Lung cancer is the leading cause of cancer deaths globally. 1

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1 ORIGINAL ARTICLE Diagnostic Performance of Integrated Positron Emission Tomography/Computed Tomography for Mediastinal Lymph Node Staging in Non-small Cell Lung Cancer A Bivariate Systematic Review and Meta-Analysis Yan-Ling Lv,* Dong-Mei Yuan, Ke Wang, Xiao-Hui Miao, Qian Qian, Shu-Zhen Wei, Xi-Xu Zhu, and Yong Song, PhD, MD Introduction: Accurate clinical staging of mediastinal lymph nodes (MLNs) of patients with non-small cell lung cancer (NSCLC) is important in determining therapeutic options and prognoses. Integrated positron emission tomography and computed tomography (PET/CT) scanning is becoming widely used for MLN staging in patients with NSCLC. We performed a bivariate meta-analysis to determine the pooled sensitivity (SEN) and specificity (SPE) of this imaging modality. Methods: The PubMed/MEDLINE, Embase, and SpringerLink databases were searched for articles related to PET/CT for MLN staging in patients with NSCLC. SEN and SPE were calculated for every study. Hierarchical summary receiver operating characteristic curves were used to summarize overall test performance and assess study quality. Potential between-study heterogeneity was explored by subgroup analyses. Results: Fourteen of 330 initially identified reports were included in the meta-analysis. When we did not consider the unit of analysis, the pooled weighted SEN and SPE were 0.73 (95% confidence interval [CI]: ) and 0.92 (95% CI: ), respectively. In the patient-based data analysis, the pooled weighted SEN was 0.76 (95% CI: ) and the pooled weighted SPE was 0.88 (95% CI: ). In the MLN-based data analysis, the pooled SEN was 0.68 (95% CI: ) and the pooled SPE was 0.95 (95% CI: ). *Department of Respiratory Medicine, Jinling Hospital, School of Medicine, Southern Medical University (Guangzhou), Nanjing, China; Department of Respiratory Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China; Institute of Respiratory Diseases, First Affiliated Hospital, Guangxi Medical University, Nanning, China; First Department of Respiratory Medicine, Nanjing Chest Hospital, Nanjing, China; Department of Respiratory Disease, Tengzhou Central People s Hospital, Tengzhou, China; and Department of Radiotherapy Center, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China. Disclosure: The authors declare no conflicts of interest. Address for correspondence: Yong Song, PhD, MD, Department of Respiratory Medicine, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing , China. yong_song6310@yahoo.com Copyright 2011 by the International Association for the Study of Lung Cancer ISSN: /11/ Conclusions: Integrated PET/CT is a relatively accurate noninvasive imaging technique, with excellent specificity for MLN staging in patients with NSCLC. Nevertheless, current evidence suggests that we should not depend on the results of PET/CT completely for MLN staging in patients with NSCLC. Key Words: Integrated positron emission tomography/computed tomography, Mediastinal lymph node staging, Non-small cell lung cancer, Systematic review, Meta-analysis. (J Thorac Oncol. 2011;6: ) Lung cancer is the leading cause of cancer deaths globally. 1 Non-small cell lung cancer (NSCLC) accounts for 80% of these cases and usually metastasizes first to hilar and mediastinal lymph nodes (MLNs). Accurate clinical staging of MLNs is crucial for selecting the optimum treatment. For example, in patients with known stage IIIA NSCLC, the addition of preoperative chemotherapy can dramatically increase survival compared with surgery alone. 2 Moreover, the involvement of MLNs is a very important prognostic factor in patients with potentially resectable NSCLC. Therefore, there is a great need for a more accurate, minimally invasive, and reproducible diagnostic method for MLN staging. Computed tomography (CT) has been widely used for clinical MLN staging in NSCLC patients, but its limitation is that it relies on the size of the MLN to differentiate benign from malignant. Gupta et al 3 confirmed that functional imaging with positron emission tomography (PET) surpasses using anatomic criteria to screen for MLN metastases with CT. Several meta-analyses also found that fludeoxyglucose (FDG)-PET was more accurate than CT (median sensitivity [SEN] and specificity [SPE] were 61 and 79%) for MLN staging in NSCLC. 4 6 Nevertheless, the poor spatial resolution of FDG-PET can lead to inaccuracies. Although mediastinoscopy remains the gold standard, the noninvasive imaging method of combining PET and CT (i.e., PET/CT) has become increasingly used for MLN staging in patients with NSCLC, integrating as it does the anatomic information of CT and the functional information of PET. Although there have been many studies that estimated the SEN and SPE of 1350 Journal of Thoracic Oncology Volume 6, Number 8, August 2011

2 Journal of Thoracic Oncology Volume 6, Number 8, August 2011 Diagnostic Performance of Integrated PET/CT PET/CT for MLN imaging, most included only a small number of patients. The aim of our study was to perform a meta-analysis that would determine the pooled SEN and SPE of integrated PET/CT for MLN staging in patients with NSCLC. MATERIALS AND METHODS Publication Search We searched the MEDLINE (PubMed), Embase, and SpringerLink databases with the terms PET, MLN, lymph node, and NSCLC. The last search was updated on December 18, Titles of research articles were screened for relevance according to predetermined inclusion criteria. Abstracts were screened if this information could not be inferred from the title. The reference lists of included studies and related reviews were also searched manually, and all references cited in relevant articles were scanned to identify all additional studies. The search period was December 1992 to December We included studies written in English and Chinese that were full articles, and excluded abstracts or meeting proceedings. Results were arbitrated by a second investigator (D-.M.Y.). Selection Criteria All the included studies examined FDG-PET/CT imaging for MLN staging in patients with NSCLC and included histological examination of lymph nodes by surgery or biopsy, used clear diagnostic criteria, provided sufficient data (true-positive [TP], false-positive [FP], true-negative [TN], and false-negative [FN]) to permit calculation of SEN and SPE, and used the English or Chinese language. We excluded studies that were not about integrated PET/CT and MLN staging, articles that were not about NSCLC, review articles, and studies of restaging after induction chemotherapy. Data Extraction and Quality Assessment From the studies finally selected, two authors (Y-.L.L. and D-.M.Y.) independently gleaned the following information: the study name (first author, year of publication), journal name, proportion of males, tumor histology, and retrospective or prospective set-up of the study. TP, FP, TN, and FN results were recorded. When authors reported on the same patient population in several publications, only the most recent or complete study was included in the analysis to avoid duplication of information. Any disagreements were subsequently resolved by discussion that included the fourth author (X-.H.M.). We assessed the quality of different studies according to the modified QUADAS tool. 7 The QUADAS checklist consists of 14 items, each of which was assessed as yes, no, or unknown. The item Were the same clinical data available when test results were interpreted as would be available when the test is used in practice (clinical review bias)? was removed from the standard QUADAS list, because the clinical factors such as gender, age, and clinical symptoms would not affect the interpretation of the positive result of PET/CT for MLN staging. For each item, the two researchers (Y-.L.L. and D-.M.Y.) independently assessed whether it was satisfied (yes, no, or unknown). The responses no and unclear showed that the quality criterion was not met. Discrepancies were resolved by consensus. The total quality score was expressed as a percentage of the maximum score of 13. Statistical Analysis For each study, we conducted 2 2 contingency tables of TP, TN, FP, and FN results and calculated SEN, SPE, and diagnostic OR (DOR) according to the formulas: SEN TP/(TP FN); SPE TN/(TN FP); and DOR (TN TP)/(FP FN). 8 SEN and SPE at a 95% confidence interval (CI) were then pooled using a bivariate regression approach. 9 By using the pooled SEN and SPE, we also calculated positive likelihood ratios (PLRs) and negative likelihood ratios (NLRs). We constructed hierarchical summary receiver operating characteristic (SROC) curves to assess the interaction between SEN and SPE. The areas under the ROC curves (AUCs) were used to analyze the diagnostic precision of PET/CT for MLN staging in NSCLC. We assessed the statistical significance of heterogeneity between different studies using the inconsistency index (I 2 ). 10 An I 2 value greater than 50% was taken to indicate significant heterogeneity. When between-study heterogeneity was detected, we explored reasonable causes by subgroup analysis. Covariates requiring that at least 80% of studies reported on a particular item were analyzed. These included data collection (prospective or retrospective), the unit of analysis (patient or MLN), diagnostic criteria (quantitative or qualitative), language (English or Chinese), selection criteria (yes or no), and index test execution (yes or no). An estimation of the potential publication bias was performed by using Deeks funnel plots. 11 A probability (p) value 0.1 was considered representative of statistically significant publication bias. All the statistical tests used in our meta-analysis were performed with STATA version 10 (STATA; College Station, TX) using the midas program. 12 RESULTS Literature Search Using the keywords, the search of PubMed/MEDLINE found 330 potentially relevant articles published before December 18, Reviewing titles and abstracts from these articles resulted in 45 that were promising, of which 14 were finally included in our meta-analysis Screening the references of these articles did not provide us with additional articles. Of the 45 articles, the main reasons for exclusion were they were not about MLN staging (13); there were insufficient data to calculate SEN and SPE (11) ; they contained duplicated data (3) ; and several were excluded because they were about restaging the mediastinum after neoadjuvant therapy (4) Finally, our systematic review covered 14 research articles that included 2550 patients. Characteristics of the included studies are presented in Table 1. Study Descriptions and Quality Assessment The characteristics of the included studies are presented in Table 1. The total number of patients was 2550, ranging Copyright 2011 by the International Association for the Study of Lung Cancer 1351

3 Lv et al. Journal of Thoracic Oncology Volume 6, Number 8, August 2011 TABLE 1. Main Characteristics of All Studies Included in the Meta-analysis Diagnostic Criteria Verification Criteria Analysis Unit ID Design Patients TP FP FN TN SEN % SPE % Tasci et al. 13 Retrospective (31) 19 (32) 2 (12) 89 (531) 88.8 (72) 81.6 (94.7) 1, 2, 4 Patient (MLN) maxsuv 5.2 Li et al. 14 Retrospective , 2 Patient maxsuv 2.5 Sit et al. 15 Retrospective , 2, 3 MLN maxsuv 2.5 Hwangbo et al. 16 Prospective , 4 Patient maxsuv 2.5 Bille et al. 17 Retrospective (22) 7 (9) 17 (24) 121 (631) 45.2 (47.8) 94.5 (98.6) 1, 2 Patient (MLN) Visually Perigaud et al. 18 Prospective Patient maxsuv 3 Sanli et al. 19 Prospective , 2, 4 Patient maxsuv 2.5 Lee et al. 20 Prospective (35) 16 (30) 9 (18) 130 (695) 75 (66) 89 (96) 1, 2 Patient (MLN) Visually Al-Sarraf et al. 21 Retrospective , 2, 3 Node maxsuv 2.5 Yang et al. 22 Retrospective (132) 11 (73) 7 (21) 86 (413) 72 (86) 89 (85) 1 Patient (MLN) Visually Hu et al. 23 Prospective Node maxsuv 2.5 Kim et al. 24 Prospective (126) 21 (48) 70 (149) 473 (2154) 61 (46) 96 (98) 1, 2 Patient (MLN) Visually Lee et al. 25 Retrospective , 2, 3 Patient Visually Bryant et al. 26 Prospective (120) 33 (67) 12 (34) 195 (1031) 91.6 (77.9) 85.5 (93.9) 1, 2, 4 Patient (MLN) maxsuv 2.5 TP, true-positive; FP, false-positive; TN, true-negative; FN, false-negative; SEN, sensitivity; SPE, specificity; 1, thoracotomy; 2, mediastinoscopy; 3, mediastinotomy; 4, VATS, video-assisted thoracoscopic surgery; MLN, mediastinal lymph nodes; maxsuv MAX, maximum standardized uptake value. from 46 to 674 patients per study. All patients underwent FDG PET/CT imaging. Histology was confirmed by mediastinoscopy, pulmonary resection, or both. Five studies reported results by using MLN as the unit of analysis, three studies used the patient as the unit of analysis, and the results of the remaining studies were reported by using both the patient and MLN as the unit of analysis. Thirteen methodological quality items were assessed for each of the 20 included research articles. Quality assessment is presented as a bar graph according to the modified QUADAS criteria (Figure 1). The total methodological quality score, expressed as a percentage of the maximum score, ranged from 54 to 85% (median, 69%). Diagnostic Performance Analysis of the Patient-Based Data and SEN, SPE, PLR, NLR, DOR, and SROC Curves We enrolled 14 research articles in which 11 studies used the patient as the unit of analysis. Four studies had standardized uptake value (SUV) cutoffs of 2.5, five considered MLNs malignant if they exhibited a focally increased SUV higher than the normal background activity as determined by qualitative analysis, and the remaining two studies had SUV cutoffs of 3 and 5.2, respectively. In the patientbased data analysis, the SEN ranged from 0.40 to 0.92, and the pooled weighted SEN was 0.76 (95% CI: ), whereas the SPE ranged from 0.60 to 0.96, and the pooled SPE was 0.88 (95% CI: ; Figure 2A). The PLR and NLR were 6.1 (95% CI: ) and 0.28 (95% CI: ), respectively. The DOR was 22 (95% CI: 13 38). I 2 values of all measures were greater than 50%, indicating significant heterogeneity between studies. Hierarchical SROC curves are shown in Figure 3. The SROC curve assesses the interaction between SEN and SPE. The AUC was 0.90 (95% CI: ; Figure 3A), showing that PET/CT has an overall high diagnostic performance. Analysis as MLN-Based Data Nine studies used the MLN as the unit of analysis. Four studies had an SUV cutoff of 2.5, and four studies were determined by qualitative analysis, and the SUV cutoff of the remaining one study was 5.2. In the MLN-based data analysis, the pooled SEN, SPE, PLR, NLR, and DOR were 0.65 (95% CI: ), 0.95 (95% CI: ; Figure 2B), (95% CI: ), 0.34 (95% CI: ), and 38 (95% CI: 31 48), respectively. Hierarchical SROC curves are shown in Figure 3B. The AUC was 0.92 (95% CI: ). There was also significant heterogeneity. When we did not consider the unit of analysis, the pooled weighted SEN, SPE, and AUC were 0.73 (95% CI: ), 0.92 (95% CI: ), and 0.90 (95% CI: ), respectively. Significant heterogeneity was present. Subgroup Analysis We found significant heterogeneity in the pooled analysis. This result was not unexpected because the studies adopted different SUV cutoffs as diagnostic criteria. In our meta-analysis, we included 14 articles in which 1 article had an SUV cutoff of 3, 1 reported 5.2, 7 articles reported 2.5, and 1352 Copyright 2011 by the International Association for the Study of Lung Cancer

4 Journal of Thoracic Oncology Volume 6, Number 8, August 2011 Diagnostic Performance of Integrated PET/CT FIGURE 1. Quality assessment of 20 included studies. the remaining 5 deemed MLNs malignant if they exhibited focally increased SUV higher than the normal background activity as determined by qualitative analysis. Based on a patient analysis with 2.5 as the SUV cutoff value, the SEN was higher than that in the qualitative analysis and had an impact on statistical significance (p 0.05). The SPE was lower, with no significant difference (p 0.26). Based on the MLN analysis, we obtained the same results but the SEN and SPE between two groups did not have an impact on statistical significance (p 0.28 and 0.35, respectively). English and SUV cutoff significantly affected SEN but not SPE. Some covariates such as data collection had a significant impact on SPE but not on SEN (Figure 4). Publication Bias We assessed the publication bias in the literature by performing Deeks funnel plot. The funnel plot for the 14 reports, including 20 studies, revealed evidence of publication bias (p 0.02). Based on the patient analysis, the results also indicated a potential for publication bias (p 0.07; Figure 5A), but based on the MLN analysis (p 0.42), there was no publication bias (Figure 5B). DISCUSSION Our results in the present meta-analysis indicate excellent overall test performance, as assessed by the AUC. In addition, integrated PET/CT has relatively high SPE (0.88 based on patient and 0.95 based on MLN) for MLN staging in patients with NSCLC. The overall SEN was 0.76 based on patient and 0.65 based on MLN. These data suggest that integrated PET/CT is likely to be helpful in MLN staging. Nevertheless, the data for PLRs and NLRs suggest that a positive result for integrated PET/CT does not signify the absence of MLN, and patients with negative results are likely to have MLN metastases. Integrated PET/CT directly links PET data on metabolic changes with highly detailed anatomic CT information, thereby creating a single image in the same setting that is not merely additive but synergistic. Thus, it can detect lesions initially not seen on CT or PET alone and enable more precise location of lesions. Recently, integrated PET/CT is becoming widely used for MLN staging in patients with NSCLC. To the best of our knowledge, this study is the first meta-analysis of the diagnostic performance of integrated PET/CT for MLN staging in NSCLC patients. In our study, we subdivided the included studies into a per-patient group and per-mln group. We pooled 14 published studies including a total of 2550 patients with NSCLC, to yield summary statistics, which indicate that integrated PET/CT is a relatively accurate noninvasive imaging technique for MLN staging in patients with NSCLC. In the patient-based data analysis, the pooled-weighted SEN and SPE were 0.76 and 0.88, respectively. In the MLN-based data analysis, SEN and SPE were 0.65 and 0.95, respectively. We found that studies using MLN as the unit of analysis may overestimate diagnostic accuracy, especially SPE. The unit of analysis clinically should be the patient and not the MLN. We think that if a patient with NSCLC has one mediastinal node metastasis, then the patient is more likely to have other lymph node metastases as well. In addition, if there is a positive MLN in a patient, then the stage that the patient belongs to is at least IIIA, and treatment decisions depend on the positive presence of MLN metastasis rather than the involved number of nodes. Therefore, we emphasize the results in which the patient was used as the unit of analysis. The SROC curve and its AUC present a global summary of test performance and display the relationship between SEN and SPE across studies, recognizing that they may have used different thresholds. Because the bivariate approach estimates the strength and the shape of the correlation between SEN and SPE, we can draw a 95% confidence ellipse and a 95% prediction ellipse. The AUC was 0.90 (95% CI: ), indicating a relatively high level of overall accuracy. The DOR of a test obtained with different combinations of SEN and SPE may be used as a single summary measure and is the ratio of the odds of positivity in disease relative to the odds of positivity in the nondiseased. The value of a DOR ranges from 0 to infinity, and the higher it is, the better it discriminates test performance. A value of 1 indicates that a test does not discriminate between patients with the disorder and those without it. Values lower than 1 point to more FN tests among the diseased. In our meta-analysis, we have Copyright 2011 by the International Association for the Study of Lung Cancer 1353

5 Lv et al. Journal of Thoracic Oncology Volume 6, Number 8, August 2011 FIGURE 2. Meta-analysis of sensitivity (SEN) and specificity (SPE) of integrated positron emission tomography/computed tomography (PET/CT) for mediastinal lymph nodes (MLN) staging in non-small cell lung cancer (NSCLC). A, Based on a patientbased analysis. B, Based on an MLN-based analysis Copyright 2011 by the International Association for the Study of Lung Cancer

6 Journal of Thoracic Oncology Volume 6, Number 8, August 2011 Diagnostic Performance of Integrated PET/CT FIGURE 3. Summary receiver operating characteristic (SROC) curves from the bivariate model of integrated positron emission tomography/computed tomography (PET/CT) for mediastinal lymph nodes (MLN) staging in non-small cell lung cancer (NSCLC). A, Based on a patient-based analysis. B, Based on an MLN-based analysis. FIGURE 4. Forest plot of subgroup analyses for sensitivity (SEN) and specificity (SPE). *p 0.05; **p 0.01; ***p found that the mean DOR was 22, indicating that integrated PET/CT seemed to be helpful for MLN staging in NSCLC. LRs are more clinically meaningful than SENs or SPEs and indicate by how much a given test would raise or lower the probability of having disease. To have the greatest diagnostic value, an LR of 10 or 0.1 would be required for ruling in and ruling out diagnoses in most circumstances, respectively. 45 If the PLR is 10 and the NLR 0.1, then the test can only rule in the disease. If the PLR is 10 and the NLR 0.1, then the test can rule out the disease. If the PLR is 10 and the NLR 0.1, then the test can neither rule in nor rule out the disease. In our meta-analysis, the value of PLR was 6.10 (i.e., 10), showing that it was not high enough for the clinical purpose. However, NLR was 0.28 (i.e., 0.1), which is not low enough to rule out the disease. Exploring the reasons for heterogeneity rather than the computation of summary measures is an important goal of meta-analysis. It is important to note that PET/CT positivity criteria varied in the different studies. Some institutions qualitatively analyzed their data and others quantitatively. Subgroup analysis revealed that, at a maximum SUV (max- SUV) of 2.5, the SEN was significantly higher in patientbased analyses than in qualitative (p 0.05). Up to now, the ideal cutoff of the maxsuv for distinguishing malignant MLN from benign has not been determined. Most studies have defined a maxsuv of 2.5 as the upper limit of normal lymph nodes. Nevertheless, Bryant et al 26 reported that when the maxsuv was 5.3, the SEN, SPE, and accuracy for detecting MLN metastasis were higher, when compared with the 2.5. Nevertheless, until more evidence is available that supports a higher maxsuvcutoff, 2.5 should be used. In addition to providing diagnostic information, a recent meta- Copyright 2011 by the International Association for the Study of Lung Cancer 1355

7 Lv et al. Journal of Thoracic Oncology Volume 6, Number 8, August 2011 FIGURE 5. The funnel plot of publication bias. A, Based on a patient-based analysis. B, Based on an mediastinal lymph nodes (MLN)-based analysis. analysis demonstrated that the maxsuv provided prognostic information as well. 46 Our meta-analysis included 2550 patients with NSCLC, and one study was of 674 cases. 24 That study showed that integrated PET/CT provided high SPE and low SEN for MLN staging of NSCLC. On a per-person basis, the SEN and SPE were 0.61 and 0.96, respectively, whereas on a per-mln basis, they were 0.46 and 0.98, respectively. Because the study included so many patients, its inclusion would have skewed the overall results of our meta-analysis by its relative weight, and we therefore ruled it out. In the patient-based analysis, the final polled SEN and SPE were 0.80 and 0.86, and in the MLN-based data analysis, the polled SEN and SPE were 0.73 and Publication bias 47 is a major concern in all forms of meta-analysis, because studies reporting positive or significant results tend to be published, whereas those whose results are nonsignificant or negative are often rejected or not even submitted. In addition, our review was restricted to articles published in English or Chinese, because other languages such as Japanese or French would not be accessible to our readers and this was also likely to introduce bias. Another source of bias is the use of the same group of patients in different publications. It may be difficult to avoid including the same patients more than once in a meta-analysis, although studies clearly based on the results from the same patient populations were excluded; we used only the most recent and complete one. Our meta-analysis had several limitations. First, this review may suffer from selection bias, because most studies included patients who received only surgical mediastinal nodal dissection or mediastinoscopic nodal biopsy. Therefore, many early-stage NSCLC patients were included, which may have contributed to a reduction in SEN. Second, the dissections of some specific nodal stations were guided by preoperative CT or integrated PET/CT findings, which might have induced a verification bias. In addition, the patients received a variety of procedures ranging from mediastinoscopy to thoracotomy and video-assisted thoracoscopic surgery. This may be another source of verification bias. Finally, several studies have supported the superiority of integrated PET/CT over standalone PET and CT in nodal staging for patients with NSCLC, but there are only a few studies that compare integrated PET/CT with other imaging methods for MLN staging. Therefore, we did not compare PET/CT with these other methods. It would be important for future studies to directly compare the results of CT, standalone PET, integrated PET/CT, EBUS-TBNA, and mediastinoscopy and to better define where integrated PET/CT might fit into the diagnostic algorithm. CONCLUSION Despite some limitations, our meta-analysis indicates that integrated PET/CT demonstrates a relatively accurate imaging technique, with excellent specificity for MLN staging in patients with NSCLC, and therefore provides great help in completing optimal therapeutic strategies. Nevertheless, current evidence suggests that we should not depend on the results of PET/CT completely to confirm the absence or presence of MLN metastases. On the basis of our data, we think biopsies of all suspicious MLNs should be done, and a 1356 Copyright 2011 by the International Association for the Study of Lung Cancer

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