to estimate the value of PET in the early detection of lung cancer in a high risk population.
- • P: High-risk population(current or former smokers, age 50 years or older with a minimum of 20 pack-years smoking history)Mass screening [MeSH]
- • I: PET [MeSH](cut point SUV: 2.5–3)
- • C: Observation
- • O: Screening or early detection of lung cancerLung neoplasm [MeSH]
- • S: Randomized controlled trial, cohort study, case control study
Materials and methods
We used systematic methods to identify relevant studies, assess study eligibility, evaluate study methodological quality and summarize findings regarding diagnostic accuracy and outcome.
Study identification and eligibility
We attempted to identify all studies that examined functional imaging with FDG for diagnosis of pulmonary nodules and mass lesions. The identified studies were published between January 2001 and September 2010 in the ACP journal club, Cochrane Library, PubMed and MEDLINE. Searches were limited to full articles that were in English. The Mesh term included ‘PET’ and ‘early detection of lung cancer’ or ‘screening of lung cancer’ or ‘early detection of lung neoplasm’. Seven eligible studies were selected from 82 potentially relevant studies.
We designed our eligibility criteria to identify studies that met minimal standards for acceptability. We also use PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement (4) to identify our review (Table 1). The PRISMA statement itself provides further details regarding its background and development. This accompanying Explanation and Elaboration document explains the meaning and rationale for each checklist item.
|Topic||Checklist item||Our review|
|Title||Identify the report as a systematic review, meta-analysis or both.||Yes|
|Abstract||Structured summary||Lack of abstract|
|Methods||Protocol and registration||No registration|
|Information sources||Yes, from Pubmed/Cochrane/Medline|
|Study selection||Yes, RCT, case control and review|
|Data collection process||No|
|Risk of bias in individual studies||Yes|
|Risk of bias across studies||No|
|Results||Study selection||Yes, see Figure 1|
|Study characteristics||Yes, see Tables 2 and 3|
|Risk of bias within studies||No|
|Results of individual studies||Yes|
|Synthesis of results||No, no meta-analysis|
|Risk of bias across studies||Yes|
|Discussion||Summary of evidence||Yes|
Our search identified 82 potentially relevant studies, including 12 abstracts, published since 2001. We excluded 60 published studies after scanning their titles and abstracts, including 18 studies where the title and abstract did not fully match inclusion criteria, 10 studies that evaluated other functional imaging tests, 6 studies that were letters to the editor, 2 studies not in English, and 2 that were not full articles. Twenty-two potentially eligible studies were subsequently appraised. Of these, we excluded six studies because the studies did not address the diagnosis of pulmonary nodules or masses, 6 studies did not use PET image, three studies presented data that has been reported previously or were replications. Only seven eligible studies were selected from 82 potentially relevant studies (Fig. 1). We also checked each of the original studies by using CRD appraisal checklists (Tables 2 and 3).
|Trial||Compare with gold standard||Blind||Sample size justified||Measure reliable||RCT||Validation study|
|Pastorino U (2003)||No||Yes||No (22)||No||Yes||No|
|Lindell RM (2005)||No||No||No (62)||Yes, pathologic proof||No||No|
|Marom EM (2002)||No||No||No (24)||Yes, pathologic proof||No||No|
|Ugo Pastorino (2009)||No||Yes||Yes (1035)||No||Yes||No|
|Olga Kagna (2009)||No||No||No (63)||Yes, pathologic proof||No||No|
|Trial||Untoward event||Number add up||Static significance||Sensitivity, specificity||RCT||Validation study|
|Pastorino U (2003)||No||Yes||No||No||Yes||No|
|Lindell RM (2005)||No||Yes||No||No||No||No|
|Marom EM (2002)||No||Yes||No||No||No||No|
|Ugo Pastorino (2009)||No||Yes||Yes||Yes||Yes||No|
|Olga Kagna (2009)||No||Yes||No||Yes||No||No|
In three recent studies, the sensitivity of 18F-FDG PET for the detection of T1 lung cancers ranged between 68% and 95% (5–7). Marom et al. (7) 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, whereas the PET findings for the remaining nine lesions were negative. The rate of detection tended to be lower for carcinoid tumors and bronchoalveolar cell carcinomas. The data appeared encouraging because the sizes of the lesions studied seemed to be in the range of tumors that one would expect in a lung cancer screening study. Less data has been reported from the Mayo Clinic (6). This institution participates in an NCI-sponsored prospective trial that assesses the role of CT in screening for lung cancer. A small subset of screened individuals with lung nodules also underwent 18F-FDG PET at the discretion of their pulmonologists. Twenty of these individuals (with 22 cancers) also underwent PET. With a threshold of 18F-FDG uptake of greater than mediastinal blood-pool activity or a standardized uptake value (SUV) of greater than 2.5, the PET findings for 14 of the 22 cancers (68%) were positive, the PET findings for 7 (32%) were negative, and the PET findings for 1 were considered indeterminate. The mean lesion size was 10 mm in both the positive and the negative groups (7). Based on their appearance on CT, nodules were classified as solid, semisolid or ground-glass opacity. Although the study had selection bias, it confirmed a lower rate of detection of BAC and adenocarcinomas with BAC features by PET. Moreover, as one should expect, among malignant lesions, the probability for positive PET results is directly related to the number and density of viable tumor cells within the lesion; thus, the probability for cancer detection in solid nodules is greater.
In 2009, Ugo Pastorino (8) tested the predictive value of FDG-PET using SUV on long-term survival of 34 lung cancer patients, detected from 1035 heavy smokers. They found that a PET scan was performed in 34 (89%) of 38 lung cancer patients diagnosed during the 5 years of screening and was positive in 32 (94%). Complete resection was achieved in 30 cases (88%), 20 (59%) were pathologic stage I and 23 (68%) were adenocarcinoma. Median SUV was 5.0 overall, being significantly lower in stage I and in adenocarcinoma. The 5-year survival of lung cancer patients was 100% for SUV levels < 2.5, 60% for SUV more than 2.5 and less than 8, and only 20% for SUV >8 (P = 0.001).
There was a retrospective study of PET/ldCT performed at the Department of Nuclear Medicine over a 2-year period between July 2001 and May 2003 to evaluate 307 consecutive patients with an indeterminate SPN. The result supported that a single-screening procedure encompassing FDG-PET and ldCT may improve screening for lung cancer in high-risk patients (9). We also found two review articles of lung cancer screening (10, 11). Both revealed that a combination of low-dose CT and PET for the evaluation of selected patients with indeterminate nodules might be a reasonable approach to lung cancer screening. Although no head-to-head study compared PET and LDCT with regards to the early detection of lung cancer, PET has a high false-negative rate in screening-detected indeterminate nodules, especially in cases of BAC and ground glass opacity.
After reviewing the value of PET in early detection of lung cancer, we found there is limited information about the true performance of whole-body PET for cancer screening. Data that might help to investigate this issue are generally derived from few case series analyzing the frequencies of malignancies incidentally detected during whole-body PET imaging and from PET screening studies.
First, there were only two randomized controlled trials (5, 8) of our seven selected eligible studies. The two studies did not have long follow-up periods. The characteristics of cancer are a long incubation period and lead time bias. Especially in cases of lung cancer, the doubling time of adenocarcinoma is about 3 months, and it may take 10 years to form a 1-cm lung tumor. If there is an insufficient follow-up period, the value of PET to detect lung cancer at an early stage maybe be masked by the long incubation period. Combined with the measurement of volume doubling time of pulmonary nodules, PET may result in a better sensitivity and specificity in indicating malignancy (12).
Second, these studies also had the challenge of small patient numbers. As a result, it may be difficult to make statistically valid conclusions.
Third, the retrospective nature of the studies (6, 7, 9) could be an issue. With respect to technical parameters, PET and ldCT were performed during shallow breathing. This may be overcome in the future with prospectively designed screening studies involving the use of optimized breathing or respiratory gating protocols. Retrospective studies are limited by the fact that PET scans were ordered at the discretion of pulmonologists rather than as part of a randomized prospective trial. There may be some bias from the information used by the physician in selecting whether a nodule was evaluated on PET.
Fourth, the outcome of these studies is limited regarding image findings and also due to the lack of surgical intervention or resection. In clinical practice, the definite diagnosis of lung cancer is pathologic proof. Differential diagnosis of lesions smaller than 6 mm can be very difficult, and this expands greatly the probability of unnecessary investigations and the total costs of screening.
Fifth, the use of PET for screening had the problem of overdiagnosis, also called pseudodisease. However, a different biological reason for criticism against lung cancer screening lies in the risk of overdiagnosis, that is detection of indolent and slowly progressing cancer, as well as in the possibility that very small cancers have already generated distant metastases.
The radiation dose of FDG is approximately 2 × 10−2 millisieverts(mSv)/megabecquerel(MBq), that is about 3–4 mSv for an administered activity of 185 MBq (13, 14). The radiation dose of PET is higher than LDCT, but is still much lower than the standard CT examination (15).
The expensive nature of PET scanning is a serious issue. Policy-level decisions regarding widespread use of FDG-PET must be considered, not only on diagnostic accuracy, but also on clinical outcomes and costs. At present, in Taiwan, FDGPET imaging is approximately $1600. In comparison, reimbursement for CT of the thorax is $200. Formal cost-effectiveness studies are needed to determine if diagnostic strategies that include FDG-PET represent good value for the health-care dollar.
In conclusion, PET or PET/CT may be used as a useful tool for early detection of lung cancer in high-risk population based on the existing information. However, there is still limited information with regards to evidence of survival benefits from PET screening in high-risk patients.