[
18
F]Fluorodeoxyglucose-positron emission
tomography
screening for lung cancer: a systematic review
and
meta-analysis
Chun-Ru Chiena,e,1, Ji-An Lianga,e,1, Jin-Hua Chenf,1, Hsiao-Nin Wangc, Cheng-Chieh
Linb,e,
Chih-Yi Chenc, Pin-Hui Wangc, Chia-Hung Kaod,e, Jun-Jun Yehg
aDepartment of Radiation Oncology, China Medical University Hospital, Taichung,
Taiwan; bDepartment of Community
Medicine and Health Examination Center, China Medical University Hospital, Taichung, Taiwan; cCancer Center, China
Medical University Hospital, Taichung, Taiwan; dDepartment of Nuclear Medicine
and PET Center, China Medical
University Hospital, Taichung, Taiwan; eSchool of Medicine, College of Medicine,
China Medical University, Taichung,
Taiwan; fBiostatistics Center and School of Public Health, Taipei Medical University,
Taipei, Taiwan; gDepartments
of Family Medicine and Chest Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan;
Chia Nan University of Pharmacy and Science, Tainan, Taiwan; Meiho University, Pingtung, Taiwan
Corresponding address: Chia-Hung Kao, Department of Nuclear Medicine and PET Center, China Medical University
Hospital, No. 2, Yuh-Der Road, Taichung 404, Taiwan. Email: [email protected].
Jun-Jun Yeh, MD, Departments of Family Medicine and Chest Medicine, Ditmanson Medical Foundation Chia-Yi
Christian Hospital, No. 539, Zhongxiao Road, Chiayi City 600, Taiwan. Email: [email protected].
1C.R. Chien, J.A. Liang and J.H. Chen contributed equally to this work.
Part of this work has been presented at the ISPOR 16th Annual International Meeting, Baltimore, MD, May 21_25, 2011;
and The European Multidisciplinary Cancer Congress 2011, Stockholm, September 23_27, 2011.
Date accepted for publication 29 August 2013
Introduction
Lung cancer is one of the major cancer-related causes of death worldwide. Low-dose computed tomography (CT) has been the recommended screening modality for highrisk populations since 2011[1,2].
[18F]Fluorodeoxyglucose (FDG)-positron emission
tomography (PET) combined with CT is helpful in the staging, imaging, and prognosis of patients with lung cancer[3_6]. It is crucial to differentiate equivocal primary
or regional lesions and to detect distant metastasis. PET has been used to effectively detect occult metastases, which may manifest in the initial stage, in a large number of patients with lung cancer. The evaluation of prognosis, including that for small tumors (53 cm), can be conducted[7]. It is also a useful tool for early detection
of lung cancer and pulmonary nodules not specifically related to screening[8,9]. A recent meta-analysis indicated
that the sensitivity and specificity in this scenario is 95% and 82%, respectively[9]. Considering the potential of
PET as an effective screening measure, it can be used as a primary procedure or in combination with CT. However, the role of PET in primary screening[10] and
in evolution of work-up for CT-detected nodules (i.e.,
selective screening) remains unclear[1]; therefore, a systematic
review was performed to evaluate the role of PET in lung cancer screening.
Materials and methods
Literature search and selection criteria
We searched for primary studies focusing on PET screening for lung cancer using the following keywords: lung
cancer AND positron emission tomography AND screen OR screening in PubMed until July 2012, similarly to a previous CT lung cancer screening systematic review[11].
All studies were independently reviewed by 2 reviewers (Reviewer 1: C.R. Chien; Reviewer 2: H.N. Wang or P.H. Wang) to identify studies that were compatible with the 3 inclusion/exclusion criteria: (1) primary research; (2) papers that focused on screening for lung cancer; and (3) PET with and without comparison as part(s) of the screening modality. A third reviewer (C.H. Kao) was considered for consensus in the event of a disagreement between the 2 reviewers. Manual searching for relevant cases was also performed for the included studies. The analysis was restricted to English and non-overlapping studies published since 2000. If overlapping patient cohorts were used between multiple studies, the latest or largest study was included.
Data extraction and quality assessment
Data were obtained for author, year of publication, study design, study period, study country, risk factor, study population characteristics, identification of lung cancer cases, and contributions from PET for all included studies. Data were extracted independently by 2 investigators (C.R. Chien and C.H. Kao), and discrepancies were
resolved by consensus. After an initial evaluation, papers in final analysis were divided into 2 categories: (1) primary PET: studies focused on primary PET screening for
cancer; and (2) selective PET: studies that reported findings in lung cancer CT screening programs with selective
PET. The primary PET studies mostly lacked information regarding false-positive or false-negative results, except for 2 studies providing information on PET screening[12]
and PET/CT[13], respectively. Subsequently, a methodological
quality analysis and meta-analysis were performed for selective PET studies because of the limited
available data. Methodological quality was assessed using the updated QUADAS-2 tools[14].
Statistical analysis
The results from each study were tabulated and summarized using descriptive analysis. Data on sensitivity, specificity, and accuracy of selective PET screening for lung
cancer were calculated from the original numbers provided in the 4 selective PET studies. The data sets were
pooled from the true-positive, false-positive, true-negative, and false-negative results from the relevant studies. The pooled sensitivity and specificity were calculated by weighted average of these statistics. The weights are the sample size of each study[15]. When the estimation of
sensitivities and specificities for each study was at least one zero cell, a correction of 1/2 was added to every cell for the study to define the estimators. We also tested the threshold effect using the Spearman correlation coefficient between sensitivity and specificity. However, the
result was non-significant and was not displayed in the pooled analysis. We attempted to fit each set of data to a summarized receiver-operating characteristic (sROC) curve, and calculate the area under the sROC curve (AUC). To examine the publication bias, we used the Deeks funnel plot using the linear regression method, which describes the association between diagnostic log odds ratio against sample size. Statistical analyses were conducted for these calculations using Meta-Disc version 1.4, a free statistical software package (Unit of Clinical Biostatistics, Ram_on y Cajal Hospital, Madrid, Spain), and Stata version 11 (StataCorp, College Station, TX, USA)[16].
Results
Literature search
The flowchart of the literature search is shown in Fig. 1. A total of 3497 searches were conducted, including database searching and manual searching. Among the identified cases, 238 studies published before 2000 were
excluded because of technology advancements in the past 10 years, 3111 cases were excluded because of irrelevant
titles and keywords, and 115 papers were excluded after reviewing the abstracts. A complete evaluation of papers led to the exclusion of 21 studies, with 12 studies remaining for analysis[12,13,17_26]. One selective PET
limited use of PET and the statistically significant imbalance
regarding tumor size among PET users and nonusers[
27].
Summary of studies included in general
The studies included did not evaluate the efficacy of primary PET screening specifically for lung cancer. Eight
studies focused on primary PET screening for cancer (Table 1)[12,13,17_22], and 4 studies reported findings
from lung cancer CT screening programs with selective PET (Table 2)[23_26].
Summary of primary PET screening studies:
detection rates of all types of cancer,
including lung cancer
All primary PET screening studies (Table 1) were singlearm (i.e., no comparator) studies performed in Far East
Asian countries (Japan, Taiwan, and Korea). Only 3 studies were conducted prospectively[12,21,22]. Only 2 studies
were not single-round studies (i.e., PET was performed once as prevalent screening)[17,21]. In addition to primary
PET, all cases used other examination procedures, such as CT, as the screening modalities. The percentage of male participants among individual studies ranged from 51% to 70%. The mean age of participants in individual studies ranged from 47 to 60 years. Lung cancer risk factors, such as history of smoking, were only reported in 2 studies[20,21]. The detection rates for all types of
cancer, including lung cancer, for each study are shown in Table 1. Among all primary PET studies (Table 1), 640 cancer cases were identified in the prevalent screen by a screening program (detection rate of 2%), and 363 cases (detection rate of 1.13%) were identified using PET. For lung cancer, 105 cases were identified in the prevalent screen by a screening program (detection rate of 0.33%), and 58 cases (detection rate 0.18%) were identified using PET.
Summary of selective PET screening studies:
diagnostic performance
prospective single-arm studies performed for a high-risk population (heavy smokers) in South Europe. The primary screening modality in these studies was chest CT,
whereas PET was reserved for specific CT findings, such as large (7_10 mm) or growing lesions in the follow-up examination. The percentage of male participants among individual studies ranged from 56% to 74%. The mean age of participants in individual studies ranged from 55 to 58 years. A quality assessment of diagnostic performance showed acceptable quality in these studies
(Fig. 2). PET evaluation was performed on approximately 3% of participants in these trials. The diagnostic
performance of selective PET in these studies is shown in Table 2. The estimated pooled sensitivity and specificity (with 95% confidence interval) was 83% (approximately 75%_89%) and 91% (approximately 86%_95%), respectively (Fig. 3). The heterogeneity chi-squared tests were
not statistically significant. The P values were 0.14 and 0.52 for pooled sensitivity and specificity, respectively (Fig. 3). The AUC value (0.945) was close to 1, which indicates that selective PET for lung cancer screening has a high diagnostic performance (Fig. 4).
Discussion
Low-dose CT is the current recommended modality for lung cancer screening for high-risk populations in the current National Comprehensive Cancer Network guideline. However, the role of PET in related work-up remains
unclear. PET is currently considered for solid or semisolid nodules of at least 8mm in size in prevalent screening, or enlarged nodules in incident screening[1]. Our
systemic review provides an up-to-date summary of the relevant evidence regarding the role of PET for lung cancer screening. The role of primary PET screening for lung cancer remains unknown. PET may be used as a screening modality; however, it may not be suitable for lung cancer because the detection rate of lung cancer is low. PET can also be used as a selective modality in combination with CT for lung cancer screening in highrisk
populations because it has high diagnostic performance; however, the prevalence of lung cancer in highrisk
populations (prescreened by CT) is high. This study is the first to conduct a systematic review to examine the
role of PET specifically for lung cancer screening. The results indicate that PET is helpful in lung cancer (early) diagnosis, staging, evaluation of treatment response, and evaluation for single pulmonary nodules in patients who are not always asymptomatic[3_6,8,9];
however, we extended its role to screen detected nodules. The implication of our findings may also be significant. Lung cancer screening with low-dose CT is a complex
and controversial issue[1,28,29], and may not be cost-effective
if used as a stand-alone modality[30]. A crucial concern
is the unnecessary operations performed because of screening. In one modeling study[31], CT screening led to
10 lung resections without any significant difference in lung cancer mortality. In another phase 3 trial[32], 77
patients in the CT arm received surgery, compared with 28 patients in the control group. Health care utilization
often increases because of potential false-positive or indeterminate screening results[33]. The high diagnostic performance
(AUC value 0.945) of selective PET screening
observed in this study may be helpful regarding this issue. In addition, the detection rate of lung cancer using primary PET was low (0.18%); this may have occurred
because the lung tumors were small and may not be easily detectable using primary (unselected) PET. The low detection rate may also be partly attributed to the use of the FDG-PET scan in the majority of the included studies instead of the current hybrid PET/CT. The diagnostic performance of PET/CT in this setting (primary
screening) must be examined in future studies. This study had several limitations, the first of which
was the external validity because of the strong geographic distribution tendency in the identified studies. All identified primary PET screening studies were conducted in
whereas all the identified selective PET studies were conducted in Europe (Italy, Spain, and Denmark). Because
of the substantial ethnic differences observed in patients with lung cancer in recent years[34], as well as the potential
effect of regional variation of granulomatous disease (a major cause of false-positive PET)[35], it is unclear
whether the results of this study can be applied to other regions; this must be validated in future studies. The second limitation is that most of the selective PET screening studies used PET instead of PET/CT[23,24,26].
However, this implied that the diagnostic performance of the current common practice (PET/CT) may be superior
to our estimates. Therefore, our results may be not applicable to PET/CT, and the role of PET/CT screening must
be further evaluated in future studies. The third limitation is that risk factors, such as smoking, were not adequately reported in most studies. The fourth limitation is that some heterogeneity may have occurred among the studies included in our meta-analysis, such as differences in
patient populations, PET indications, diagnostic criteria, and PET technology; however, the heterogeneity tests
were not statistically significant. The fifth limitation is the potential publication bias because the P value in the
Deeks funnel plot was 0.09. Therefore, the summary sensitivity and specificity must be interpreted with caution.
Despite these limitations, this study offers a unique
contribution to the current trend, and showed that guidelines are required for the clinical work-up of indeterminate
nodules identified using CT screening programs[28];
this study provides a strong rationale for the consideration of PET in these work-ups.
Conclusion
The role of primary PET screening for lung cancer remains unknown. However, PET has high sensitivity and specificity as a selective screening modality (i.e., for diagnosing lung cancer in patients with a pulmonary nodule found using CT screening). Further studies to evaluate the use of PET or PET/CT screening for highrisk
populations must be conducted, preferably using randomized trials or prospective registration.
