Diagnostic Performance of PET or PET/CT with Different Radiotracers in Patients with Suspicious Lung Cancer or Pleural Tumours according to Published Meta-Analyses

Purpose Several meta-analyses have reported data about the diagnostic performance of positron emission tomography or positron emission tomography/computed tomography (PET or PET/CT) with different radiotracers in patients with suspicious lung cancer (LC) or pleural tumours (PT). This review article aims at providing an overview on the recent evidence-based data in this setting. Methods A comprehensive literature search of meta-analyses published in PubMed/MEDLINE and Cochrane Library database from January 2010 through March 2020 about the diagnostic performance of PET or PET/CT with different radiotracers in patients with suspicious LC or PT was performed. This combination of keywords was used: (A) “PET” OR “positron emission tomography” AND (B) “lung” OR “pulmonary” OR “pleur∗” AND (C) meta-analysis. Only meta-analyses on PET or PET/CT in patients with suspicious LC or PT were selected. Results We have summarized the diagnostic performance of PET or PET/CT with fluorine-18 fluorodeoxyglucose (18F-FDG) and other radiotracers taking into account 17 meta-analyses. Evidence-based data demonstrated a good diagnostic performance of 18F-FDG PET or PET/CT for the characterization of solitary pulmonary nodules (SPNs) or pleural lesions with overall higher sensitivity than specificity. Evidence-based data do not support the routine use of dual time point (DTP) 18F-FDG PET/CT or fluorine-18 fluorothymidine (18F-FLT) PET/CT in the differential diagnosis of SPNs. Even if 18F-FDG PET/CT has high sensitivity and specificity as a selective screening modality for LC, its role in this setting remains unknown. Conclusions Evidence-based data about the diagnostic performance of PET/CT with different radiotracers for suspicious LC or PT are increasing, with good diagnostic performance of 18F-FDG PET/CT. More prospective multicenter studies and cost-effectiveness analyses are warranted.


Introduction
Positron emission tomography (PET) is a noninvasive functional imaging method currently used for several oncological indications.
is method can early detect pathophysiological changes in affected tissues in oncological patients, including patients with lung cancer (LC) or pleural tumours (PT), and these functional changes may occur before anatomical changes detected by conventional radiological techniques. Currently, hybrid imaging techniques as positron emission tomography/computed tomography (PET/CT) may provide combined functional and morphological information for early diagnosis of LC or PT [1]. Fluorine-18 fluorodeoxyglucose ( 18 F-FDG) is the most used PET radiotracer in oncology: this radiolabelled glucose analogue is taken up by the cells via cell membrane glucose transporters and subsequently phosphorylated by hexokinase inside the cells. e ability of 18 F-FDG PET or PET/CT to identify tumour lesions is mainly related to the increased glycolytic activity of the majority of tumour cells [1]. Beyond 18 F-FDG, other PET radiotracers evaluating different metabolic pathway or receptor status have been used and approved for oncological indications [2].
Meta-analysis is a statistical technique for combining the findings of independent studies included in a systematic review and it is often used to assess the diagnostic performance of imaging methods. All meta-analyses are actually systematic reviews with components of statistical pooling of data [3]. Several meta-analyses have been published about the diagnostic performance of PET or PET/CT with different radiotracers in oncology [3]. e aim of this review article is to provide an overview of the findings of recent meta-analyses about the diagnostic performance of PET or PET/CT with different radiotracers in patients with suspicious LC or PT.

Methods
A comprehensive literature search of PubMed/MEDLINE and Cochrane Library databases was performed to find recently published meta-analyses on the diagnostic performance of PET or PET/CT with different radiotracers in patients with suspicious LC or PT.
A search algorithm based on the combination of the following terms was used: (A) "PET" OR "positron emission tomography" AND (B) "lung" OR "pulmonary" OR "pleur * " AND (C) meta-analysis. e literature search was updated until March 25, 2020. No language restriction was used. Recent meta-analyses (published from 2010 until the last search date) investigating the diagnostic performance of PET or PET/CT by using different radiotracers in patients with suspicious LC or PT were eligible for inclusion. Titles and abstracts of the retrieved meta-analyses were reviewed, applying the inclusion criteria mentioned above.
For each selected meta-analysis, information was collected about the indication of PET or PET/CT (including the used radiotracer), authors, year of publication, number of original articles included, number of patients or lesions included, and pooled diagnostic performance measures with 95% confidence interval values (95% CI) if available. Finally, the main findings of the selected meta-analyses were briefly described.
In particular, we have summarized: (1) the diagnostic performance of 18 F-FDG PET or PET/CT as a screening method for LC; (2) the diagnostic performance of single time point (STP) and dual time point (DTP) 18  3.1. Lung Cancer Screening. Chien et al. [4] conducted a meta-analysis to describe the role of 18 F-FDG PET in LC screening. Four studies reported evidence of LC screening programs with selective 18 F-FDG PET with a pooled sensitivity and specificity of 83% and 91%, respectively. Even if 18 F-FDG PET has high sensitivity and specificity as a selective screening modality, the role of primary 18 F-FDG PET or PET/CT screening for LC remains unknown. Further studies must be conducted to evaluate the use of this imaging method as screening modality for high-risk populations, preferably using randomized trials or prospective registration.

Characterization of Solitary Pulmonary Nodules with Single
Time Point 18 F-FDG PET or PET/CT. Characterizing SPNs detected incidentally or, as is the case more recently, on CT screening for LC, is a major public health issue. In the last decade, a robust evidence has been produced on the use of single time point (STP) 18 F-FDG PET or PET/CT in the characterization of SPNs [5][6][7][8][9][10][11]. Two examples of 18 F-FDG PET/CT images in the characterization of SPNs are shown in Figure 1.
Deppen et al. [5] performed a meta-analysis to estimate the diagnostic accuracy of 18 F-FDG PETor PET/CTfor SPNs suspicious for LC. e pooled sensitivity and specificity of 18 F-FDG PET or PET/CT were 89% and 75%, respectively, with significant heterogeneity across the studies. ere was a 16% lower specificity in regions with endemic infectious lung disease (61%) compared with nonendemic regions (77%). In general, the sensitivity did not change appreciably by endemic infection status. Overall, the accuracy of 18 F-FDG PET or PET/CT for diagnosing LC among SPNs was extremely heterogeneous. ese data support the use of 18 F-FDG PET to diagnose LC among SPNs in regions where pulmonary infections are not endemic.
Wang et al. [6] suggested in their analysis that 18 F-FDG PET/CT providing high sensitivity (98.7%) and moderate specificity (58.2%) could be applied for early diagnosis of LC.
Recently, Ruilong et al. [7] carried out a meta-analysis on the performance of 18 F-FDG PET/CT for the evaluation of SPNs reporting a pooled sensitivity and specificity of 82% and 81%, respectively. As significant heterogeneity was observed, and a subgroup analysis showed that the best results for sensitivity (90%) and accuracy (93%) were present in prospective studies. Overall, their analysis suggested that 18 F-FDG PET/CT is a useful tool for detecting malignant   Another meta-analysis on the same topic [8] reported a pooled sensitivity of 89% and a pooled specificity of 70% for the diagnosis of malignant SPNs by 18 F-FDG PET/CT. e authors concluded that this method cannot replace the "gold standard" pathology by resection or percutaneous biopsy and larger studies are required for further evaluation.
Recently, Divisi et al. [9] confirmed these findings reporting a pooled sensitivity and specificity of 81.9% and 62.4%, respectively, suggesting that 18 F-FDG PET/CT has good diagnostic accuracy in SPN evaluation, but it should not be considered as a discriminatory test rather than a method to be included in a clinical and diagnostic pathway.
Two recent meta-analyses compared the diagnostic performance of 18 F-FDG PET/CT with other radiological methods. Jia et al. [10] performed an indirect comparison among 18 F-FDG PET/CT and CT for differentiating benign and malignant SPNs. e pooled sensitivity and specificity for 18 F-FDG PET/CT were 89% and 78%, respectively. e corresponding values for CT were 94% and 73%, respectively. No significant differences were observed between CT and 18 F-FDG PET/CT about the diagnostic parameters; both imaging methods showed a moderate-to-high diagnostic value for differentiating benign and malignant SPNs.
Lastly, a recent meta-analysis investigated the diagnostic performance of 18 F-FDG PET/CT compared with diffusionweighted magnetic resonance imaging (DW-MRI) for distinguishing malignant and benign SPNs [11]. DW-MRI had a pooled sensitivity and specificity of 83% and 91%, respectively, compared with 78% and 81%, respectively, for 18 F-FDG PET/CT. e authors concluded that the diagnostic performance of DW-MRI is comparable or superior to that of 18 F-FDG PET/CT in the differentiation of malignant and benign pulmonary lesions.

Characterization of Solitary Pulmonary Nodules with Dual Time Point 18 F-FDG PET or PET/CT. Several meta-
analyses have also explored the potential use of a dual time point (DTP) 18 F-FDG PET or PET/CT in differentiating malignant from benign SPNs, performing both standard and delayed PET scans [12][13][14][15].
Lin et al. [12] performed a meta-analysis to assess the potential value of DTP compared with STP 18 F-FDG PET in differentiating malignant from benign SPNs. e authors found a significant heterogeneity among the studies and a statistically nonsignificant trend toward higher sensitivity with DTP 18 F-FDG PET, at moderate levels of specificity, when compared with initial STP 18 F-FDG PET. Although the results of this analysis do not support the routine use of DTP 18 F-FDG PET in the differential diagnosis of SPNs, this technique may provide additional information in selected cases with equivocal results from initial scanning, but further prospective research is required to better define the potential benefits of DTP 18 F-FDG PET.
On the same topic, Barger and Nandalur [13] reported that the pooled sensitivity of DTP 18 F-FDG PET was 85% and the pooled specificity was 77%. Significant heterogeneity was found. DTP 18 F-FDG PET demonstrated similar sensitivity and specificity to STP 18 F-FDG PET in the diagnosis of SPNs. erefore, the additive value of DTP 18 F-FDG PET is questionable.
Zhang et al. [14] reported a pooled sensitivity and specificity of DTP 18 F-FDG PET of 79% and 73%, respectively. e corresponding values for STP 18 F-FDG PET were 77% and 59%, respectively. ese findings confirmed the similar accuracy of DTP and STP 18 F-FDG PET in the differential diagnosis of SPNs, even if DTP 18 F-FDG PET appears to be more specific than STP 18 F-FDG PET.
Lastly, a recent meta-analysis on the same topic [15] reported a pooled sensitivity of 80% and a pooled specificity of 75% for DTP 18  high-quality research is required to explore the potential value of DTP 18 F-FDG PET/CT in this setting.

18 F-FLT PET for Evaluation of Pulmonary
Lesions. e potential role of PET with 18 F-FLT, a biomarker of proliferation, in the evaluation of pulmonary lesions was assessed by two meta-analyses. Li et al. [16] compared the diagnostic performance of 18 F-FLT PET with 18 F-FDG PET in evaluating patients with pulmonary lesions. is metaanalysis showed that 18 F-FLT PET had a higher specificity (70%), but lower sensitivity (81%) compared to 18 F-FDG PET (sensitivity: 92%; specificity: 50%). erefore, 18 F-FLT and 18 F-FDG together could add diagnostic confidence for pulmonary lesions.
Wang et al. [17] performed a meta-analysis on the same topic: the direct comparisons showed lower sensitivity (80% vs. 89%) yet higher specificity (82% vs. 66%) for 18 F-FLT PET compared with 18 F-FDG PET. Although 18 F-FLT PET cannot replace 18 F-FDG PET in detecting small and early LC, it may help to prevent patients with larger or inflammatory lesions from cancer misdiagnosis or even overtreatment.

18 F-FDG PETor PET/CTfor Evaluation of Pleural Lesions.
18 F-FDG PET and PET/CT demonstrated to be accurate diagnostic imaging methods in the differential diagnosis between malignant and benign pleural lesions in patients with or without known cancer history; nevertheless, possible sources of false-negative and false-positive results should be kept in mind and it cannot replace histopathological evaluation [18][19][20]. In patients without known cancer, pooled sensitivity and specificity of 18 F-FDG PET and PET/CT were 95% and 82%, respectively [18]. In patients with known cancer, pooled sensitivity and specificity of 18 F-FDG PET and PET/CT were 86% and 80%, respectively [19]. Porcel et al. in their meta-analysis [20] demonstrated that semiquantitative 18 F-FDG PET assessment had a significantly lower sensitivity for diagnosing malignant pleural effusions than visual assessments. e pooled sensitivity and specificity of 18 F-FDG PET or PET/CT using qualitative interpretation were 91% and 64%, respectively; the same pooled estimates using semiquantitative interpretation for identifying malignant pleural effusions were 81% and 74%, respectively. e moderate accuracy of semiquantitative PET assessment precludes its routine recommendation for discriminating malignant from benign pleural effusions.

Discussion
Our overview demonstrates that there is increasing evidence about the diagnostic performance of PET or PET/CT with different radiotracers in patients with suspicious LC or PT with good diagnostic accuracy values for some indications (Table 1).
Overall, current evidence-based data demonstrated the following points: Awareness of the results described in this evidence-based review may affect patient care by providing supportive evidence for more effective use of PET/CT with different radiotracers in patients with suspicious LC or PT. Nevertheless, we would like to point out that diagnostic performance of an imaging method is not a measure of clinical effectiveness and good diagnostic accuracy of PET or PET/CT with different radiotracers for a specific indication does not necessarily result in improved patient outcomes. According to health technology assessment (HTA) principles which are valid also for PET imaging [21], other factors beyond the diagnostic performance of a test should be taken into account to support the clinical usefulness of an imaging method as availability, safety, legal, organization and economic aspects, and cost-effectiveness. To this regard, a recent cost-effectiveness analysis by Lopci et al. demonstrated that, despite a higher average cost for outpatient's diagnostics, the implementation of 18 F-FDG PET/CT in the workup of undetermined lung nodules results in reduced unnecessary harm and costs related to inpatient's procedures [22]. ese findings are in line with those of previous cost-effectiveness analyses which reported that the additional information gained from 18 F-FDG PET or PET/CT in the characterization of SPNs is worth the cost in the context of proper medical indications [23,24]. erefore, it is expected that 18 F-FDG PET/CT is reported in the list of approved procedures for the investigation of SPNs in several countries [24]. On the other hand, it is expected that 18 F-FDG PET/CT may not be cost-effective for early diagnosis of LC in regions or countries where the specificity of this method is low (i.e., in countries where infectious lung diseases are endemic) Contrast Media & Molecular Imaging [25]. In summary, in countries with a low incidence of pulmonary inflammatory or infectious diseases and a high incidence of LC, the diagnostic workup of SPNs should include 18 F-FDG PET/CT as a main pillar. In countries with a high incidence of pulmonary inflammatory or infectious diseases and a low incidence of LC, this diagnostic workup needs to be adapted [26].
No cost-effectiveness analyses are currently available for the use of 18 F-FDG PET/CT as a screening method for LC, for the use of DTP 18 F-FDG PET/CT or 18 F-FLT PET/CT for characterization of SPNs, and for the use of 18 F-FDG PET/ CT for characterization of pleural lesions.
About international guidelines, the last version of National Comprehensive Cancer Network (NCCN) guidelines recommends the use of 18 F-FDG PET/CT for characterization of solid SPNs with diameter >8 mm [27]; this indication was set taking into account the significant risk of false-negative findings of 18 F-FDG PET/CT for small lesions and nonsolid nodules [27].
Some limitations of the included meta-analyses should be underlined because they could hamper the achievement of definitive conclusions on the diagnostic performance of PET or PET/CT with different radiotracers in patients with suspicious LC or PT. In some meta-analyses, there is a limited number of included original studies, and this could have influenced the statistical power of the meta-analysis. In several meta-analyses, a significant heterogeneity across studies was described; this potential bias could be due to differences among patients included, methods and reference standard used, quality, and study design among the different included articles [28]. Furthermore, publication bias was reported in some meta-analyses pointing out that studies with significant findings were more likely to be published than those reporting nonsignificant results [28].
As a suggestion for further research, large multicenter prospective studies and in particular more cost-effectiveness analyses comparing 18 F-FDG PET/CT with other imaging modalities in patients with suspicious LC and PT are warranted.

Conflicts of Interest
e authors declare no conflicts of interest.