SEARCH

SEARCH BY CITATION

Keywords:

  • 18F-FDG PET/CT;
  • non–small-cell lung cancer;
  • metastases;
  • diagnostic value

Abstract

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgements
  8. References
  9. Supporting Information

In the recent years, fluorine 18 fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) has emerged as a new modality for staging non–small-cell lung cancer (NSCLC) patients. The aim of this meta-analysis was to assess the diagnostic value of 18F-FDG PET/CT in detecting metastatic lesions in NSCLC patients. Meta-analysis methods were used to pool sensitivity, specificity, positive and negative likehood ratios, diagnostic odd ratios and to construct a summary receiver-operating characteristic curve. Data from included studies were pooled to compare the diagnostic accuracy between PET/CT and PET or CT alone in nodal staging. Totally, 56 studies involving 8,699 patients met the inclusion criteria. The pooled sensitivities and specificities of 18F-FDG PET/CT were 0.72 [95% confidence interval (CI): 0.65–0.78] and 0.91 (95% CI: 0.86–0.94) in determining mediastinal nodal staging; 0.71 (95% CI: 0.60–0.80) and 0.83 (95% CI: 0.77–0.88) in intrathoracic staging; 0.78 (95% CI: 0.64–0.87) and 0.90 (95% CI: 0.84–0.94) in intrathoracic staging on a per-node basis. For detecting extrathoracic metastases, the pooled sensitivities and specificities of 18F-FDG PET/CT were 0.77 (95% CI: 0.47–0.93) and 0.95 (95% CI: 0.92–0.97) for all extrathoracic metastases; 0.91 (95% CI: 0.80–0.97) and 0.98 (95% CI: 0.94–0.99) for bone metastases. 18F-FDG PET/CT is beneficial in detecting lymph node metastases and extrathoracic metastases although PET/CT showed low sensitivity in detecting brain metastases. 18F-FDG PET/CT confers significantly higher sensitivity and specificity than contrast-enhanced CT (both p < 0.01) and higher sensitivity than 18F-FDG PET in staging NSCLC (p < 0.05).

Lung cancer is the leading cause of tumor-related deaths worldwide, and non–small-cell lung cancer (NSCLC) accounts for about 80% of all lung cancers.1 The current criteria for staging NSCLC is based on the TNM system,2 which determines treatment options and predicts survival.3 So, staging NSCLC is important, and accurate clinical methods are in great need. Various diagnostic methods have been used for staging NSCLC.4–7 Computed tomography (CT) has been widely used to evaluate the nodal status of lung cancer based on the size or shape of the lymph nodes.8 However, the sensitivity and the specificity were relatively low, because the lymph node size may not correlate with the presence of metastatic disease.9 Based on the fact that malignant cells show higher rates of glycolysis than most surrounding normal structures,10 fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) has been introduced and developed as an effective modality for tumor staging in a variety of cancers.11 However, PET has relatively poor spatial resolution, thus limits its anatomical localization of lesions.12 Mediastinoscopy, endobronchial and endoscopic ultrasound, and other surgical procedures are frequently used for thoracic nodal evaluation in lung cancer, but these techniques are invasive and cumbersome.7, 13 In the past recent years, 18F-FDG PET/CT has emerged as a new modality for staging NSCLC patients.4, 14 The aim of this study was to evaluate the diagnostic accuracy of 18F-FDG PET/CT in detecting metastases in NSCLC patients.

Material and Methods

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgements
  8. References
  9. Supporting Information

Selection criteria

Selection criteria were given as follows: (1) 18F-FDG PET/CT was used for the evaluation of lymph node (LN) metastases or extrapulmonary metastases in NSCLC; (2) histologic assessment should be applied as reference standard for LN metastases; for studies evaluated extrathoracic metastases, other reference standards such as imaging modality, radiological and clinical follow-up were also applied; (3) absolute numbers of true-positive (TP), false-positive (FP), true-negative (TN) and false-negative (FN) results were provided or could be derived. Studies were excluded if they were performed in patients after induction of chemotherapy or surgery.

Literature search

We searched PUBMED, EMBASE and Cochrane (up to October 2011) to identify eligible studies. The following search algorithm was used: “lung neoplasm” OR “lung cancer” OR “pulmonary neoplasm” OR “pulmonary cancer”; “PET-CT” OR “PET/CT” OR “positron emission tomography/computed tomography” OR “positron emission tomography and computed tomography”; “metastasis” OR “metastases” OR “staging.” References of relevant articles were also scanned for potentially missing studies. Titles and abstracts were scanned, and then full articles were reviewed. Articles as full papers in English and Chinese were retrieved. The retrieved studies were carefully examined to exclude potential duplicates or overlapping data.

Data extraction and quality assessment

The following information was extracted from each study: authors, year of publication, country of each study, study design (prospective or retrospective), patient characteristics (including sample size, gender and mean age), reference standard, FDG dose and CT portion (contrast enhanced or unenhanced) of PET/CT and diagnostic performance of PET/CT. Data were extracted independently by two investigators (Dr. Wu YH and Dr. Li PW).We considered mediastinal LNs as N2 and N3 nodes and intrathoracic LNs as hilar and mediastinal LNs (N1, N2 and N3 nodes), based on the 1997 revision of the lung cancer staging system.15 Discrepancies were resolved by a third investigator. The quality of methodology for each study was assessed using the quality assessment of diagnostic accuracy studies (QUADAS).16 For each component, a score of 1 was applied if the answer was “yes”; otherwise, a score 0 was applied.

Statistical analysis

The following analyses were performed: sensitivity, specificity, likelihood ratios (LRs) and diagnostic odds ratio. Data were finally summarized in receiver-operating characteristic curves (sROC). Confidence intervals (CIs) were computed, assuming asymptotic normality after a log transformation for variance parameters and for LRs and a logit transformation for proportions. We analyzed the numbers of TP, FP, TN and FN to calculate sensitivity and specificity. The formula for a positive LR is sensitivity/(1 − specificity), and the formula for a negative LR is (1 − sensitivity)/specificity. A clinically useful test was defined as having a positive LR greater than 5.0 and a negative LR less than 0.2.17, 18 Thus, the combined LRs provide the diagnostic odds ratio (positive LR/negative LR).19, 20

Heterogeneity was assessed using I2 test.21 To test publication bias, Deek's funnel plot method was applied.22

Source of heterogeneity was explored by regression meta-analysis: diagnostic criteria, country of each study, study design, QUADAS score, sample size, FDG dose and CT portion of PET/CT. Statistical analyses were performed using the STATA software (version 11.0, STATA Corp., College Station, TX) and Meta-Disc (version 1.4, Unit of clinical biostatics, the Ramoy Cajal Hospital, Madrid, Spain). All p values presented were two-sided. The association was considered significant if the p value was less than or equal to 0.05.

Results

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgements
  8. References
  9. Supporting Information

Description of trials

After searching PUBMED, EMBASE and Cochrane, we identified 1,010 articles. Review of titles and abstracts resulted in exclusion of 906 articles, and another 4 articles were excluded as no full texts could be retrieved. For the remaining 100 articles in full text, reasons for exclusion were articles not on right topic or targeted population (27 works), insufficient data (13 works), multiple publications (3 works) and language was neither English nor Chinese (1 work). Finally, 56 studies were included (selection process see Supporting Information Fig. 1). The characteristics of the 56 studies was shown in Supporting Information Table 1.4–6, 14, 23–74 Among the included studies, 46 evaluated LN metastatic disease and 13 assessed extrathoracic metastatic disease. The QUADAS scores of the 56 studies were shown in Supporting Information Table 2.

Lymph node staging

The overall results of the diagnostic performance were shown in Table 1.

Table 1. Diagnostic value of 18F-FDG PET/CT in lymph node staging
inline image
Mediastinal staging on a per-patient basis
Mediastinal staging in NSCLC patients

Twenty-seven studies containing 3,248 NSCLC patients assessed the diagnostic accuracy of 18F-FDG PET/CT in mediastinal staging. The pooled sensitivity and specificity were 0.72 (95% CI: 0.65–0.78) and 0.91 (95% CI: 0.86–0.94), respectively (Fig. 1a1). Significant heterogeneity was observed both in sensitivity (Q = 118.51; df = 26; p < 0.005; I2 = 78.06%) and specificity (Q = 222.51; df = 26; p < 0.005; I2 = 88.32%). Through meta-regression and subgroup analysis, FDG doses and CT portion of PET/CT, study design and diagnostic criteria were found to be the source of heterogeneity (Table 2).

thumbnail image

Figure 1. Diagnostic performance of 18F-FDG PET/CT in the detection of lymph node metastases in NSCLC patients. (a1) Pooled sensitivity and specificity in mediastinal staging. (a2) ROC curve analysis in mediastinal staging. (b1) Pooled sensitivity and specificity in hilar and mediastinal staging on a per-patient basis. (b2) ROC curve analysis in hilar and mediastinal staging on a per-patient basis. (c1) Pooled sensitivity and specificity in hilar and mediastinal staging on a per-node basis. (c2) ROC curve analysis in hilar and mediastinal staging on a per-node basis.

Download figure to PowerPoint

Table 2. Subgroup analysis to explore potential heterogeneity in lymph node staging
inline image

The positive and negative LRs were 7.6 (95% CI: 5.2–11.1) and 0.31 (95% CI: 0.25–0.39), respectively. This result indicated a high performance of 18F-FDG PET/CT, confirming the presence of mediastinal metastasis but a low efficacy in ruling out lesions. The pooled diagnostic odds ratio was 25 (95% CI: 15–40). The area under the sROC curve was 0.88 (95% CI: 0.85–0.91; Fig. 1a2), indicating that the diagnostic performance of 18F-FDG PET/CT is high.

Mediastinal staging in stage T1 NSCLC patients

Three studies evaluated the efficacy of 18F-FDG PET/CT in detecting mediastinal nodal metastases in a total of 477 T1 NSCLC patients. The pooled sensitivity, specificity, positive LR, negative LR, diagnostic odds ratio value and the area under the sROC curve were 0.51 (95% CI: 0.40–0.61), 0.98 (95% CI: 0.96–0.99), 41.4 (95% CI: 2.9–595.1), 0.51 (95% CI: 0.41–0.62), 76 (95% CI: 7–776) and 0.42, respectively. The pooled sensitivity and specificity were shown in Supporting Information Figures 2a and 2b, while the sROC curve was shown in Supporting Information Figure 3a. There was significant heterogeneity in specificity (Q = 14.23; df = 2; p < 0.005; I2 = 85.90%) but not in sensitivity (Q = 0.62; df = 2; p = 0.73; I2 = 0.00%).

Mediastinal staging in NSCLC patients with a high prevalence of tuberculosis

Four studies including 927 patients evaluated the diagnostic accuracy of 18F-FDG PET/CT in mediastinal nodal staging in patients with a high prevalence of tuberculosis. The pooled sensitivity and specificity were 0.64 (95% CI: 0.57–0.70) and 0.89 (95% CI: 0.87–0.91), respectively (Supporting Information Figs. 2c and 2d). The area under the sROC curve was 0.80 (Supporting Information Fig. 3b). The positive LR, negative LR and diagnostic odds ratio value were 4.7 (95% CI: 1.4–15.9), 0.43 (95% CI: 0.27–0.68) and 12 (95% CI: 3–49). Significant heterogeneity was observed both in sensitivity (Q = 7.82; df = 3; p < 0.05; I2 = 61.60%) and specificity (Q = 70.21; df = 3; p < 0.005; I2 = 95.70%).

Intrathoracic LN staging on a per-patient basis

The accuracy of 18F-FDG PET/CT for intrathoracic staging was assessed by 18 studies with 2,304 patients. The pooled sensitivity and specificity were 0.71 (95% CI: 0.60–0.80) and 0.83 (95% CI: 0.77–0.88), respectively (Fig. 1b1). The positive and negative LRs were 4.2 (95% CI: 3.1–5.8) and 0.35 (95% CI: 0.25–0.49), respectively, suggesting that 18F-FDG PET/CT has limited value in evaluating intrathoracic lymph node metastasis. The diagnostic odds ratio value was 12 (95% CI: 7–21). The area under the sROC curve was 0.85 (95% CI: 0.82–0.88; Fig. 1b2). Significant heterogeneity was observed in both sensitivity (Q = 164.03; df = 17; p < 0.005; I2 = 89.64%) and specificity (Q = 160.63; df = 17; p < 0.005; I2 = 89.42%). Heterogeneity in sensitivity and specificity was caused by several confounding factors including diagnostic criteria, country of origin, FDG doses and CT portion of PET/CT (Table 2).

Intrathoracic staging on a per-node basis

Nine studies assessed the accuracy of 18F-FDG PET/CT in detecting intrathoracic LN metastases on a per-node basis. These studies included 674 patients and 5,383 lymph nodes. The pooled sensitivity, specificity, positive LR, negative LR and the diagnostic odds ratio value were 0.78 (95% CI: 0.64–0.87), 0.90 (95% CI: 0.84–0.94), 7.9 (95% CI: 5.1–12.0), 0.25 (95% CI: 0.16–0.40) and 31 (95% CI: 20–50), respectively (Fig. 1c1). The area under the sROC curve was 0.92 (95% CI: 0.89–0.94; Fig. 1c2). Significant heterogeneity was found in both sensitivity (Q = 138.66; df = 8; p < 0.005; I2 = 94.23%) and specificity (Q = 220.93; df = 8; p < 0.005; I2 = 96.38%). Diagnostic criteria were the most important source of heterogeneity while other factors including country of origin, study quality and FDG dose also contributed to the heterogeneity (Table 2).

Efficacy of 18F-FDG PET/CT for the detection of extrathoracic metastases

M-staging on a per-patient basis

Four studies including 360 patients evaluated the use of PET/CT in M staging. The pooled sensitivity was 0.77 (95% CI: 0.47–0.93), and the pooled specificity was 0.95 (95% CI: 0.92–0.97; Fig. 2a). Heterogeneity was found to be significant in sensitivity (Q = 11.74; df = 3; p = 0.01; I2 = 74.45%) but not in specificity (Q = 3.98; df = 3; p = 0.26; I2 = 24.56%). The positive LR, negative LR and the diagnostic odds ratio values were 16.5 (95% CI: 9.5–28.6), 0.24 (95% CI: 0.09–0.68) and 68 (95% CI: 18–253), respectively. The area under the sROC curve was 0.96 (95% CI: 0.94–0.97; Fig. 2b).

thumbnail image

Figure 2. Diagnostic performance of 18F-FDG PET/CT in the detection of all extrathoracic metastases and in bone metastases. (a) Pooled sensitivity and specificity in detection of all extrathoracic metastases. (b) ROC curve analysis in detection of all extrathoracic metastases. (c) Pooled sensitivity and specificity in detection of bone metastases. (d) ROC curve analysis in detection of bone metastases.

Download figure to PowerPoint

Detection of bone metastases

Six studies involving 1,894 patients assessed diagnostic value of 18F-FDG PET/C in detecting bone metastases. The pooled sensitivity and specificity of detecting bone metastases were 0.91 (95% CI: 0.80–0.97) and 0.98 (95% CI: 0.94–0.99), respectively (Fig. 2c). Significant heterogeneity was found both in sensitivity (Q = 29.49; df = 5; p < 0.005; I2 = 83.04%) and in specificity (Q = 63.84; df = 5; p < 0.005; I2 = 92.17%). One study contained only 11 patients with bone metastases.23 The small sample size may contribute to the heterogeneity in sensitivity. After excluding this study, the heterogeneity in sensitivity no longer existed (Q = 2.00; df = 4; p = 0.74; I2 = 0.00%). However, no significant source of heterogeneity in specificity was found. The positive LR, negative LR and diagnostic odds ratio values were 49.8 (95% CI: 15.7–158.1), 0.09 (95% CI: 0.04–0.21) and 567 (95% CI: 177–1851), respectively. The area under the sROC curve was 0.99 (95% CI: 0.97–0.99; Fig. 2d).

Detection of brain metastases and adrenal metastases

Two studies with 546 patients evaluated the accuracy of detecting brain metastases by PET/CT on a per-patient basis.24, 25 In the study of Kruger et al.,24 PET/CT was performed with contrast medium while in the study of Lee et al.,25 the CT portion of PET/CT was unenhanced. The sensitivities of these two studies were 0.27 and 0.24, and the specificities were 0.98 and 1.00, respectively.

One study containing 51 patients assessed the diagnostic performance of 18F-FDG PET/CT in detecting adrenal metastases.26 Using SUVmax > 2.7 as the diagnostic criteria, the sensitivity was 0.89 and the specificity was 0.88.

Differences among the efficacy of CT, 18F-FDG PET and 18F-FDG PET/CT in nodal staging

Differences of CT, 18F-FDG PET and 18F-FDG PET/CT in mediastinal staging

Three studies compared the differential diagnostic performances between 18F-FDG PET and 18F-FDG PET/CT. Two hundred and eighteen and 302 patients were included in evaluating the performance of 18F-FDG PET and 18F-FDG PET/CT, respectively. The overall sensitivity of 18F-FDG PET/CT was significantly higher than 18F-FDG PET (0.83 vs. 0.69, p < 0.05). However, the specificity of18F-FDG PET/CT was significantly lower than that of 18F-FDG PET (0.82 vs. 0.90, p < 0.05; Fig. 3a). The AUC of PET/CT was slightly higher than that of PET (0.89 vs. 0.85).

thumbnail image

Figure 3. Differences among the efficacy of CT, 18F-FDG PET and 18F-FDG PET/CT in the detection of lymph node metastases. (a) Differences of sensitivities and specificities between PET and PET/CT in mediastinal staging. (b) Differences of sensitivities and specificities between CECT and PET/CT in mediastinal staging. (c) Differences of sensitivities and specificities between PET and PET/CT in intrathoracic staging on a per-patient basis. (d) Differences of sensitivities and specificities between CECT and PET/CT in intrathoracic staging on a per-patient basis. (e) Differences of sensitivities and specificities between CECT and PET/CT in detection of intrathoracic lymph node on a per-node basis.

Download figure to PowerPoint

Efficacies of contrast-enhanced CT (CECT) and PET/CT in mediastinal staging were compared to six studies containing 806 patients. PET/CT demonstrated significant higher sensitivity (0.78 vs. 0.53, p < 0.0001) and specificity (0.73 vs. 0.87, p < 0.0001) than CECT (Fig. 3b). The AUC of 18F-FDG PET/CT was 0.89 (95% CI: 0.86–0.91), whereas the AUC of CT was 0.70 (95% CI: 0.66–0.74).

The accuracies of noncontrast CT and PET/CT were compared to two studies with 122 patients. Li et al. demonstrated that PET/CT has higher sensitivity (0.68 vs. 0.63) and specificity (1 vs. 0.90) than noncontrast CT. In another study, PET/CT showed higher sensitivity (1 vs. 0.38) but lower specificity (0.88 vs. 0.94) than noncontrast CT.

Differences of CT, 18F-FDG PET and 18F-FDG PET/CT in intrathoracic staging

Three studies including 193 patients evaluated the difference between the accuracies of 18F-FDG PET and 18F-FDG PET/CT. Results indicated that PET/CT has significantly higher sensitivity (0.83 vs. 0.70, p = 0.0337) and specificity (0.75 vs. 0.59, p = 0.0152; Fig. 3c). The AUC of PET/CT was slightly higher than that of PET alone (0.90 vs. 0.87).

The accuracies of CECT and PET/CT were compared to four studies with 246 patients. PET/CT showed significantly higher sensitivity (0.73 vs. 0.57, p = 0.0056) and specificity (0.80 vs. 0.52, p < 0.0001) than CECT (Fig. 3d). The AUC of 18F-FDG PET/CT was 0.83 (95% CI: 0.80–0.86), while the AUC of CECT was 0.56 (95% CI: 0.52–0.61).

One study indicated that compared to noncontrast CT, PET/CT had higher sensitivity (0.90 vs. 0.40) and specificity (0.81 vs. 0.78).27

Differences of CT and 18F-FDG PET/CT for detecting intrathoracic LN metastases on a per-node basis

Five studies evaluated the difference between the accuracies of CECT and 18F-FDG PET/CT on a per-node basis. There were 3,379 lymph nodes in total evaluated by CECT, while 3,342 lymph nodes evaluated by 18F-FDG PET/CT. Results showed that PET/CT has significant higher sensitivity (0.76 vs. 0.54, p < 0.0001) and specificity (0.91 vs. 0.81, p < 0.0001; Fig. 3e). The AUC of PET/CT was 0.92 (95% CI: 0.89–0.94), while the AUC of CECT was 0.77 (95% CI: 0.73–0.80).

Liu et al.28 showed higher sensitivity (0.61 vs. 0.49) and specificity (0.83 vs. 0.69) of PET/CT than noncontrast CT.

Publication bias

No publication bias was found except in detecting bone metastases (Supporting Information Figs. 4 and 5).

Discussion

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgements
  8. References
  9. Supporting Information

This meta-analysis included 56 trials evaluating the diagnostic value of 18F-FDG PET/CT. Among them, 46 studies involving 6,186 patients focused on lymph node metastases, while 13 studies containing 2,873 patients focused on extrathoracic metastases.

Assessing mediastinal nodal metastases is important for newly diagnosed NSCLC patients. PET/CT has a relatively high AUC (0.88) and pooled specificity (0.91), with relatively lower pooled sensitivity (0.72) in mediastinal staging. The low sensitivity indicates high chance of false-negative results, which may be due to its inability to detect microscopic malignancy or low-metabolic malignancy.29 The diagnostic accuracy of PET/CT was also evaluated in special populations including T1-stage NSCLC patients and patients with a high prevalence of tuberculosis. Pooled results showed that PET/CT had a relatively low sensitivity but a high specificity in T1 patients. Besides, the positive LR was 41.4, whereas the negative LR was 0.51, indicating that PET/CT might be useful in ruling in but not in ruling out nodal metastases in T1 patients. In patients with a high prevalence of tuberculosis, the pooled sensitivity was significantly lower than other patients (0.64 vs. 0.72, p = 0.016), whereas the pooled specificity was slightly lower (0.89 vs. 0.91, p = 0.33), suggesting that NSCLC patients with tuberculosis might be more difficult to confirm. The low specificity was not unexpected as tuberculosis can cause lymph node enlargement and hypermetabolism and thus increases the false-positive rate.30 Besides, three studies included a large number of patients with surgically resectable NSCLC, and thus more early-stage patients with microscopic metastatic nodes were included, which might be the reason of the low sensitivity.30–32

The diagnostic efficacy of PET/ CT was further compared to CT or PET scan alone in mediastinal staging. Our results suggest that the sensitivity and specificity of PET/CT were significantly higher than those of CECT scan (p < 0.0001). Compared to PET scan, PET/CT showed higher sensitivity (0.83 vs. 0.69, p = 0.047); however, PET alone appeared to have better specificity than PET/CT (p = 0.013). It is speculated that PET alone might miss small hypermetabolic lesions without anatomic information from CT. These small hypermetabolic lesions that can only be identified by PET/CT might increase the false-positive rates, thus decrease the specificity of PET/CT. Further studies are warranted to clarify this issue.

Compared to mediastinal staging, the sensitivity of intrathoracic staging was similar (0.71 vs. o.72, p > 0.05) while the specificity was lower (0.83 vs. 0.91, p < 0.0001). Explanation might be that the high-FDG uptake of primary tumor may affect the detection of metastatic N1 nodes in the same side; thus, PET/CT has difficulty in distinguishing N0 from N1.28 Furthermore, PET/CT had significantly higher sensitivity and specificity than PET or CT alone. However, the positive LR (4.2) and negative LR (0.35) suggested that PET/CT had a limited value in diagnosing intrathoracic nodal metastases in NSCLC patients.

This meta-analysis also assessed PET/CT performance in detecting intrathoracic nodal metastases on a per-node basis. PET/CT also showed significantly higher sensitivity and specificity than CT alone in detecting intrathoracic nodal metastases on a per-node basis.

One of the advantages of PET/CT is the assessment of distant metastases. PET/CT conferred a good specificity (0.95) in M staging, although the sensitivity was relatively low (0.77). And the AUC was high (0.96), suggesting that PET/CT has an excellent overall diagnostic performance in M staging. PET/CT demonstrates excellent sensitivity (0.91) and specificity (0.98) for bone metastases. Besides, studies showed high specificity but low sensitivity of PET/CT in detecting brain metastases.24, 25 One study indicated that PET/CT has high sensitivity (0.89) and specificity (0.88) in detecting adrenal metastases.

Determining the sources of heterogeneity is also an important goal of meta-analysis. For lymph node detection, the FDG dose and CT portion of PET/CT can greatly influence diagnostic performance and explain most of the heterogeneity. High-FDG dose was associated with higher pooled sensitivities in mediastinal staging (0.81 vs. 0.64, p < 0.0001) and intrathoracic staging (0.82 vs. 0.73, p = 0.0009). Compared to studies applying low-FDG dose, the pooled specificities of studies applying high-FDG dose were significantly lower in mediastinal staging (0.88 vs. 0.94, p < 0.0001) and in the detection of intrathoracic LN on a per-node basis (0.84 vs. 0.93, p < 0.0001). High-FDG dose might make small or low-metabolism lesions easier to find and thus reduced false-negative rate while increased the false-positive rate. The CT portion of PET/CT can also greatly influence diagnostic performance. Studies applying contrast agents demonstrated higher sensitivity in mediastinal staging (0.85 vs. 0.71, p < 0.05) and higher specificities in both mediastinal staging (0.95 vs. 0.88, p < 0.05) and intrathoracic staging (0.89 vs. 0.81, p = 0.0006).

Other factors, such as country of origin and diagnostic criteria, were also the source of heterogeneity. The pooled specificity from studies of Western population was significantly lower than studies of Asian population (0.75 vs. 0.84, p < 0.0001) in intrathoracic staging on a per-patient basis. It is probably because most studies of Western population performed PET/CT with a relatively high-FDG dose, which tends to decrease specificity as our study shows. Different diagnostic criteria of PET/CT greatly affected sensitivity and specificity. Compared to studies qualitatively analyzed their data showed higher sensitivities in mediastinal staging (0.73 vs. 0.68, p = 0.0094) and intrathoracic staging (0.71 vs. 0.68, p = 0.003), while the specificities were lower in mediastinal staging (0.89 vs. 0.90, p = 0.043) and intrathoracic staging (0.82 vs. 0.85, p < 0.0001). For quantitative analyses, most studies used SUVmax > 2.5 as the diagnostic criteria. However, Bryant et al.33 and Tasci et al.34 reported that “5.3” and “5.2” were obtained as cut-off levels, respectively. Other studies applied SUVmax of 2, 3 and 4.1 in distinguishing malignant from benign.6, 35, 36 As SUV measurement has significant variations and differs from machines to machines and protocols to protocols, the best SUV cut-off value for malignancy is still unclear. Besides, study design, study quality and the sample size also contributed to heterogeneity in our study.

PET/CT has been used as an effective method for the detection of metastases in NSCLC patients. However, studies have shown that PET/CT could not reduce the need of invasive staging in NSCLC patients, because compared to invasive-staging methods, the diagnostic performance of PET/CT is not good enough.29, 37–41 Mediastinoscopy showed higher sensitivity and specificity than PET/CT and is still the most reliable method in NSCLC lymph node staging.39, 41 Endobronchial ultrasound-guided transbronchial needle aspiration and endoscopic ultrasound-guided fine-needle aspiration also showed better diagnostic performance than PET/CT and are recommended before surgery or mediastinoscopy as they are less invasive.38, 40 For bone metastases, studies have reported that FDG PET/CT is superior to conventional bone scintigraphy (BS), and thus additional BS might be avoided.42–44

Our meta-analysis has several strengths. First, 56 studies involving 8,699 patients were included, which is sufficient to allow adequate statistical power to calculate the results. Second, the diagnostic efficacy of PET/CT was evaluated comprehensively. For instance, we evaluated PET/CT not only in nodal metastases but also extrathoracic metastases. As to nodal metastases, the diagnostic accuracy of PET/CT was evaluated in mediastinal staging and intrathoracic nodal staging; and in addition, intrathoracic lymph node metastases were also assessed on a per-node basis. Trials focused on the efficacy of PET/CT in M staging or detecting bone or brain metastases were also assessed. Third, the diagnostic accuracies of PET/CT, CT and PET were compared in nodal staging by evaluating those studies including not only PET/CT but also CT or PET. Finally, no publication bias was found, and we had performed sufficient subgroup analyses to assess the validity and reliability of the primary results.

The current analysis also has several limitations. First, significant interstudy heterogeneity was found and could not be completely explained. Second, the included trials vary in sample size and diagnostic criteria. Finally, although we conducted meta-regression and subgroup analyses, some potential factors might be missed such as the manufacture and the experience of clinical radiologists.

Conclusions

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgements
  8. References
  9. Supporting Information

18F-FDG PET/CT is beneficial in detecting lymph node metastases and extrathoracic metastases. 18F-FDG PET/CT confers significantly higher sensitivity and specificity than conventional CT and higher sensitivity than 18F-FDG PET in staging NSCLC.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgements
  8. References
  9. Supporting Information

The corresponding author (Dr. Jun Yang) has the right to grant on behalf of all authors. Dr. Jun Yang contributed to conception and design of the study; Drs. Yihua Wu and Peiwei Li contributed to conception, design and editing the manuscript; Drs. Yu Shi and Honghe Zhang contributed to statistical analysis and editing the manuscript; Drs. Jinjie Zhang and Yufeng Qian contributed to the data acquisition, analysis and interpretation of the data; Drs. Yufeng Qian and Chao Li critically revised the article for important intellectual content. We thank Dr. Gholam Berenji and Dr. Li YX (Nuclear Medicine, University of California, LA) for their invaluable support during this study and for editing the manuscript. We declare that we have no conflict of interest.

References

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgements
  8. References
  9. Supporting Information
  • 1
    Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin 2011; 61: 6990.
  • 2
    Nair A, Klusmann MJ, Jogeesvaran KH, et al. Revisions to the TNM staging of non-small cell lung cancer: rationale, clinicoradiologic implications, and persistent limitations. Radiographics 2011; 31: 21538.
  • 3
    Spira A, Ettinger DS. Multidisciplinary management of lung cancer. N Eng J Med 2004; 350: 37992.
  • 4
    Antoch G, Stattaus J, Nemat AT, et al. Non-small cell lung cancer: dual-modality PET/CT in preoperative staging. Radiology 2003; 229: 52633.
  • 5
    Chin AY, Lee KS, Kim BT, et al. Efficacy of helical dynamic CT versus integrated PET/CT for detection of mediastinal nodal metastasis in non-small cell lung cancer. AJR 2007; 188: 31825.
  • 6
    Ohno Y, Koyama H, Nogami M, et al. STIR turbo SE MR imaging vs. coregistered FDG-PET/CT: quantitative and qualitative assessment of N-stage in non-small-cell lung cancer patients. J Magn Reson Imaging 2007; 26: 107180.
  • 7
    Detterbeck FC, Jantz MA, Wallace M, et al. Invasive mediastinal staging of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 2007; 132: 202S20S.
  • 8
    Glazer GM, Orringer MB, Gross BH, et al. The mediastinum in non-small cell lung cancer: CT-surgical correlation. AJR 1984; 142: 110115.
  • 9
    De Leyn P, Vansteenkiste J, Cuypers P, et al. Role of cervical mediastinoscopy in staging of non-small cell lung cancer without enlarged mediastinal lymph nodes on CT scan. Eur J Cardiothorac Surg 1997; 12: 70612.
  • 10
    Dahlbom M, Hoffman EJ, Hoh CK, et al. Whole-body positron emission tomography, part 1: methods and performance characteristics. J Nucl Med 1992; 33: 11919.
  • 11
    Marom EM, McAdams HP, Erasmus JJ, et al. Staging non-small cell lung cancer with whole-body PET. Radiology 1999; 212: 8039.
  • 12
    Bruzzi JF, Munden RF. PET/CT imaging of lung cancer. J Thorac Imaging 2006; 21: 12336.
  • 13
    De Leyn P, Lardinois D, Van Schil PE, et al. ESTS guidelines for preoperative lymph node staging for non-small cell lung cancer. Eur J Cardiothorac Surg 2007; 32: 18.
  • 14
    Cerfolio RJ, Ojha B, Bryant AS, et al. The accuracy of integrated PET-CT compared with dedicated PET alone for the staging of patients with nonsmall cell lung cancer. Ann Thorac Surg 2004; 78: 101723; discussion 23.
  • 15
    Mountain CF. Revisions in the international system for staging lung cancer. Chest 1997; 111: 171017.
  • 16
    Whiting P, Rutjes AW, Reitsma JB, et al. The development of QUADAS: a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews. BMC Med Res Methodol 2003; 3: 25.
  • 17
    Fischer JE, Bachmann LM, Jaeschke R. A readers' guide to the interpretation of diagnostic test properties: clinical example of sepsis. Intens Care Med 2003; 29: 104351.
  • 18
    Jaeschke R, Guyatt GH, Sackett DL. Users' guides to the medical literature. III. How to use an article about a diagnostic test. B. What are the results and will they help me in caring for my patients? The Evidence-Based Medicine Working Group. JAMA 1994; 271: 7037.
  • 19
    Deeks JJ. Systematic reviews in health care: systematic reviews of evaluations of diagnostic and screening tests. BMJ 2001; 323: 15762.
  • 20
    Deville WL, Buntinx F, Bouter LM, et al. Conducting systematic reviews of diagnostic studies: didactic guidelines. BMC Med Res Methodol 2002; 2: 9.
  • 21
    Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21: 153958.
  • 22
    Deeks JJ, Macaskill P, Irwig L. The performance of tests of publication bias and other sample size effects in systematic reviews of diagnostic test accuracy was assessed. J Clin Epidemiol 2005; 58: 88293.
  • 23
    Heusner T, Golitz P, Hamami M, et al. “One-stop-shop” staging: should we prefer FDG-PET/CT or MRI for the detection of bone metastases? Eur J Radiol 2011; 78: 4305.
  • 24
    Kruger S, Mottaghy FM, Buck AK, et al. Brain metastasis in lung cancer. Comparison of cerebral MRI and 18F-FDG-PET/CT for diagnosis in the initial staging. Nuklearmedizin 2011; 50.
  • 25
    Lee HY, Lee KS, Kim BT, et al. Diagnostic efficacy of PET/CT plus brain MR imaging for detection of extrathoracic metastases in patients with lung adenocarcinoma. J Kor Med Sci 2009; 24: 11328.
  • 26
    Cho AR, Lim I, Na II, et al. Evaluation of adrenal masses in lung cancer patients using F-18 FDG PET/CT. Nucl Med Mol Imaging 2011; 45: 528.
  • 27
    Toba H, Kondo K, Otsuka H, et al. Diagnosis of the presence of lymph node metastasis and decision of operative indication using fluorodeoxyglucose-positron emission tomography and computed tomography in patients with primary lung cancer. J Med Invest 2010; 57: 30513.
  • 28
    Liu BJ, Dong JC, Xu CQ, et al. Accuracy of 18F-FDG PET/CT for lymph node staging in non-small-cell lung cancers. Chin Med J 2009; 122: 174954.
  • 29
    Darling GE, Maziak DE, Inculet RI, et al. Positron emission tomography-computed tomography compared with invasive mediastinal staging in non-small cell lung cancer: results of mediastinal staging in the early lung positron emission tomography trial. J Thorac Oncol 2011; 6: 136772.
  • 30
    Lee SH, Min JW, Lee CH, et al. Impact of parenchymal tuberculosis sequelae on mediastinal lymph node staging in patients with lung cancer. J Kor Med Sci 2011; 26: 6770.
  • 31
    Lee JW, Kim BS, Lee DS, et al. 18F-FDG PET/CT in mediastinal lymph node staging of non-small-cell lung cancer in a tuberculosis-endemic country: consideration of lymph node calcification and distribution pattern to improve specificity. Eur J Nucl Med Mol Imaging 2009; 36: 1794802.
  • 32
    Kim YK, Lee KS, Kim BT, et al. Mediastinal nodal staging of nonsmall cell lung cancer using integrated 18F-FDG PET/CT in a tuberculosis-endemic country: diagnostic efficacy in 674 patients. Cancer 2007; 109: 106877.
  • 33
    Bryant AS, Cerfolio RJ, Klemm KM, et al. Maximum standard uptake value of mediastinal lymph nodes on integrated FDG-PET-CT predicts pathology in patients with non-small cell lung cancer. Ann Thorac Surg 2006; 82: 41722; discussion 22–3.
  • 34
    Tasci E, Tezel C, Orki A, et al. The role of integrated positron emission tomography and computed tomography in the assessment of nodal spread in cases with non-small cell lung cancer. Interact Cardiovasc Thorac Surg 2010; 10: 2003.
  • 35
    Perigaud C, Bridji B, Roussel JC, et al. Prospective preoperative mediastinal lymph node staging by integrated positron emission tomography-computerised tomography in patients with non-small-cell lung cancer. Eur J Cardiothorac Surg 2009; 36: 7316.
  • 36
    Morikawa M, Demura Y, Ishizaki T, et al. The effectiveness of 18F-FDG PET/CT combined with STIR MRI for diagnosing nodal involvement in the thorax. J Nucl Med 2009; 50: 817.
  • 37
    Tournoy KG, Maddens S, Gosselin R, et al. Integrated FDG-PET/CT does not make invasive staging of the intrathoracic lymph nodes in non-small cell lung cancer redundant: a prospective study. Thorax 2007; 62: 696701.
  • 38
    Hwangbo B, Lee HS, Lee HS, et al. Application of endobronchial ultrasound-guided transbronchial needle aspiration following integrated PET/CT in mediastinal staging of potentially operable non-small cell lung cancer. Chest 2009; 135: 12807.
  • 39
    Metin M, Citak N, Sayar A, et al. The role of extended cervical mediastinoscopy in staging of non-small cell lung cancer of the left lung and a comparison with integrated positron emission tomography and computed tomography: does integrated positron emission tomography and computed tomography reduce the need for invasive procedures? J Thorac Oncol 2011; 6: 171319.
  • 40
    Ohnishi R, Yasuda I, Kato T, et al. Combined endobronchial and endoscopic ultrasound-guided fine needle aspiration for mediastinal nodal staging of lung cancer. Endoscopy 2011; 43: 10829.
  • 41
    Sivrikoz CM, Ak I, Simsek FS, et al. Is mediastinoscopy still the gold standard to evaluate mediastinal lymph nodes in patients with non-small cell lung carcinoma? Thorac Cardiovasc Surg 2012; 60: 11621.
  • 42
    Min JW, Um SW, Yim JJ, et al. The role of whole-body FDG PET/CT, Tc 99m MDP bone scintigraphy, and serum alkaline phosphatase in detecting bone metastasis in patients with newly diagnosed lung cancer. J Kor Med Sci 2009; 24: 27580.
  • 43
    Kruger S, Buck AK, Mottaghy FM, et al. Detection of bone metastases in patients with lung cancer: 99mTc-MDP planar bone scintigraphy, 18F-fluoride PET or 18F-FDG PET/CT. Eur J Nucl Med Mol Imaging 2009; 36: 180712.
  • 44
    Song JW, Oh YM, Shim TS, et al. Efficacy comparison between 18F-FDG PET/CT and bone scintigraphy in detecting bony metastases of non-small-cell lung cancer. Lung Cancer 2009; 65: 3338.
  • 45
    Ohno Y, Koyama H, Yoshikawa T, et al. N stage disease in patients with non-small cell lung cancer: efficacy of quantitative and qualitative assessment with STIR turbo spin-echo imaging, diffusion-weighted MR imaging, and fluorodeoxyglucose PET/CT. Radiology 2011; 261: 60515.
  • 46
    Okereke IC, Gangadharan SP, Kent MS, et al. [18F]Fluorodeoxyglucose positron emission tomography-computerized tomography and lung cancer: a significant referral bias exists. Eur J Cardiothorac Surg: Off J Eur Assoc Cardiothorac Surg 2011; 39: 5604.
  • 47
    Usuda K, Zhao XT, Sagawa M, et al. Diffusion-weighted imaging is superior to positron emission tomography in the detection and nodal assessment of lung cancers. Ann Thorac Surg 2011; 91: 168995.
  • 48
    Li M, Wu N, Liu Y, et al. Regional nodal staging with 18F-FDG PET-CT in non-small cell lung cancer: additional diagnostic value of CT attenuation and dual-time-point imaging. Eur J Radiol 2012; 81: 188690.
  • 49
    Hu M, Han A, Xing L, et al. Value of dual-time-point FDG PET/CT for mediastinal nodal staging in non-small-cell lung cancer patients with lung comorbidity. Clin Nucl Med 2011; 36: 42933.
  • 50
    Gunluoglu MZ, Melek H, Medetoglu B, et al. The validity of preoperative lymph node staging guidelines of European Society of Thoracic Surgeons in non-small-cell lung cancer patients. Eur J Cardiothorac Surg 2011; 40: 28790.
  • 51
    Li XD, Yin JL, Liu WK, et al. [Value of positron emission tomography-computed tomography in the diagnosis of mediastinal lymph node metastasis of non-small cell lung cancer]. Nan Fang yi ke da Xue Xue Bao [J Southern Med Univ] 2010; 30: 5068.
  • 52
    Fischer BM, Mortensen J, Hansen H, et al. Multimodality approach to mediastinal staging in non-small cell lung cancer. Faults and benefits of PET-CT: a randomised trial. Thorax 2011; 66: 294300.
  • 53
    Jeon TY, Lee KS, Yi CA, et al. Incremental value of PET/CT over CT for mediastinal nodal staging of non-small cell lung cancer: comparison between patients with and without idiopathic pulmonary fibrosis. Am J Roentgenol 2010; 195: 3706.
  • 54
    Yang W, Zhang Y, Fu Z, et al. Imaging of proliferation with 18F-FLT PET/CT versus 18F-FDG PET/CT in non-small-cell lung cancer. Eur J Nucl Med Mol Imaging 2010; 37: 12919.
  • 55
    Ventura E, Islam T, Gee MS, et al. Detection of nodal metastatic disease in patients with non-small cell lung cancer: comparison of positron emission tomography (PET), contrast-enhanced computed tomography (CT), and combined PET-CT. Clin Imaging 2010; 34: 208.
  • 56
    Liu N, Ma L, Zhou W, et al. Bone metastasis in patients with non-small cell lung cancer: the diagnostic role of F-18 FDG PET/CT. Eur J Radiol 2010; 74: 2315.
  • 57
    Bille A, Pelosi E, Skanjeti A, et al. Preoperative intrathoracic lymph node staging in patients with non-small-cell lung cancer: accuracy of integrated positron emission tomography and computed tomography. Eur J Cardiothorac Surg 2009; 36: 4405.
  • 58
    Sanli M, Isik AF, Zincirkeser S, et al. Reliability of positron emission tomography-computed tomography in identification of mediastinal lymph node status in patients with non-small cell lung cancer. J Thorac Cardiovasc Surg 2009; 138: 12005.
  • 59
    Takenaka D, Ohno Y, Matsumoto K, et al. Detection of bone metastases in non-small cell lung cancer patients: comparison of whole-body diffusion-weighted imaging (DWI), whole-body MR imaging without and with DWI, whole-body FDG-PET/CT, and bone scintigraphy. J Magn Reson Imaging 2009; 30: 298308.
  • 60
    Yang WF, Tan GZ, Fu Z, et al. [Evaluation of the diagnostic value of 18F-FDG PET-CT and enhanced CT for staging of lymph node metastasis in non-small cell lung cancer]. Zhonghua Zhong Liu Za Zhi [Chin J Oncol] 2009; 31: 9258.
  • 61
    Carnochan FM, Walker WS. Positron emission tomography may underestimate the extent of thoracic disease in lung cancer patients. Eur J Cardiothorac Surg 2009; 35: 7815.
  • 62
    Lee HJ, Kim YT, Kang WJ, et al. Integrated positron-emission tomography for nodal staging in lung cancer. Asian Cardiovasc Thorac Ann 2009; 17: 6226.
  • 63
    Chin AY, Kyung MS, Kyung SL, et al. Non-small cell lung cancer staging: efficacy comparison of integrated PET/CT versus 3.0-T whole-body MR imaging. Radiology 2008; 248: 63242.
  • 64
    Al-Sarraf N, Gately K, Lucey J, et al. Mediastinal lymph node staging by means of positron emission tomography is less sensitive in elderly patients with non-small-cell lung cancer. Clin Lung Cancer 2008; 9: 3943.
  • 65
    Hu M, Yu JM, Liu NB, et al. [Significance of dual-time-point 18F-FDG PET imaging in evaluation of hilar and mediastinal lymph node metastasis in non-small-cell lung cancer]. Zhonghua Zhong Liu Za Zhi [Chin J Oncol] 2008; 30: 3069.
  • 66
    Shin KM, Lee KS, Shim YM, et al. FDG PET/CT and mediastinal nodal metastasis detection in stage T1 non-small cell lung cancer: prognostic implications. Kor J Radiol 2008; 9: 4819.
  • 67
    Al-Sarraf N, Aziz R, Doddakula K, et al. Factors causing inaccurate staging of mediastinal nodal involvement in non-small cell lung cancer patients staged by positron emission tomography. Interact Cardiovasc Thorac Surg 2007; 6: 3503.
  • 68
    Lee BE, von Haag D, Lown T, et al. Advances in positron emission tomography technology have increased the need for surgical staging in non-small cell lung cancer. J Thorac Cardiovasc Surg 2007; 133: 74652.
  • 69
    Pfannenberg AC, Aschoff P, Brechtel K, et al. Low dose non-enhanced CT versus standard dose contrast-enhanced CT in combined PET/CT protocols for staging and therapy planning in non-small cell lung cancer. Eur J Nucl Med Mol Imaging 2007; 34: 3644.
  • 70
    De Wever W, Ceyssens S, Mortelmans L, et al. Additional value of PET-CT in the staging of lung cancer: comparison with CT alone, PET alone and visual correlation of PET and CT. Eur Radiol 2007; 17: 2332.
  • 71
    Kim BT, Lee KS, Shim SS, et al. Stage T1 non-small cell lung cancer: preoperative mediastinal nodal staging with integrated FDG PET/CT—a prospective study. Radiology 2006; 241: 5019.
  • 72
    Low SY, Eng P, Keng GH, et al. Positron emission tomography with CT in the evaluation of non-small cell lung cancer in populations with a high prevalence of tuberculosis. Respirology (Carlton, Vic) 2006; 11: 849.
  • 73
    Halpern BS, Schiepers C, Weber WA, et al. Presurgical staging of non-small cell lung cancer: positron emission tomography, integrated positron emission tomography/CT, and software image fusion. Chest 2005; 128: 228997.
  • 74
    Vansteenkiste JF, Stroobants SG, Dupont PJ, et al. FDG-PET scan in potentially operable non-small cell lung cancer: do anatometabolic PET-CT fusion images improve the localisation of regional lymph node metastases? Eur J Nucl Med 1998; 25: 1495501.

Supporting Information

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgements
  8. References
  9. Supporting Information

Additional Supporting Information may be found in the online version of this article.

FilenameFormatSizeDescription
IJC_27779_sm_SuppTable.doc1082KSupporting Information Table 1. Characteristics of included studies

Please note: Wiley Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.