Test Performance of Positron Emission Tomography and Computed Tomography for Mediastinal Staging in Patients with NonSmall-Cell Lung Cancer

Context Is computed tomography (CT) or positron emission tomography with 18-fluorodeoxyglucose (FDG-PET) better for mediastinal staging of nonsmall-cell lung cancer? Contribution This synthesis of 39 studies found that FDG-PET was more accurate than CT for identifying lymph node involvement. Positron emission tomography with 18-fluorodeoxyglucose was more sensitive but less specific when CT showed enlarged nodes than when CT showed no node enlargement. Implications Positron emission tomography with 18-fluorodeoxyglucose is more accurate than CT for mediastinal staging. Because FDG-PET has more true-positive and false-positive findings in patients with enlarged nodes, positive findings warrant biopsy confirmation. Interpretation of negative FDG-PET findings should rely heavily on pretest probability of metastasis regardless of CT findings. The Editors Accurate mediastinal staging is crucial in managing patients with nonsmall-cell lung cancer. Regional lymph node status is an important determinant of prognosis, and decisions about treatment depend critically on tumor stage. Conventional methods for mediastinal staging include computed tomography (CT) and various biopsy procedures. However, CT has poor sensitivity and specificity for identifying mediastinal metastases (1-3), and biopsy procedures are inconvenient and potentially risky. Positron emission tomography (PET) with 18-fluorodeoxyglucose (FDG) is a promising but expensive functional imaging test that is rapidly gaining acceptance as a tool for lung cancer staging (4, 5). Positron emission tomography with 18-fluorodeoxyglucose identifies malignant cells in tumors and lymph nodes on the basis of their increased metabolic rate (6). In the past decade, several studies of PET imaging for mediastinal staging were published. These studies suggested that FDG-PET is more accurate than CT for identifying mediastinal metastases. However, most were small and potentially limited by other methodologic shortcomings. In addition, previous studies have not systematically addressed the conditional test performance of FDG-PET and CT. Conditional test performance refers to the possibility that the sensitivity and specificity of 1 test might differ depending on the results of the other test (7). The results of FDG-PET and CT might be mutually dependent, despite the fact that they identify malignant lymph nodes by different mechanisms. In a preliminary analysis, we found that FDG-PET was more sensitive but less specific in patients with lymph node enlargement on CT (8). If confirmed, this finding has important implications for selecting and interpreting tests in mediastinal staging. For example, if FDG-PET is more sensitive when lymph node enlargement is present on CT, then a negative PET result would rule out disease more reliably (because its negative predictive value would be higher). Consequently, confirmatory mediastinal biopsy might not be necessary in some of these patients, especially when pretest probability is low. We performed this meta-analysis to compare the accuracy of FDG-PET and CT for identifying mediastinal metastasis in patients with nonsmall-cell lung cancer. We also aimed to determine whether the results of FDG-PET and CT are conditionally dependent, that is, whether the sensitivity and specificity of FDG-PET depend on the presence or absence of lymph node enlargement on CT. Finally, we explored whether various aspects of study methods affected diagnostic accuracy. Methods We used systematic review methods to identify potentially relevant studies, assess studies for eligibility, evaluate study quality, and derive summary estimates of diagnostic test performance (9-12). We previously used similar methods to evaluate the accuracy of FDG-PET imaging for diagnosis of pulmonary nodules and mass lesions (13). Additional details about our methods can be found in the Appendix. Study Identification We attempted to identify all published studies that examined FDG-PET imaging for mediastinal staging in patients with known or suspected nonsmall-cell lung cancer. We sought studies that evaluated both FDG-PET and CT, but we did not attempt to identify studies that examined only CT for mediastinal staging. An investigator and a professional librarian searched MEDLINE, CancerLit, and EMBASE databases in August 2001 and repeated searches in June 2002 (Appendix Table 1). We updated the literature search in MEDLINE, EMBASE, Current Contents, and BIOSIS through 27 March 2003 as part of a technology assessment performed for the U.S. Department of Veterans Affairs (Appendix Table 2). We augmented our computerized literature searches by manually reviewing the reference lists of identified studies and review articles. We included studies published in any language but did not include abstracts. For English-language studies, 2 investigators independently evaluated studies for inclusion, rated the methodologic quality of included studies, and abstracted relevant data. Disagreements were resolved by discussion. One reviewer performed these tasks for non-English-language studies. Reviewers were blinded to journal, author, institutional affiliation, and date of publication. Study Eligibility We included studies that examined FDG-PET imaging for mediastinal lymph node staging in patients with known or suspected nonsmall-cell lung cancer; enrolled at least 10 participants, including at least 5 participants with lymph node metastases; and provided enough data to permit calculation of sensitivity and specificity for identifying malignant lymph node involvement. Study Quality We adapted an existing instrument (11, 13) to examine 7 aspects of study quality: technical quality of the index tests, technical quality and application of the reference test, independence of test interpretation, description of the study population, cohort assembly, sample size, and unit of analysis (Appendix Table 3). Data Abstraction We abstracted data about the demographic characteristics of participants, the prevalence of malignant lymph node involvement, and the sensitivity and specificity of CT and FDG-PET for identifying malignant lymph nodes. For studies that reported results by using the patient as the unit of analysis, we determined the ability of CT and FDG-PET to distinguish ipsilateral or contralateral mediastinal lymph node involvement (N2 or N3) from hilar, intrapulmonary, or no lymph node involvement (N0 or N1). This distinction is critical because involvement of N2 or N3 nodes usually indicates non-surgically treatable disease. When it was not possible to make this distinction, we determined test sensitivity and specificity for distinguishing N0 lymph node status from N1, N2, or N3 lymph node status. For studies in which the individual patient was not the unit of analysis, we determined the test sensitivity and specificity for identifying malignant lymph nodes or lymph node stations. Because observations are not independent when several lymph nodes from the same patient are analyzed separately, these studies may yield biased estimates of diagnostic test performance. Therefore, we analyzed data from these studies separately. To determine whether the sensitivity and specificity of FDG-PET depended on the presence or absence of enlarged nodes on CT, we recorded the results of FDG-PET, CT, and the reference test or tests for each patient. This enabled us to derive separate estimates for the sensitivity and specificity of FDG-PET in patients with and without lymph node enlargement on CT. Data Synthesis and Statistical Analysis For each study, we constructed 2 2 contingency tables in which all participants were classified as having positive (N2 or N3) or negative (N0 or N1) results and as having or not having mediastinal lymph node involvement as determined by the reference test or tests. We calculated the true-positive rate (true-positive rate = sensitivity), the false-positive rate (false-positive rate = 1 specificity), and the log odds ratio (log odds true-positive rate log odds false-positive rate) for CT and FDG-PET. The log odds ratio is a measure of diagnostic test performance that accounts for the correlation between the true-positive rate and the false-positive rate. We calculated exact 95% CIs for the true-positive rate and the false-positive rate on the basis of the binomial distribution (14). To derive summary estimates of diagnostic test performance, we constructed summary receiver-operating characteristic (ROC) curves by using the method of Moses (12, 13, 15, 16), which confirmed that the curves were symmetrical and could be described by a single parameter, the summary log odds ratio. Because this method requires the use of a correction factor when the reported sensitivity or specificity is 100%, we calculated the summary diagnostic odds ratios by using a fixed-effects model (17), or a random-effects model when there was evidence of heterogeneity (18), and reported results derived from these models. Because the summary log odds ratio is difficult to interpret clinically, we express our results in terms of the maximum joint sensitivity and specificity (12), a transformation of the summary log odds ratio that is a global measure of diagnostic accuracy, similar to the area under the ROC curve. The maximum joint sensitivity and specificity is the point on the summary ROC curve at which sensitivity and specificity are equal. It varies from 0.5 for a test that provides no diagnostic information to 1.0 for a test that is perfect. We used meta-regression to make all statistical comparisons (19), with 1 exception. To compare the sensitivity and specificity of FDG-PET in patients with and without lymph node enlargement, we used discriminant function analysis (20) and a nonparametric permutation test (21). We considered a 2-sided P value less than 0.05 to be significant for all statistical tests. Sensitivity Analysis In prespecified analyses, we examined the effect of year of publication, language, and