Abstract

Lung cancer is the leading cause of cancer-related death in industrialized countries. The overall mortality rate for lung cancer is high, and early diagnosis provides the best chance for survival. Diagnostic tests guide lung cancer management decisions, and clinicians increasingly use diagnostic imaging in an effort to improve the management of patients with lung cancer. This systematic review, an expansion of a health technology assessment conducted in 2001 by the Institute for Clinical and Evaluative Sciences, evaluates the accuracy and utility of 18 fluorodeoxyglucose positron emission tomography (PET) in the diagnosis and staging of lung cancer. Through a systematic search of the literature, we identified relevant health technology assessments, randomized trials, and meta-analyses published since the earlier review, including 12 evidence summary reports and 15 prospective studies of the diagnostic accuracy of PET. PET appears to have high sensitivity and reasonable specificity for differentiating benign from malignant lesions as small as 1 cm. PET appears superior to computed tomography imaging for mediastinal staging in non–small cell lung cancer (NSCLC). Randomized trials evaluating the utility of PET in potentially resectable NSCLC report conflicting results in terms of the relative reduction in the number of noncurative thoracotomies. PET has not been studied as extensively in patients with small-cell lung cancer, but the available data show that it has good accuracy in staging extensive- versus limited-stage disease. Although the current evidence is conflicting, PET may improve results of early-stage lung cancer by identifying patients who have evidence of metastatic disease that is beyond the scope of surgical resection and that is not evident by standard preoperative staging procedures. Further trials are necessary to establish the clinical utility of PET as part of the standard preoperative assessment of early-stage lung cancer.

Lung cancer is the leading cause of cancer-related deaths in both men and women in industrialized countries. The overall mortality rate for lung cancer is high, and early diagnosis provides the best chance for survival. Diagnostic tests guide lung cancer management decisions, and diagnostic imaging is increasingly being used in an effort to improve the clinical management of patients with lung cancer.

Whereas traditional radiologic imaging technologies (e.g., computed tomography [CT] scan, magnetic resonance imaging) provide structural information and define disease states on the basis of gross anatomical changes, 18fluorodeoxyglucose positron emission tomography (PET) imaging provides information on the biochemical processes that may precede gross anatomic change. PET imaging is potentially useful in tumor imaging in particular due to the uptake of the radiolabeled glucose analog 18 fluorodeoxyglucose ( 18 FDG) by tumor tissue as a result of increased glycolysis in some cancers as compared with most normal tissue ( 1 , 2 ). This increased glycolysis has been linked to both an increase in the number of glucose membrane transporters and an increase in the activity of the principal enzymes that control the glycolytic pathways ( 3 ).

Two main types of instrumentation have been used for PET imaging: dedicated PET scanners and gamma cameras that have been modified for coincidence imaging ( 4–8 ). Dedicated PET scanners consist of multiple detectors that are arranged in a partial or full ring; the detection sensitivity of a partial ring scanner is less than that of a full ring scanner. Gamma-camera coincidence imaging uses a modified two- or three-headed gamma camera that rotates around the patient. These units are less expensive than dedicated PET, but they are also less sensitive and are no longer being manufactured. They do, however, remain in use in some institutions and are the subject of some of the literature on PET. Recent advances in imaging technology combine PET and CT to provide both functional and anatomical information simultaneously, thus improving localization accuracy ( 9 , 10 ).

PET data may be analyzed qualitatively, semiquantitatively, or fully quantitatively. Qualitative visual interpretation of PET data involves the subjective assessment of differences in contrast and requires only a static emission scan, with or without a transmission scan and attenuation correction ( 4–10 ). This analytic approach is particularly useful in assessing substantial changes (e.g., decrease in tumor metabolic activity following therapy or the development of new lesions) but is not as valuable as other approaches in assessing more subtle metabolic changes ( 11 ). Semiquantitative approaches include analyses of tumor to normal tissue ratios and standardized uptake values (SUVs). The SUV is the ratio of activity in tissue per unit volume to the activity in the injected dose per patient body weight and is widely used because of its simplicity. It requires only a static scan with accurate instrument calibration, and it is about as discriminating as fully quantitative methods ( 12 ). A number of fully quantitative (or kinetic) methods are used to measure glucose metabolic rate dynamically, thereby providing more detailed information about tumor response ( 8 ). All three types of methods have strengths and weaknesses, and the optimal approach has yet to be established in prospective trials ( 11 ). A full review of PET scan technology was published in 2004 ( 13 ).

Staging with PET has the potential to allow clinicians to define more accurately than with conventional staging methods those patients who have metastatic disease and who would, therefore, not benefit from surgery or other localized therapies. Conventional lung cancer staging procedures are imperfect in their ability to identify those asymptomatic patients with occult metastases for whom surgical intervention would be futile, as manifested by the fact that a substantial proportion of such patients go on to develop metastatic disease shortly after thoracotomy. Moreover, if PET scanning could accurately stage non–small cell lung cancer (NSCLC) and also enable concurrent detection of mediastinal and distant metastases, cervical mediastinoscopy or other imaging studies that are presently required to evaluate the mediastinum in patients with NSCLC might be avoided.

PET also has the potential to solve the dilemma of the diagnostic workup of a solitary pulmonary nodule (SPN) when the SPN is not amenable to fine needle aspiration biopsy because of size, location, or associated medical comorbidities. Similarly, open biopsy would not need to be risked if the SPN were known to be benign. Finally, the result of a fine needle aspiration biopsy may not be diagnostic of malignancy because it may be falsely negative if the needle was inaccurately placed or scant cellular material was obtained.

PET has the potential to be useful in the staging of small-cell lung cancer (SCLC) ( 14–16 ). SCLC is the most aggressive type of lung cancer; tumors are typically fast growing and 60% to 70% of patients present with extensive-stage disease ( 17 ). However, there is less information on PET in the staging of SCLC, and thus uncertainty remains about its utility for distinguishing patients with extensive disease from those with limited disease.

In an initial search for evidence-based reports on PET in the diagnosis and staging of lung cancer, we identified a 2001 report from the Institute for Clinical and Evaluative Sciences (ICES) ( 18 ). This systematic review of the PET scanning literature in general covered the period through December 2000; with subsequent updates ( 19 ), the literature review was current to September 2004. The ICES report reviewed the diagnostic accuracy, effect on patient outcomes, and cost-effectiveness of PET based on a systematic review of the peer-reviewed and online PET scanning literature, focusing on the use of dedicated PET scanners. The ICES report provided evidence for the better efficacy of PET than CT in predicting the histologic status of mediastinal lymph nodes and for detecting pleural involvement and malignant pleural effusion in patients with carcinoma of the lung.

The ICES review was regarded as a high-quality review of the evidence and was expanded in the current systematic review to serve as the basis for clinical practice recommendations. In this review, the Lung Cancer Disease Site Group of Cancer Care Ontario's Program in Evidence-Based Care provides updated evidence on the use of PET in lung cancer. The conclusions from the ICES review and the results of primary studies retrieved as part of this updated search related to the accuracy or utility of PET in diagnosis or staging are organized into three sections: diagnosis of SPNs, staging of NSCLC at initial diagnosis, and staging of SCLC. Within each section, we summarize the findings of the ICES review and the primary studies included in the ICES report, followed by a detailed description of the results of the systematic reviews and primary studies retrieved in the updated search. This systematic review and the resulting guideline recommendations are intended to promote evidence-based practice in Ontario, Canada.

Study Identification

Literature Search Strategy

The literature search was conducted in the Cochrane Database of Systematic Reviews (2006, Issue 1), EMBASE (1996 through 2006, week 19), and MEDLINE (1996 through May 2006). In addition, the conference proceedings of the American Society of Clinical Oncology (2004–2005) and Physician Data Query clinical trials database were searched for primary studies. The following subject-specific terms (i.e., MeSH terms in MEDLINE and EMTREE terms in EMBASE) were searched: “Lung carcinoma,” “Lung carcinogenesis,” “Lung metastasis,” “Carcinoma, non-small-cell lung,” “Carcinoma, small cell,” “Lung neoplasms,” “Lung cancer,” and the phrase “Non-small cell lung” used as a text word were combined with “Positron emission tomography,” “Tomography, emission computed,” “fluorodeoxyglucose F18,” and both of the following phrases used as text words: “PET” and “Positron emission tomography”. These terms were then combined with the search terms for the following publication types: practice guideline, systematic review, biomedical technology assessment, and meta-analysis. The search was restricted to publications in the English language. In addition, Web sites of practice guideline and health technology assessment organizations were searched in late 2004 and early 2005. The Canadian Medical Association Infobase, the National Guidelines Clearing House, and the National Institute for Clinical Excellence were searched on May 13, 2005; the Web site of the Canadian Coordinating Office for Health Technology Assessment was searched on December 23, 2004; and the Centre for Reviews and Dissemination was searched on February 1, 2005.

Study Inclusion Criteria

Evidence-based reports (i.e., health technology assessments, practice guidelines, systematic reviews, and meta-analyses) that evaluated the use of PET in the staging and diagnosis of lung cancer were reviewed for inclusion in this systematic review if they were published in English after 1999. Primary studies (full reports or abstracts) that were published after the period covered in the ICES review or that examined the use of PET in staging SCLC were selected if they met the following criteria: (a) they were randomized or single-arm prospective studies that focused on PET scanning in the diagnosis and/or staging of lung cancer compared with an appropriate reference standard and (b) they reported at least one of the following measures of effectiveness/benefit: PET specificity and or sensitivity, measures of accuracy of staging, changes in patient management, or improvements in patient outcomes (e.g., survival). Studies involving NSCLC were excluded if they had fewer than 35 subjects; there was no sample-size limitation for studies involving SCLC.

Literature Search Results

In addition to the ICES report, 12 additional evidence-based reports were retrieved. The ICES report was the most comprehensive of the reports; therefore, we include in our systematic review only those reports that were meta-analyses or addressed a question not covered by the ICES report ( 21–26 ). The ICES report included 21 prospective, observational studies and 22 randomized controlled trials (RCTs) on the diagnosis of SPN or the staging of primary NSCLC, all of which were included in other evidence-based reports. We also identified 15 prospective studies (including one RCT) that examined PET in the staging and diagnosis of lung cancer that were published after completion of the ICES report (October 2004 or later). Table 1 lists all prospective studies in ICES and those identified and included in this update. We included multiple publications from the same study if each report provided additional relevant data.

Table 1

Summary of included literature by evidence source and by topic *

 Reference numbers of prospective studies retrieved from 
Topic ICES Updated search 
SPN: diagnosis (27–30) (20,32,33) 
Primary NSCLC: staging (34–46,48,49,51) (47,52–59) 
Primary NSCLC: mediastinal  staging (14,34,36,37,39–43,45) (53,54,57–59) 
Primary NSCLC:  extrathoracic staging NA (53) 
SCLC: diagnosis and staging NA (14–16) 
 Reference numbers of prospective studies retrieved from 
Topic ICES Updated search 
SPN: diagnosis (27–30) (20,32,33) 
Primary NSCLC: staging (34–46,48,49,51) (47,52–59) 
Primary NSCLC: mediastinal  staging (14,34,36,37,39–43,45) (53,54,57–59) 
Primary NSCLC:  extrathoracic staging NA (53) 
SCLC: diagnosis and staging NA (14–16) 
*

ICES = Institute for Clinical and Evaluative Sciences; SPN = solitary pulmonary nodule; NSCLC = non–small cell lung cancer; SCLC = small-cell lung cancer; NA = not applicable.

Diagnosis of Solitary Pulmonary Nodules

Findings of Institute for Clinical and Evaluative Sciences

The ICES report ( 18 , 19 ) evaluated four prospective studies ( 27–30 ) on the role of PET in the diagnosis of SPN ( Table 2 ). The ICES report concluded that PET has proven efficacious in distinguishing benign from malignant SPN and, by reducing the number of unnecessary thoracotomies performed for SPN, would reduce patient morbidity.

Table 2

Characteristics of prospective studies on diagnosis and diagnostic accuracy of 18fluorodeoxyglucose positron emission tomography for solitary pulmonary nodules *

First author (reference) No. of patients Eligibility Method of analysis Reference standard Test Prev % Acc% Se % Sp % PPV % NPV % 
Trials included in the ICES report ( 19 )  
Bury 1996 ( 27 )  50 Indeterminate SPNs from chest radiography and CT Visual Histology PET vs histology 66 96 100 88 94 100 
Croft 2002 ( 28 ) † 90 Lung nodule or mass on chest x-ray Visual and semiquantitative  CT ‡ + histology  PET vs histology 82 84 93 40 88 55 
Imdahl 2001 ( 29 ) §  87 ‖ Pulmonary lesions of unknown origin verified by CT Visual and semiquantitative Histology PET vs histology 79 87 90 78 94 67 
Lowe 1998 ( 30 )  89 Pulmonary lesions of unknown origin verified by CT Visual and semiquantitative Histology Visual PET vs histology 67 89 98 69 87 95 
   ≤1.5 cm – 85 100 74 75 100 
   >1.5 cm – 91 98 60 92 86 
   ≤3.0 cm – 88 98 69 86 95 
SUV PET vs histology 67 91 92 90 95 84 
   ≤1.5 cm – 88 80 95 92 86 
   >1.5 cm – 93 96 80 96 80 
   ≤3.0 cm – 91 90 92 96 83 
Trials published after completion of the ICES review 
Nomori 2004 ( 32 )  131 Noncalcified pulmonary nodules <3 cm in diameter Semiquantitative Histology + CT + x-ray PET vs histology       
   Nodules 1–3 cm 63 74 79 65 79 65 
   Nodules with CT solid images 62 83 90 71 84 82 
   Nodules with CT GGO images 67 13 10 20 20 10 
Nomori 2005a ( 20 )  NR Noncalcified pulmonary nodules 1–3 cm in diameter Visual and semiquantitative Histology Definitely positive or negative by visual estimation       
   Visual PET vs histology 65 69 70 67 80 54 
   SUV vs histology 65 65 58 77 83 49 
   CR-lung vs histology 65 71 70 73 83 56 
   CR-brain vs histology 65 69 68 71 82 54 
Faintly positive by visual estimation       
   SUV vs histology 77 23 100 NA 23 
   CR-lung vs histology 77 64 53 100 100 38 
   CR-brain vs histology 77 41 29 80 83 25 
Nomori 2005b ( 33 )  50 Pulmonary nodules 1–3 cm in diameter with GGO images over their whole or peripheral area on CT Visual and semiquantitative Histology PET vs histology – 48 38 71 74 34 
11 C-acetate positron emission tomography vs histology  – 57 51 71 79 40 
First author (reference) No. of patients Eligibility Method of analysis Reference standard Test Prev % Acc% Se % Sp % PPV % NPV % 
Trials included in the ICES report ( 19 )  
Bury 1996 ( 27 )  50 Indeterminate SPNs from chest radiography and CT Visual Histology PET vs histology 66 96 100 88 94 100 
Croft 2002 ( 28 ) † 90 Lung nodule or mass on chest x-ray Visual and semiquantitative  CT ‡ + histology  PET vs histology 82 84 93 40 88 55 
Imdahl 2001 ( 29 ) §  87 ‖ Pulmonary lesions of unknown origin verified by CT Visual and semiquantitative Histology PET vs histology 79 87 90 78 94 67 
Lowe 1998 ( 30 )  89 Pulmonary lesions of unknown origin verified by CT Visual and semiquantitative Histology Visual PET vs histology 67 89 98 69 87 95 
   ≤1.5 cm – 85 100 74 75 100 
   >1.5 cm – 91 98 60 92 86 
   ≤3.0 cm – 88 98 69 86 95 
SUV PET vs histology 67 91 92 90 95 84 
   ≤1.5 cm – 88 80 95 92 86 
   >1.5 cm – 93 96 80 96 80 
   ≤3.0 cm – 91 90 92 96 83 
Trials published after completion of the ICES review 
Nomori 2004 ( 32 )  131 Noncalcified pulmonary nodules <3 cm in diameter Semiquantitative Histology + CT + x-ray PET vs histology       
   Nodules 1–3 cm 63 74 79 65 79 65 
   Nodules with CT solid images 62 83 90 71 84 82 
   Nodules with CT GGO images 67 13 10 20 20 10 
Nomori 2005a ( 20 )  NR Noncalcified pulmonary nodules 1–3 cm in diameter Visual and semiquantitative Histology Definitely positive or negative by visual estimation       
   Visual PET vs histology 65 69 70 67 80 54 
   SUV vs histology 65 65 58 77 83 49 
   CR-lung vs histology 65 71 70 73 83 56 
   CR-brain vs histology 65 69 68 71 82 54 
Faintly positive by visual estimation       
   SUV vs histology 77 23 100 NA 23 
   CR-lung vs histology 77 64 53 100 100 38 
   CR-brain vs histology 77 41 29 80 83 25 
Nomori 2005b ( 33 )  50 Pulmonary nodules 1–3 cm in diameter with GGO images over their whole or peripheral area on CT Visual and semiquantitative Histology PET vs histology – 48 38 71 74 34 
11 C-acetate positron emission tomography vs histology  – 57 51 71 79 40 
*

PET = 18 fluorodeoxyglucose positron emission tomography; Prev = prevalence; Se = sensitivity; Sp = specificity; Sp = specificity; PPV = positive predictive value; NPV = negative predictive value; ICES = Institute for Clinical and Evaluative Sciences; SPN = solitary pulmonary nodule; CT = computed tomography; SUV = standardized uptake value; GGO = ground-glass opacity; CR = contrast ratio; NR = not reported; NA = not applicable.

Patients from region with high histoplasmosis prevalence.

No results reported for CT test.

§

Three different Se/Sp were reported in the paper, and it was unclear how they were calculated.

109 patients underwent PET, but only 87 received the reference standard.

Results of Systematic Reviews

Two systematic reviews ( 23 , 24 ) assessed the accuracy of PET in the diagnosis of SPN. Fischer et al. ( 23 ) estimated the mean sensitivity and specificity independently for the identification of malignant pulmonary nodules and masses. The mean sensitivities and specificities were 0.96 (standard error [SE] = 0.01) and 0.78 (SE = 0.03), respectively, for dedicated PET and 0.92 (SE = 0.04) and 0.86 (SE = 0.04), respectively, for gamma-camera PET. Sensitivity was statistically significantly lower with gamma-camera PET than with dedicated PET ( P <.005). Relative to the ability of PET to discriminate between malignant and benign pulmonary changes, there was no statistically significant difference between the methods of interpretation (SUV, visual, or both) of PET scans. The authors concluded that PET has value for determining if a pulmonary nodule is malignant or benign but recommended that studies be conducted in populations with low prevalence of NSCLC.

The meta-analysis by Gould et al. ( 24 ) included 40 studies of pulmonary lesions and used a meta-analytic method to construct summary receiver operating characteristic (SROC) curves. An SROC curve is used to summarize ROC data from multiple studies, i.e., in the context of a meta-analysis ( 31 ). The maximum joint sensitivity and specificity of PET from the SROC curve was 91.2% (95% confidence interval [CI] = 89.1% to 92.9%). In clinical practice, at a median specificity of 78%, the sensitivity of PET from the SROC curve would correspond to 97% because most studies use thresholds that favor sensitivity over specificity. There was no difference in the diagnostic accuracy of PET imaging for pulmonary nodules based on size ( P = .43), for semiquantitative versus qualitative methods of analysis ( P = .52), or for studies using dedicated PET versus gamma-camera PET ( P = .19). Gould et al. ( 24 ) concluded that PET has high sensitivity and intermediate specificity for identifying malignant pulmonary nodules and larger mass lesions but that limited data exist for nodules less than 1 cm in diameter.

Results of Primary Studies

Seven prospective studies ( 20 , 27–30 , 32 , 33 ) have examined the use of PET to differentiate benign and malignant SPN ( Table 2 ). Most of the seven studies enrolled patients with indeterminate pulmonary lesions on chest radiography and used histopathology results as the reference standard. Sensitivity in these seven studies ranged from 79% to 100%, except for those that used ground-glass opacity images (see below). Specificity was more variable and ranged from 40% to 90%. Croft et al. ( 28 ) reported a specificity of 40%; however, their patient population had a high incidence of granulomas, which increased the number of false positives. Nomori et al. ( 33 ) also reported a low sensitivity and specificity; however, this study selected nodules on the basis of ground-glass opacity images on CT, which show low uptake of 18 FDG on PET imaging. PET data were evaluated independently of the reference standard in six of the studies ( 20 , 27–30 , 33 ). In one trial ( 29 ), only some of the study group received confirmation of the diagnosis by the reference standard, which could result in biased estimates of overall diagnostic accuracy. Six of the studies ( 20 , 28–30 , 32 , 33 ) clearly specified explicit criteria for defining a positive PET test result. Two studies ( 20 , 32 ) were conducted by the same research group, and it is not clear if the same patients were included in both studies.

Nomori et al. ( 32 ) evaluated 151 noncalcified nodules that were less than 3 cm in diameter in 131 patients. Of these, 15 nodules could not be diagnosed as malignant or benign and were excluded from analyses. Among the remaining 136 nodules, PET could not detect abnormal 18 FDG activity in the 20 nodules that were less than 1 cm in diameter, of which eight were malignant. PET correctly detected 57 of 63 malignant nodules that were solid on CT but was positive for only one out of 10 malignant nodules with a faint or ground-glass appearance on CT. All of the malignant nodules with ground-glass images on CT were histologically adenocarcinoma.

Another trial by Nomori et al. ( 20 ) compared visual and semiquantitative analyses for nodules of 1–3 cm in diameter. In nodules greater than 1 cm, PET was negative or faintly positive in patients with histologically well- or moderately differentiated adenocarcinoma. The study also found no difference in sensitivity and specificity between visual assessment and semiquantitative methods for nodules graded as definitely positive or negative. However, in nodules that were faintly positive, using the contrast ratio to the contralateral lung and contrast ratio to the cerebellum resulted in statistically significantly higher sensitivity than the SUV.

Primary Non–Small Cell Lung Cancer Staging: Utility and Accuracy of 18Fluorodeoxyglucose Positron Emission Tomography

Findings of Institute for Clinical and Evaluative Sciences

The ICES report included 14 prospective studies ( 34–46 ) examining the effectiveness of PET in determining the true extent or stage of primary NSCLC ( Tables 3 and 4 ). According to the ICES report, the evidence on whether preoperative PET would reduce the number of unnecessary thoracotomies for patients diagnosed with lung cancer was “conflicting.”

Table 3

Characteristics of prospective studies on 18 fluorodeoxyglucose positron emission tomography staging of primary non–small cell lung cancer *

First author (reference) No. of patients Eligibility Method of analysis Reference standard 
Trials included in the ICES report ( 19 )  
Reed 2003 ( 45 )   287 †  Suspected or confirmed NSCLC found to be surgical candidates (stage I, II, or IIIA ‡ ) by routine staging procedures  Visual with and without CT and other conventional imaging results  Confirmatory procedures § 
Kahn 2004 ( 46 )  157 Suspected of having operable and potentially curable lung cancer by abnormal CT scan Visual and SUV Histology 
Saunders 1999 ( 39 )   97 ‖ Biopsy proven or strongly suspected lung cancer by clinical and CT criteria and judged to be operable (<stage IIIA) Visual and SUV Histology, CT, and follow-up 
Vesselle 2002 ( 41 )  142 Potentially resectable NSCLC based on CT. Patients with lesions <1cm or insufficient cellularity, or with unknown histological type were excluded Visual, read with thoracic CT scans Histology, additional imaging 
Poncelet 2001 ( 43 )  64 Potentially resectable NSCLC based on CT. Excluded patients with N3 or M1 as detected by PET NR Histology 
Pieterman 2000 ( 40 )  102 Potentially resectable NSCLC Visual Histology, follow up, additional imaging 
Gupta 1999 ( 37 )  103 Suspected or proven NSCLC considered to be surgically resectable SUV Histology 
Gupta 2000 ( 38 )  118 Suspected or proven NSCLC considered to be surgically resectable Visual and SUV Histology, CT 
Bury 1998 ( 51 )  110 Histological diagnosis of NSCLC Visual Bone scintigraphy, histology, additional radiology 
Bury 1996 ( 34 )  50 Potentially resectable NSCLC Visual Histology 
Chin 1995 ( 35 )  43 Potentially resectable NSCLC. Excluded patients with obvious stage IIIB or IV Visual Histology 
Stokkel 1999 ( 36 )  33 Newly diagnosed patients with NSCLC Visual with dual-headed gamma camera Histology 
Albes 2002 ( 42 )  40 Suspected or proven NSCLC. Excluded patients with distant metastases. SUV Histology 
Lardinois 2003 ( 44 )  50 Suspected or proven NSCLC Integrated PET–CT or visually correlated PET and CT or PET alone Histology 
Trials published after completion of the ICES review 
Halter 2004 ( 52 )  155 Suspected lesions of the lung based on helical CT NR Histology 
Cerfolio 2004 ( 55 )  129 Patients with an indeterminate pulmonary nodule or biopsy-proven NSCLC Integrated PET–CT, visually correlated PET and CT Histology 
Oturai 2004 ( 56 )  86 Suspected lung cancer based on the radiograph Visual dedicated-PET, gamma-camera PET Histology, follow-up 
Nomori 2004 ( 54 )  80 Patients with peripheral-type lung cancer Semiquantitatively using contrast ratio Histology 
Verhagen 2004 ( 53 )  66 Suspected or proven primary NSCLC Visual Histology 
Halpern 2005 ( 57 )  36 Suspected or biopsy-proven NSCLC Visual Histology 
Shim 2005 ( 58 )  106 Histopathologically proven NSCLC SUV Histology 
Pozo-Rodriguez 2005 ( 59 )  132 Histologically diagnosed potentially resectable stage I, II, and selected stage Ill NSCLC Visual, plus in parallel with helical CT Histology, follow-up 
First author (reference) No. of patients Eligibility Method of analysis Reference standard 
Trials included in the ICES report ( 19 )  
Reed 2003 ( 45 )   287 †  Suspected or confirmed NSCLC found to be surgical candidates (stage I, II, or IIIA ‡ ) by routine staging procedures  Visual with and without CT and other conventional imaging results  Confirmatory procedures § 
Kahn 2004 ( 46 )  157 Suspected of having operable and potentially curable lung cancer by abnormal CT scan Visual and SUV Histology 
Saunders 1999 ( 39 )   97 ‖ Biopsy proven or strongly suspected lung cancer by clinical and CT criteria and judged to be operable (<stage IIIA) Visual and SUV Histology, CT, and follow-up 
Vesselle 2002 ( 41 )  142 Potentially resectable NSCLC based on CT. Patients with lesions <1cm or insufficient cellularity, or with unknown histological type were excluded Visual, read with thoracic CT scans Histology, additional imaging 
Poncelet 2001 ( 43 )  64 Potentially resectable NSCLC based on CT. Excluded patients with N3 or M1 as detected by PET NR Histology 
Pieterman 2000 ( 40 )  102 Potentially resectable NSCLC Visual Histology, follow up, additional imaging 
Gupta 1999 ( 37 )  103 Suspected or proven NSCLC considered to be surgically resectable SUV Histology 
Gupta 2000 ( 38 )  118 Suspected or proven NSCLC considered to be surgically resectable Visual and SUV Histology, CT 
Bury 1998 ( 51 )  110 Histological diagnosis of NSCLC Visual Bone scintigraphy, histology, additional radiology 
Bury 1996 ( 34 )  50 Potentially resectable NSCLC Visual Histology 
Chin 1995 ( 35 )  43 Potentially resectable NSCLC. Excluded patients with obvious stage IIIB or IV Visual Histology 
Stokkel 1999 ( 36 )  33 Newly diagnosed patients with NSCLC Visual with dual-headed gamma camera Histology 
Albes 2002 ( 42 )  40 Suspected or proven NSCLC. Excluded patients with distant metastases. SUV Histology 
Lardinois 2003 ( 44 )  50 Suspected or proven NSCLC Integrated PET–CT or visually correlated PET and CT or PET alone Histology 
Trials published after completion of the ICES review 
Halter 2004 ( 52 )  155 Suspected lesions of the lung based on helical CT NR Histology 
Cerfolio 2004 ( 55 )  129 Patients with an indeterminate pulmonary nodule or biopsy-proven NSCLC Integrated PET–CT, visually correlated PET and CT Histology 
Oturai 2004 ( 56 )  86 Suspected lung cancer based on the radiograph Visual dedicated-PET, gamma-camera PET Histology, follow-up 
Nomori 2004 ( 54 )  80 Patients with peripheral-type lung cancer Semiquantitatively using contrast ratio Histology 
Verhagen 2004 ( 53 )  66 Suspected or proven primary NSCLC Visual Histology 
Halpern 2005 ( 57 )  36 Suspected or biopsy-proven NSCLC Visual Histology 
Shim 2005 ( 58 )  106 Histopathologically proven NSCLC SUV Histology 
Pozo-Rodriguez 2005 ( 59 )  132 Histologically diagnosed potentially resectable stage I, II, and selected stage Ill NSCLC Visual, plus in parallel with helical CT Histology, follow-up 
*

ICES = Institute for Clinical and Evaluative Sciences; NSCLC = non–small cell lung cancer; CT = computed tomography; SUV = standardized uptake value; PET = 18 fluorodeoxyglucose positron emission tomography; NR = not reported.

Four hundred forty-five patients were registered. Three hundred and three underwent PET, but only 287 were evaluable for metastatic disease.

Staging according to (50).

§

Included biopsy, additional imaging, judgment of the surgeon, and 6-month follow-up.

Thirteen patients had distant metastases and did not undergo mediastinal sampling.

Table 4

Diagnostic accuracy of 18 fluorodeoxyglucose positron emission tomography for staging primary non–small cell lung cancer *

First author (reference) No. of patients  Test † Prev % Acc % Se % Sp % PPV % NPV % 
Trials included in the ICES report ( 19 )  
Reed 2003 ( 45 )   Detection of distant metastases       
287     PET vs biopsy/additional imaging/judgment of the surgeon ‡ /6-mo follow-up  90 83 90 36 99 
302 Staging mediastinal (N0/N1 vs N2/N3) disease       
    PET vs histology 78 61 84 56 87 78 
Kahn 2004 ( 46 )  157 Primary lung lesion       
    Visual PET vs histology/12-mo follow-up – – 96 71 92 83 
    SUV vs histology/12-mo follow-up – – 90 80 – – 
128 Hilar/mediastinal lymph nodes       
    PET vs histology – – 81 77 53 93 
139 Detecting stage <IIIB vs IIIB/IV       
    PET vs histology or CT or MRI or bone scintigraphy – – 63 84 – – 
Saunders 1999 ( 39 )  84 Staging mediastinal (N0/N1 vs N2/N3) disease       
    PET vs histology 21 92 71 97 86 93 
Vesselle 2002 ( 41 )  118 Staging mediastinal (N0/N1 vs N2/N3) disease       
    PET vs histology 36 91 81 96 92 90 
Poncelet 2001 ( 43 )  62 Staging mediastinal (N0/N1 vs N2/N3) disease       
    PET vs histology 15 82 67 85 43 94 
Pieterman 2000 ( 40 )  102 Detection of distant metastases       
    PET vs histology – – 82 93 – – 
 Detection of mediastinal (N0/N1 vs N2/N3) disease       
    PET vs histology 31 87 91 86 74 95 
    CT and PET vs histology 31 88 94 86 75 97 
Gupta 1999 ( 37 )  Lymph nodes 126 Detection of mediastinal (N0/N1 vs N2/N3) disease       
   PET vs histology 40 94 93 94 92 94 
Gupta 2000 ( 38 )  Lymph nodes Staging mediastinal metastases       
168    PET vs histology – 94 96 93 – – 
53     Lymph nodes <1 cm – 92 80 95 – – 
107     Lymph nodes 1–3 cm – 95 100 91 – – 
    Lymph nodes >3 – 88 100 75 – – 
Bury 1998 ( 51 )   Detection of bone metastases       
110    PET vs bone scan, histology, additional imaging – 96 90 98 90 98 
Bury 1996 ( 34 ) §  Detection of mediastinal (N0 vs N1/N2/N3) disease       
50    PET vs histology 58 84 83 86 89 78 
Chin 1995 ( 35 )   Detection of N2 status       
30    PET vs histology 30 80 78 81 64 89 
 Primary lung lesion       
    PET vs histology – 89 94 33 94 33 
Stokkel 1999 ( 36 )  Lymph nodes 187 Mediastinal lymph node involvement (N0/N1 vs N2)       
   PET vs histology – 96 90 97 85 98 
Albes 2002 ( 42 )  38 Primary tumor       
    T0: PET vs histology – – 67 100 100 – 
    T1/2: PET vs histology – – 79 83 92 – 
    T3: PET vs histology – – 83 88 56 – 
    T4: PET vs histology – – 67 89 33 – 
38 Mediastinal lymph node involvement       
    N0: PET vs histology – – 89 86 84 – 
    N1/2: PET vs histology – – 71 86 80 – 
    N3: PET vs Histology – – 80 94 67 – 
Lardinois 2003 ( 44 )  40  Tumor stage ‖       
   PET alone – 40 – – – – 
   Visual correlation of PET and CT – 65 – – – – 
   Integrated PET–CT – 88 – – – – 
Node stage ‖       
   PET alone – 49 – – – – 
   Visual correlation of PET and CT – 59 – – – – 
   Integrated PET–CT – 81 – – – – 
Trials published after completion of the ICES review 
Halter 2004 ( 52 )  116 Lymph node status (N0 vs N1/N2/N3) 71 89 88 91 96 76 
155 Primary tumor 75 91 91 90 96 78 
  Stage PET–CT vs PET 
Cerfolio 2004 ( 55 )  10    0 – 90/70 – – – – 
42    I – 52/33 – – – – 
17    II – 70/36 – – – – 
23    IIIA – 70/48 – – – – 
   IIIB – 56/33 – – – – 
19    IV – 89/84 – – – – 
91 T status (overall) – 70/47 – – – – 
11    T0 – 100/81 – – – – 
21    T1 – 76/57 – – – – 
39    T2 – 65/41 – – – – 
12    T3 – 58/8 – – – – 
   T4 – 63/63 – – – – 
110 N status (overall) – 78/56 – – – – 
55    N0 – 76/56 – – – – 
15    N1 – 93/53 – – – – 
35    N2 – 77/57 – – – – 
   N3 – 60/60 – – – – 
129 M status (overall) – 92/87 – – – – 
110    M0 – 93/88 – – – – 
19    M1 – 89/79 – – – – 
Oturai 2004 ( 56 )  84 Detection of primary lung lesion       
    gPET vs histology 62 82 98 56 78 95 
     PET vs histology 62 81 100 50 76 100 
67 Regional lymph nodes (N0 vs N1/N2/N3)       
    gPET vs histology 27 82 61 90 69 86 
     PET vs histology 27 82 78 84 64 91 
Nomori 2004 ( 54 )  564 lymph nodes Mediastinal lymph node involvement       
    PET vs histology – 97 78 98 74 98 
Verhagen 2004 ( 53 )  66 Mediastinal lymph node status (N0 vs N1/N2/N3)       
     PET vs histology – – 58 90 83 71 
Halpern 2005 ( 57 )  36 Mediastinal lymph node status (N0 vs N1/N2/N3)       
     PET vs histology – 69 50 77 45 80 
    Integrated PET–CT vs histology – 78 60 85 60 85 
 T stage       
     PET vs histology – 67 – – – – 
    Integrated PET–CT vs histology – 97 – – – – 
 TNM stage       
     PET vs histology – 57 – – – – 
    Integrated PET–CT vs histology – 83 – – – – 
Shim 2005 ( 58 )   Integrated PET–CT vs histology       
    Mediastinal lymph node status – 84 85 84 – – 
    T stage – 86 – – – – 
    Overall stage – 87 – – – – 
    Stage I – 89 – – – – 
    Stage II – 94 – – – – 
    Stage III – 71 – – – – 
Pozo-Rodriguez 2005 ( 59 )   Mediastinal lymph node status (N0/N1 vs N2/N3)       
132     PET vs histology 28 77 81 76 56 91 
     PET and helical CT vs histology 28 65 92 55 43 95 
First author (reference) No. of patients  Test † Prev % Acc % Se % Sp % PPV % NPV % 
Trials included in the ICES report ( 19 )  
Reed 2003 ( 45 )   Detection of distant metastases       
287     PET vs biopsy/additional imaging/judgment of the surgeon ‡ /6-mo follow-up  90 83 90 36 99 
302 Staging mediastinal (N0/N1 vs N2/N3) disease       
    PET vs histology 78 61 84 56 87 78 
Kahn 2004 ( 46 )  157 Primary lung lesion       
    Visual PET vs histology/12-mo follow-up – – 96 71 92 83 
    SUV vs histology/12-mo follow-up – – 90 80 – – 
128 Hilar/mediastinal lymph nodes       
    PET vs histology – – 81 77 53 93 
139 Detecting stage <IIIB vs IIIB/IV       
    PET vs histology or CT or MRI or bone scintigraphy – – 63 84 – – 
Saunders 1999 ( 39 )  84 Staging mediastinal (N0/N1 vs N2/N3) disease       
    PET vs histology 21 92 71 97 86 93 
Vesselle 2002 ( 41 )  118 Staging mediastinal (N0/N1 vs N2/N3) disease       
    PET vs histology 36 91 81 96 92 90 
Poncelet 2001 ( 43 )  62 Staging mediastinal (N0/N1 vs N2/N3) disease       
    PET vs histology 15 82 67 85 43 94 
Pieterman 2000 ( 40 )  102 Detection of distant metastases       
    PET vs histology – – 82 93 – – 
 Detection of mediastinal (N0/N1 vs N2/N3) disease       
    PET vs histology 31 87 91 86 74 95 
    CT and PET vs histology 31 88 94 86 75 97 
Gupta 1999 ( 37 )  Lymph nodes 126 Detection of mediastinal (N0/N1 vs N2/N3) disease       
   PET vs histology 40 94 93 94 92 94 
Gupta 2000 ( 38 )  Lymph nodes Staging mediastinal metastases       
168    PET vs histology – 94 96 93 – – 
53     Lymph nodes <1 cm – 92 80 95 – – 
107     Lymph nodes 1–3 cm – 95 100 91 – – 
    Lymph nodes >3 – 88 100 75 – – 
Bury 1998 ( 51 )   Detection of bone metastases       
110    PET vs bone scan, histology, additional imaging – 96 90 98 90 98 
Bury 1996 ( 34 ) §  Detection of mediastinal (N0 vs N1/N2/N3) disease       
50    PET vs histology 58 84 83 86 89 78 
Chin 1995 ( 35 )   Detection of N2 status       
30    PET vs histology 30 80 78 81 64 89 
 Primary lung lesion       
    PET vs histology – 89 94 33 94 33 
Stokkel 1999 ( 36 )  Lymph nodes 187 Mediastinal lymph node involvement (N0/N1 vs N2)       
   PET vs histology – 96 90 97 85 98 
Albes 2002 ( 42 )  38 Primary tumor       
    T0: PET vs histology – – 67 100 100 – 
    T1/2: PET vs histology – – 79 83 92 – 
    T3: PET vs histology – – 83 88 56 – 
    T4: PET vs histology – – 67 89 33 – 
38 Mediastinal lymph node involvement       
    N0: PET vs histology – – 89 86 84 – 
    N1/2: PET vs histology – – 71 86 80 – 
    N3: PET vs Histology – – 80 94 67 – 
Lardinois 2003 ( 44 )  40  Tumor stage ‖       
   PET alone – 40 – – – – 
   Visual correlation of PET and CT – 65 – – – – 
   Integrated PET–CT – 88 – – – – 
Node stage ‖       
   PET alone – 49 – – – – 
   Visual correlation of PET and CT – 59 – – – – 
   Integrated PET–CT – 81 – – – – 
Trials published after completion of the ICES review 
Halter 2004 ( 52 )  116 Lymph node status (N0 vs N1/N2/N3) 71 89 88 91 96 76 
155 Primary tumor 75 91 91 90 96 78 
  Stage PET–CT vs PET 
Cerfolio 2004 ( 55 )  10    0 – 90/70 – – – – 
42    I – 52/33 – – – – 
17    II – 70/36 – – – – 
23    IIIA – 70/48 – – – – 
   IIIB – 56/33 – – – – 
19    IV – 89/84 – – – – 
91 T status (overall) – 70/47 – – – – 
11    T0 – 100/81 – – – – 
21    T1 – 76/57 – – – – 
39    T2 – 65/41 – – – – 
12    T3 – 58/8 – – – – 
   T4 – 63/63 – – – – 
110 N status (overall) – 78/56 – – – – 
55    N0 – 76/56 – – – – 
15    N1 – 93/53 – – – – 
35    N2 – 77/57 – – – – 
   N3 – 60/60 – – – – 
129 M status (overall) – 92/87 – – – – 
110    M0 – 93/88 – – – – 
19    M1 – 89/79 – – – – 
Oturai 2004 ( 56 )  84 Detection of primary lung lesion       
    gPET vs histology 62 82 98 56 78 95 
     PET vs histology 62 81 100 50 76 100 
67 Regional lymph nodes (N0 vs N1/N2/N3)       
    gPET vs histology 27 82 61 90 69 86 
     PET vs histology 27 82 78 84 64 91 
Nomori 2004 ( 54 )  564 lymph nodes Mediastinal lymph node involvement       
    PET vs histology – 97 78 98 74 98 
Verhagen 2004 ( 53 )  66 Mediastinal lymph node status (N0 vs N1/N2/N3)       
     PET vs histology – – 58 90 83 71 
Halpern 2005 ( 57 )  36 Mediastinal lymph node status (N0 vs N1/N2/N3)       
     PET vs histology – 69 50 77 45 80 
    Integrated PET–CT vs histology – 78 60 85 60 85 
 T stage       
     PET vs histology – 67 – – – – 
    Integrated PET–CT vs histology – 97 – – – – 
 TNM stage       
     PET vs histology – 57 – – – – 
    Integrated PET–CT vs histology – 83 – – – – 
Shim 2005 ( 58 )   Integrated PET–CT vs histology       
    Mediastinal lymph node status – 84 85 84 – – 
    T stage – 86 – – – – 
    Overall stage – 87 – – – – 
    Stage I – 89 – – – – 
    Stage II – 94 – – – – 
    Stage III – 71 – – – – 
Pozo-Rodriguez 2005 ( 59 )   Mediastinal lymph node status (N0/N1 vs N2/N3)       
132     PET vs histology 28 77 81 76 56 91 
     PET and helical CT vs histology 28 65 92 55 43 95 
*

Prev = prevalence; Acc = accuracy; Se = sensitivity; Sp = specificity; PPV = positive predictive value; NPV = negative predictive value; ICES = Institute for Clinical and Evaluative Sciences; PET = 18 fluorodeoxyglucose positron emission tomography; SUV = standardized uptake value; CT = computed tomography; MRI = magnetic resonance imaging; gPET = gamma PET; TNM = tumor–node–metastasis.

Staging according to (50).

Judgment of the surgeon was not specified in the protocol as a confirmatory procedure.

§

Values were calculated based on results given; however, they are different from what the study reported.

Results that were correct but based on equivocal evidence were not included in calculating diagnostic accuracy. False positives (FP) and false negatives (FN) were not reported.

Results of Primary Studies of 18Fluorodeoxyglucose Positron Emission Tomography Utility in Non–Small Cell Lung Cancer Staging

Three randomized clinical trials have evaluated the value of preoperative PET assessment for NSCLC ( 47–49 ), two of which ( 48 , 49 ) were included in the ICES report ( Table 5 ). The PLUS (PET in Lung Cancer Staging) multicenter trial ( 48 ) randomly assigned 188 patients with suspected lung cancer to either PET followed by further standard diagnostic and therapeutic procedures or standard diagnostic and therapeutic procedures alone. Half of the patients had a definite diagnosis of NSCLC, and 70% of the patients in each group had clinical stage I–II disease at baseline ( 50 ). The primary outcome was the number of futile thoracotomies. Thoracotomy was regarded as futile if the patient had benign disease, exploratory thoracotomy only, pathological stage IIIA (mediastinal node positive) or IIIB disease, or postoperative relapse or death within 12 months of randomization. The addition of PET to conventional workup led to a 51% (95% CI = 32 to 80, P = .003) relative reduction in futile thoracotomies (from 41% in the conventional workup arm to 21% in the conventional plus PET arm) and prevented unnecessary surgery in 20% of patients with suspected NSCLC. Twenty-seven percent of patients in the combined PET and conventional workup were reclassified as a higher stage as a result of the PET evaluation, compared with 12% of patients in the conventional workup group.

Table 5

Outcomes of randomized clinical trials studying preoperative staging with 18 fluorodeoxyglucose positron emission tomography *

First author (reference) No. of patients  Tests ‡ Method of analysis Outcome Results 
Trials included in the ICES report ( 19 )  
     Conventional workup Conventional workup + PET P value † 
Van Tinteren 2002 ( 48 )  188 Suspected or proven NSCLC judged to be medically operable and potentially resectable based on clinical staging Visual correlation with CT Futile thoracotomies    
   Relative Reduction 51% (95% CI = 32 to 80) .003  
   Absolute difference 41%−21% = 20% NR  
   Stage I/II ‡ 46% (31/68) 29% (8/28) NR 
   Stage III ‡ 29% (8/28) 11% (3/27) NR 
Viney 2004 ( 49 )  183 Histologically or cytologically proven stage I–II NSCLC Visual analysis Thoracotomy rate 98% (90/92) 96% (87/91) .2 
1-y survival 77% (95% CI = 67 to 85) 80% (95% CI = 70 to 87) NR 
Trials published after completion of the ICES review 
     Conventional workup PET upfront workup P value  
Herder 2006 ( 47 )  465 Suspected NSCLC based on history, physical exam and chest x-ray Excluded patients with overt disseminated disease at first presentation Visual analysis Mean of all tests 7.88 (SD = 1.95) 7.90 (SD = 1.88) .90 
Mean of functional tests 2.13 (SD = 0.91) 2.23 (SD = 0.94) .27 
Mean of staging tests 4.75 (SD = 0.91) 4.69 (SD = 1.52) .66 
Mean of imaging tests 3.74 (SD = 1.16) 3.80 (SD = 1.09) .54 
Mean of invasive tests 0.96 (SD = 0.95) 0.85 (SD = 0.79) .18 
≥1 invasive test for N staging, No. (%) 92 (39%) 52 (22%) <.0001 
Thoracotomy, No. (%) 88 (38%) 96 (41%) .43 
Mediastinoscopy, No. (%) 79 (34%) 31 (13%)  >.05 § 
Proportion of patients requiring at least 3 tests (%) 52% 51% .82 
Agreement between clinical and final stage, κ 0.85 (95% CI 0.80 to 0.90) κ = 0.78 (95% CI 0.72 to 0.84) .073 
Median time to diagnosis (days) 23 14 <.0001 
First author (reference) No. of patients  Tests ‡ Method of analysis Outcome Results 
Trials included in the ICES report ( 19 )  
     Conventional workup Conventional workup + PET P value † 
Van Tinteren 2002 ( 48 )  188 Suspected or proven NSCLC judged to be medically operable and potentially resectable based on clinical staging Visual correlation with CT Futile thoracotomies    
   Relative Reduction 51% (95% CI = 32 to 80) .003  
   Absolute difference 41%−21% = 20% NR  
   Stage I/II ‡ 46% (31/68) 29% (8/28) NR 
   Stage III ‡ 29% (8/28) 11% (3/27) NR 
Viney 2004 ( 49 )  183 Histologically or cytologically proven stage I–II NSCLC Visual analysis Thoracotomy rate 98% (90/92) 96% (87/91) .2 
1-y survival 77% (95% CI = 67 to 85) 80% (95% CI = 70 to 87) NR 
Trials published after completion of the ICES review 
     Conventional workup PET upfront workup P value  
Herder 2006 ( 47 )  465 Suspected NSCLC based on history, physical exam and chest x-ray Excluded patients with overt disseminated disease at first presentation Visual analysis Mean of all tests 7.88 (SD = 1.95) 7.90 (SD = 1.88) .90 
Mean of functional tests 2.13 (SD = 0.91) 2.23 (SD = 0.94) .27 
Mean of staging tests 4.75 (SD = 0.91) 4.69 (SD = 1.52) .66 
Mean of imaging tests 3.74 (SD = 1.16) 3.80 (SD = 1.09) .54 
Mean of invasive tests 0.96 (SD = 0.95) 0.85 (SD = 0.79) .18 
≥1 invasive test for N staging, No. (%) 92 (39%) 52 (22%) <.0001 
Thoracotomy, No. (%) 88 (38%) 96 (41%) .43 
Mediastinoscopy, No. (%) 79 (34%) 31 (13%)  >.05 § 
Proportion of patients requiring at least 3 tests (%) 52% 51% .82 
Agreement between clinical and final stage, κ 0.85 (95% CI 0.80 to 0.90) κ = 0.78 (95% CI 0.72 to 0.84) .073 
Median time to diagnosis (days) 23 14 <.0001 
*

ICES = Institute for Clinical and Evaluative Sciences; PET = 18 fluorodeoxyglucose positron emission tomography; NSCLC = non–small cell lung cancer; CT = computed tomography; CI = confidence interval; NR = not reported; NR = not reported; SD = standard deviation, κ = Kappa.

All P values are two-sided.

Staging according to (50).

§

Abstract reported that mediastinoscopies occurred statistically significantly less often in the PET arm.

An Australian multicenter trial ( 49 ) randomly assigned 183 patients with histologically or cytologically proven stage I–II NSCLC to conventional workup, either with or without PET imaging ( 49 ). The primary endpoint was the proportion of patients undergoing thoracotomy. PET led to reclassification to a higher stage of 24 patients and confirmed staging in 61 patients. There was no statistically significant difference between the trial arms in the number of thoracotomies performed ( P = .2), and PET resulted in changes in patient management in only 14% of patients. PET could have altered patient management in 11 additional patients (12.6%).

The Dutch cooperative randomized study of Herder et al. ( 47 ) randomly assigned 465 patients with suspected NSCLC to either traditional staging workup or a PET scan. PET was followed by histologic and or cytologic verification of lesions or further imaging and follow-up. The primary outcome was the number of tests and procedures to finalize staging and define operability. No statistically significant difference was found between the two groups for the mean number of tests to finalize staging. Secondary outcomes were the length of the diagnostic process, morbidity associated with staging procedures, and cost. The median time to diagnosis was statistically significantly shorter for the PET group (14 days versus 23 days, P <.0001). There was no difference in the morbidity associated with the staging procedures. The mean number of functional tests, noninvasive procedures, invasive procedures, and thoracotomies did not differ between the arms; however, the percentage of patients who needed more than one invasive test for lymph node staging and the numbers of mediastinoscopies were statistically significantly lower for the PET group. However, it is not clear from the report whether these outcomes were a priori or post hoc comparisons or whether statistical analyses were adjusted for multiple comparisons.

Results of Primary Studies of 18Fluorodeoxyglucose Positron Emission Tomography Accuracy in Non–Small Cell Lung Cancer Staging

Twenty-two prospective observational studies ( 34–46 , 51–59 ), 14 of which were included in ICES ( 34–46 , 51 ), examined the use of PET in staging primary NSCLC ( Tables 3 and 4 ). Most studies enrolled patients with potentially resectable NSCLC and used histopathologic results as the reference standard. The protocols for nodal sampling varied between the trials and were not always clearly described. The methods used for reporting PET scans as positive varied, with some studies visually interpreting the scan and others using semiquantitative methods, such as calculating the SUV. PET data were evaluated independently of the reference standard in 20 studies ( 34–46 , 51 , 52 , 55–60 ). PET was included in the reference standard in one study ( 51 ), which could have led to an overestimation of diagnostic accuracy. In four trials ( 37 , 44–46 ), fewer than 100% of patients had confirmation of the diagnosis by the reference standard, which could have led to biased estimates of overall diagnostic accuracy. Eighteen of the studies ( 34–42 , 45 , 46 , 51 , 54–59 ) specified explicit criteria for defining a positive PET test result. Four studies ( 36–38 , 54 ) reported results using lymph nodes as the unit of analysis. The observations in these four studies are not statistically independent in that a patient with one positive lymph node is likely to have other positive lymph nodes, which may bias the estimates of diagnostic accuracy. Results from studies examining staging of the primary tumor were variable, as were the criteria used to determine a positive result (e.g., N0 versus N1/2/3 or N0/N1 versus N2/3). Sensitivity of PET for detecting distant metastases ranged from 82% to 90% and specificity ranged from 90% to 98%. Eight studies reported on the usefulness of PET for detecting unexpected distant metastases ( 37 , 39–41 , 44–46 , 53 ); in these studies, PET detected distant metastases in 4%–17% of patients.

With the introduction of integrated PET–CT diagnostic imaging machines, additional observational studies have been published on the accuracy of this newer imaging technology. Cerfolio et al. ( 55 ) compared integrated PET–CT with dedicated PET for staging in 129 patients with NSCLC. Integrated PET–CT was more accurate than dedicated PET for predicting stage I and II disease and was a better predictor of overall tumor and node status; all differences were statistically significant. Integrated PET–CT was also more accurate overall for detecting N2 and N1 nodes, as well as defining T2, T3, N0, and N1 disease. Lardinois et al. ( 44 ) also compared integrated PET–CT with dedicated PET and found that integrated PET–CT improved the accuracy of tumor and node staging and the detection of metastases. In another comparison of integrated PET–CT with dedicated PET, Halpern et al. ( 57 ) found that integrated PET–CT was more accurate for assigning T stage and had greater accuracy for determining the overall tumor–node–metastasis stage. Shim et al. ( 58 ) compared integrated PET–CT with stand-alone CT and found that integrated PET–CT was statistically significantly more accurate than CT for nodal and overall staging but was not for tumor staging.

Finally, Oturai et al. ( 56 ) compared gamma-camera PET with dedicated PET and found no statistically significant difference for detecting primary pulmonary lesions or evaluating regional lymph nodes between the two techniques. Gamma-camera PET did have reduced sensitivity for detecting lymph nodes as compared with dedicated PET. Overall, the published literature indicates that PET–CT provides greater diagnostic accuracy in the staging of NSCLC than does PET alone.

Primary Non–Small Cell Lung Cancer: Accuracy of 18Fluorodeoxyglucose Positron Emission Tomography for Mediastinal Lymph Node Staging

Findings of Institute for Clinical and Evaluative Sciences

The ICES report concluded that evidence exists that PET is efficacious in predicting the histological status of mediastinal lymph nodes and in detecting pleural involvement and malignant pleural effusion for patients with carcinoma of the lung. The report also concluded that PET is more efficacious than CT in identifying abnormalities in mediastinal lymph nodes.

Results of Systematic Reviews

Fischer et al. ( 23 ) estimated the mean sensitivity and specificity independently for staging metastases in the mediastinum. The mean sensitivities and specificities were 0.83 (SE = 0.02) and 0.96 (SE = 0.01), respectively, for dedicated PET and 0.81 (SE = 0.04) and 0.95 (SE = 0.02), respectively, for gamma-camera PET. The authors concluded that PET is a valuable tool for staging NSCLC and noted that although its use for preoperative staging is strengthened by its high specificity, further examinations in populations with a lower prevalence of NSCLC are still required.

A meta-analysis by Birim et al. ( 21 ) included 17 studies ( 35 , 38–40 , 43 , 60–71 ) that compared PET with CT in detecting mediastinal lymph node metastases. The maximum joint sensitivity and specificity of PET from the SROC curve was 90% (95% CI = 86% to 95%). Birim et al. ( 21 ) concluded that PET was more accurate than CT imaging in detecting mediastinal lymph node metastases. The authors recommended that PET images be correlated with a CT scan because PET has limited ability to determine precise anatomic localization of mediastinal lymph nodes. A meta-analysis by Gould et al. ( 25 ) also concluded that PET is more accurate than CT ( P <.001) for mediastinal staging in patients with potentially resectable NSCLC. For the 32 studies in the Gould et al. (25) meta-analysis in which the patient was the unit of analysis ( 34 , 35 , 39–41 , 43 , 61–63 , 65 , 67–69 , 71–89 ), a maximum joint sensitivity and specificity of PET was calculated from the SROC curve as 86% (95% CI = 84% to 88%), which at a median specificity of 90% would correspond to a sensitivity of 81%. Gould et al. (25) also examined the use of PET for identifying mediastinal metastasis in patients with and without enlarged lymph nodes on CT in a meta-analysis of data from 14 studies ( 34 , 35 , 39 , 40 , 61 , 63 , 65 , 67 , 69 , 71 , 76 , 78 , 79 , 90 ) and found that PET was more sensitive but less specific when the CT scan showed enlarged mediastinal lymph nodes than when it did not. The authors concluded that biopsy should confirm positive PET findings before curative surgery is excluded as a treatment option and that negative PET findings should be interpreted in light of the patient's pretest probability of mediastinal metastases and whether CT reveals enlarged mediastinal nodes ( 25 ).

Results of Primary Studies

Halter et al. ( 52 ) evaluated PET in staging mediastinal lymph nodes in 155 patients with pulmonary tumors. PET was associated with accuracies of 91%, 77%, 95%, and 100% for N0, N1, N2, and N3 disease, respectively. Verhagen et al. ( 53 ) assessed the reliability of PET for staging mediastinal lymph nodes in 66 patients with NSCLC. Although the negative predictive value for staging mediastinal lymph nodes was 71%, the negative predictive value for patients with positive N1 nodes and/or a centrally located primary tumor was only 17%, compared with 96% for patients with negative N1 nodes and a noncentrally located primary tumor ( 53 ). Nomori et al. ( 54 ) measured the size of metastatic foci in lymph nodes for which the PET results were true positives and false negatives to determine the lower size limit of metastatic lymph nodes that PET can detect. Metastatic foci in the lymph nodes with true positive results had a mean size of 10 mm (range 4–18 mm), and those with false negative results had a mean size of 3 mm (range 0.5–9 mm). Lymph nodes with false positive results had a mean size of 12 mm (range 9–16 mm), and those with true positive results had mean size of 10 mm (range 6–15 mm). PET did not detect any metastatic foci smaller than 4 mm. Lardinois et al. ( 44 ) compared integrated PET–CT with dedicated PET and found that integrated PET–CT improved the accuracy of staging mediastinal metastases. Pozo-Rodriguez et al. ( 59 ) evaluated contrast-enhanced helical CT and PET, both alone and combined. Helical CT and PET performed similarly in the diagnostic accuracy of mediastinal staging, although the authors concluded that both tests are conditionally dependent and provide complementary information ( 59 ).

Primary Non–Small Cell Lung Cancer: Accuracy of 18Fluorodeoxyglucose Positron Emission Tomography for Extrathoracic Staging

Findings of Evidence-Based Reports

Although the ICES report did not address extrathoracic staging with PET, this topic was addressed in four other evidence-based reports. The Health Technology Board for Scotland report ( 22 ) evaluated 19 studies on the detection of distant metastases ( 34 , 37 , 39 , 40 , 51 , 60 , 63 , 69 , 84 , 87 , 91–99 ) and concluded that there is evidence that PET may be useful in staging patients believed to be free of distant metastases, especially in the detection of adrenal gland and bone metastases, but recommended that this be confirmed in controlled trials. In addition, a review by the National Institute for Clinical Excellence ( 26 ) provided an SROC curve for the detection of distant metastases and calculated a summary sensitivity of 93% and specificity of 96%. This review also found that an average of 15% of patients had unexpected distant metastases detected by PET.

Results of Primary Studies

Only one prospective study reported on the staging of extrathoracic metastases. Verhagen et al. ( 53 ) assessed the value of PET in detecting extrathoracic metastases in 72 patients with NSCLC. PET detected extrathoracic metastases in 15% (10/66) of patients in whom conventional staging showed no evidence of metastases.

Staging of Small-Cell Lung Cancer with 18Fluorodeoxyglucose Positron Emission Tomography

Results of Primary Studies

Three prospective studies ( 14–16 ) examined the use of PET in staging primary SCLC ( Table 6 ). The reference standards varied among the studies, and none of the studies confirmed all lesions with histologic results. Brink et al. ( 15 ) confirmed only 20% of lesions with histopathologic results. PET was evaluated independently of the reference standard in two of the studies ( 14 , 15 ). Only one study clearly specified explicit criteria for defining a positive PET test result ( 15 ). Sensitivity for staging extensive- versus limited-stage disease ranged from 89% to 100% and specificity ranged from 78% to 95%. Chin et al. ( 16 ) compared PET with conventional staging and reported that PET agreed with conventional staging in 15 of 18 cases (83%). PET showed more extensive disease in two of the three patients for which PET and conventional staging disagreed. These data suggest that total-body PET may be useful in the staging of SCLC.

Table 6

Diagnostic accuracy of 18 fluorodeoxyglucose positron emission tomography for staging primary small-cell lung cancer *

Trial (reference) No. of patients Eligibility Method of analysis Test Prev % Acc % Se % Sp % PPV % NPV % 
Bradley ( 14 )  24 Histologically or cytologically confirmed limited SCLC based on conventional imaging Visual and SUV Staging extensive vs limited disease       
PET vs biopsy and additional imaging 96 100 95 67 100 
Chin ( 16 )  18 Newly diagnosed SCLC NR Staging extensive vs limited disease       
PET vs conventional staging 50 83 89 78 80 88 
Brink ( 15 )   Histologically confirmed SCLC Visual PET vs histology or consensus       
120 Staging extensive vs limited disease 63 99 100 98 99 100 
118 Detection of lymph node metastases 45 99 100 98 98 100 
70 Detection of distant metastases (except brain) 66 96 98 92 96 96 
91 Detection of brain metastases 14 90 46 97 75 92 
Trial (reference) No. of patients Eligibility Method of analysis Test Prev % Acc % Se % Sp % PPV % NPV % 
Bradley ( 14 )  24 Histologically or cytologically confirmed limited SCLC based on conventional imaging Visual and SUV Staging extensive vs limited disease       
PET vs biopsy and additional imaging 96 100 95 67 100 
Chin ( 16 )  18 Newly diagnosed SCLC NR Staging extensive vs limited disease       
PET vs conventional staging 50 83 89 78 80 88 
Brink ( 15 )   Histologically confirmed SCLC Visual PET vs histology or consensus       
120 Staging extensive vs limited disease 63 99 100 98 99 100 
118 Detection of lymph node metastases 45 99 100 98 98 100 
70 Detection of distant metastases (except brain) 66 96 98 92 96 96 
91 Detection of brain metastases 14 90 46 97 75 92 
*

Prev = prevalence; Acc = accuracy; Se = sensitivity; Sp = specificity; PPV = positive predictive value; NPV = negative predictive value; SCLC = small-cell lung cancer; SUV = standardized uptake value; NR = not reported; PET = 18 fluorodeoxyglucose positron emission tomography.

Integrating 18Fluorodeoxyglucose Positron Emission Tomography into the Clinical Management of Patients with Lung Cancer

For patients with an established diagnosis of lung cancer (NSCLC or SCLC), accurate staging is essential to determine appropriate treatment decisions. Conventional staging procedures are imperfect in their ability to define those patients with the potential for cure with surgery or locoregional chemoradiotherapy approaches. PET has the potential to improve staging accuracy, but health technology assessment reports have concluded that the amount of improvement in diagnostic accuracy of PET in staging NSCLC is difficult to define due to the variations in study quality and the lack of direct evidence on whether PET improves patient outcomes ( 22 , 26 ). Meta-analyses found sensitivity to range from 81% to 90% and specificity to range from 89% to 90% for the distinction between N0-1 and N2-3 patients ( 21 , 25 , 100 ). Accuracy studies havehad similar results, with PET results being superior to CT imaging for mediastinal staging. Studies that interpret PET images with CT results have higher accuracy than when PET is interpreted independently ( 40 , 44 ). However, results from Nomori et al. ( 54 ) indicate that PET is unable to detect metastatic foci smaller than 4 mm. On the other hand, false positives with respect to staging the mediastinum can also occur with infection and inflammation. The available evidence indicates that a positive PET scan of the mediastinum must be confirmed histologically or cytologically to ensure that patients are not denied potentially curative surgery. It should also be recognized that false negative results can occur when the primary tumor obscures mediastinal lymph nodes or the metastatic foci are small.

PET has been found to have high accuracy (89%–96%) for detecting distant metastases and has detected extrathoracic metastases in patients in whom conventional imaging showed no evidence of distant metastases ( 99 ). The role of PET in the evaluation of distant metastases appears to be greatest for adrenal and bone metastases. PET is not useful for detection of brain metastases due to the high glucose uptake of normal brain tissue.

A number of factors could contribute to the apparent discrepancy between two of the trials evaluating the value of preoperative PET assessment. One factor is the difference in the patient populations included in the trials. The PLUS trial ( 48 ) entered patients with both suspected and proven NSCLC based on clinical and not pathologic assessment. As a result, this study included patients with both benign and malignant lesions, whereas the Australian trial ( 49 ) only included patients with histologically or cytologically proven NSCLC prior to randomization. Moreover, 29% of patients in the PLUS trial had clinical stage III disease on entry to the study, whereas the Australian trial only included patients demonstrating clinical stage I or II disease. The approach to the management of patients with early-stage lung cancer also differed between the two studies. Patients in the Australian trial with stage IIIA disease underwent surgery, whereas thoracotomy was considered to be futile in the PLUS trial if the patients had stage IIIA/N2 disease. Finally, the definition of a futile thoracotomy (benign disease, exploratory thoracotomy only, pathological stage IIIA (mediastinal node positive) or IIIB disease or postoperative relapse or death within 12 months of randomization) in the PLUS study differed from the Australian trial definition of avoided thoracotomies (patients who were able to avoid thoracotomy as determined at the discretion of the surgeon). As a result, the different designs of these studies and their contradicting results contribute to the confusion concerning the clinical utility of PET in the management of patients with early-stage lung cancer.

PET has not been studied as extensively in staging patients with SCLC. PET appears to have good accuracy (83%–99%) in differentiating extensive- versus limited-stage SCLC ( 14–16 ), which could help in deciding which patients would be the best candidates for combined modality (chemoradiotherapy) therapy in limited-stage disease.

Evaluation of new imaging techniques is important because high costs, an increasing demand for healthcare, and limited budgets have resulted in a need to prioritize the implementation of new techniques ( 101 ). PET scanning could improve the results of surgical therapy for early-stage lung cancer by excluding patients from surgical resection who have evidence of metastatic disease that is not evident by standard preoperative staging procedures. Similarly, the results for the management of locally advanced disease might also be expected to improve because of the addition of patients with minimal contralateral nodal disease that precluded surgery. Moreover, if PET imaging spares patients from the potential morbidity and risk of mortality from an unnecessary surgical procedure or chemoradiotherapeutic intervention, it would not only have a substantial impact on individual patients but allow for more efficient and effective utilization of limited health care resources.

One of the limitations of this systematic review of PET in lung cancer is that the conclusions that can be drawn are constrained by the available evidence, and the available evidence may not be directly relevant to current practice. For example, the type of PET device used in the published trials impacts on the generalizability of the findings from the review. Some studies reported using gamma cameras or coincidence imaging devices, which are rapidly being replaced by higher precision scanners (e.g., PET/CT hybrid). Although coincidence scanners are no longer marketed, these devices continue to be used in some settings. We do not consider this to be a serious limitation of this review as many of the trials included in this review have been published since 2000 and have evaluated devices that are in standard use today.

Future research is needed to determine not only if PET should be integrated into the standard staging and diagnostic process of lung cancer but also how PET would be incorporated into the staging algorithm. The Ontario Clinical Oncology Group is currently conducting two prospective randomized controlled trials on the use of PET, and the province of Ontario has established a registry study of PET in patients with SPN.

Fine needle aspiration biopsy should continue to be the first-line diagnostic approach in the workup of SPN because of its ability to provide a definitive diagnosis in a high percentage of patients and its relative safety. However, based on this review, PET can be considered to be useful in those situations in which a biopsy is inconclusive or contraindicated. For potential surgical candidates, it is essential that PET-positive mediastinal lesions be confirmed histologically or cytologically by mediastinoscopy or other diagnostic procedure to verify that PET-positive mediastinal lesions are due to cancer. Tissue confirmation is essential to ensure that patients are not denied potentially curative surgery. Solitary extrathoracic sites of PET positivity should also be confirmed to be metastatic if at all possible to ensure that patients are not inappropriately denied the chance of potentially curative therapy.

References

(1)
Som
P
Atkins
HL
Bandoypadhyay
D
Fowler
JS
MacGregor
RR
Matsui
K
, et al.  . 
A fluorinated glucose analog, 2-fluoro-2-deoxy-D-glucose (F-18): nontoxic tracer for rapid tumor detection
J Nucl Med
 , 
1980
, vol. 
21
 (pg. 
670
-
5
)
(2)
Warburg
O
On the metabolism of tumors in the body
Metabolism of tumors
 , 
1930
London
Constable
(pg. 
254
-
70
)
(3)
Hatanaka
M
Transport of sugars in tumor cell membranes
Biochim Biophys Acta
 , 
1974
, vol. 
355
 (pg. 
77
-
104
)
(4)
Humm
JL
Rosenfeld
A
Del
GA
From PET detectors to PET scanners
Eur J Nucl Med Mol Imaging
 , 
2003
, vol. 
30
 (pg. 
1574
-
97
)
(5)
Narin
Y
Urhan
M
Canpolat
N
Vardereli
E
Bayhan
H
Lesion detectability and clinical effectiveness of dual-head coincidence gamma camera imaging in comparison with dedicated PET systems in tumour patients
J Int Med Res
 , 
2007
, vol. 
35
 (pg. 
467
-
73
)
(6)
Schelper
LF
Gosink
HJ
Meller
B
Richter
E
Baehre
M
Performance comparison of two dual headed coincidence cameras of the first and latest generation
Med Phys
 , 
2006
, vol. 
33
 (pg. 
329
-
36
)
(7)
Townsend
DW
Physical principles and technology of clinical PET imaging
Ann Acad Med Singapore
 , 
2004
, vol. 
33
 (pg. 
133
-
45
)
(8)
Young
H
Baum
R
Cremerius
U
Herholz
K
Hoekstra
O
Lammertsma
AA
, et al.  . 
Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. European Organization for Research and Treatment of Cancer (EORTC) PET Study Group
Eur J Cancer
 , 
1999
, vol. 
35
 (pg. 
1773
-
82
)
(9)
Beyer
T
Townsend
DW
Brun
T
Kinahan
PE
Charron
M
Roddy
R
, et al.  . 
A combined PET/CT scanner for clinical oncology
J Nucl Med
 , 
2000
, vol. 
41
 (pg. 
1369
-
79
)
(10)
Kluetz
PG
Meltzer
CC
Villemagne
VL
Kinahan
PE
Chander
S
Martinelli
MA
, et al.  . 
Combined PET/CT imaging in oncology. Impact on patient management
Clin Positron Imaging
 , 
2000
, vol. 
3
 (pg. 
223
-
30
)
(11)
Hoekstra
CJ
Paglianiti
I
Hoekstra
OS
Smit
EF
Postmus
PE
Teule
GJ
, et al.  . 
Monitoring response to therapy in cancer using [18F]-2-fluoro-2-deoxy-D-glucose and positron emission tomography: an overview of different analytical methods
Eur J Nucl Med
 , 
2000
, vol. 
27
 (pg. 
731
-
43
)
(12)
Thie
JA
Understanding the standardized uptake value, its methods, and implications for usage
J Nucl Med
 , 
2004
, vol. 
45
 (pg. 
1431
-
4
)
(13)
Zanzonico
P
Positron emission tomography: a review of basic principles, scanner design and performance, and current systems
Semin Nucl Med
 , 
2004
, vol. 
34
 (pg. 
87
-
111
)
(14)
Bradley
JD
Dehdashti
F
Mintun
MA
Govindan
R
Trinkaus
K
Siegel
BA
Positron emission tomography in limited-stage small-cell lung cancer: a prospective study
J Clin Oncol
 , 
2004
, vol. 
22
 (pg. 
3248
-
54
)
(15)
Brink
I
Schumacher
T
Mix
M
Ruhland
S
Stoelben
E
Digel
W
, et al.  . 
Impact of [18F]FDG-PET on the primary staging of small-cell lung cancer
Eur J Nucl Med Mol Imaging
 , 
2004
, vol. 
31
 (pg. 
1614
-
20
)
(16)
Chin
R
Jr
McCain
TW
Miller
AA
Dunagan
DP
Acostamadiedo
J
Douglas
CL
, et al.  . 
Whole body FDG-PET for the evaluation and staging of small cell lung cancer: a preliminary study
Lung Cancer
 , 
2002
, vol. 
37
 (pg. 
1
-
6
)
(17)
Tas
F
Aydiner
A
Topuz
E
Camlica
H
Saip
P
Eralp
Y
Factors influencing the distribution of metastases and survival in extensive disease small cell lung cancer
Acta Oncol
 , 
1999
, vol. 
38
 (pg. 
1011
-
5
)
(18)
Institute for Clinical Evaluative Sciences (ICES)
Health technology assessment of positron emission tomography (PET) in oncology—a systematic review
 
ICES Web site; 2001 [cited November 11, 2004] Available at: http://www.ices.on.ca/file/Health_Technology_Assessment-Pet_May-2001.pdf . [Last accessed: October 25, 2007.]
(19)
Institute for Clinical Evaluative Sciences (ICES)
Health technology assessment of positron emission tomography (PET) in oncology—a systematic review. ICES investigative report. Quarterly update—April 2004
 
ICES Web site; 2004 [cited November 11, 2004]. Available at: http://www.ices.on.ca/file/Pet_report_apr_2004[1].pdf . [Last accessed: October 25, 2007.]
(20)
Nomori
H
Watanabe
K
Ohtsuka
T
Naruke
T
Suemasu
K
Uno
K
Visual and semiquantitative analyses for F-18 fluorodeoxyglucose PET scanning in pulmonary nodules 1 cm to 3 cm in size
Ann Thorac Surg
 , 
2005
, vol. 
79
 (pg. 
984
-
8
)
(21)
Birim
O
Kappetein
AP
Stijnen
T
Bogers
AJ
Meta-analysis of positron emission tomographic and computed tomographic imaging in detecting mediastinal lymph node metastases in nonsmall cell lung cancer
Ann Thorac Surg
 , 
2005
, vol. 
79
 (pg. 
375
-
82
)
(22)
Bradbury
I
Bonnell
E
Boynton
J
Cummins
E
Facey
K
Iqbal
K
Positron emission tomography (PET) imaging in cancer management
Health Technology Assessment Report No.: 2
 , 
2002
Glasgow (Scotland)
Health Technology Board for Scotland
(23)
Fischer
BM
Mortensen
J
Hojgaard
L
Positron emission tomography in the diagnosis and staging of lung cancer: a systematic, quantitative review
Lancet Oncol
 , 
2001
, vol. 
2
 (pg. 
659
-
66
)
(24)
Gould
MK
Maclean
CC
Kuschner
WG
Rydzak
CE
Owens
DK
Accuracy of positron emission tomography for diagnosis of pulmonary nodules and mass lesions: a meta-analysis
JAMA
 , 
2001
, vol. 
285
 (pg. 
914
-
24
)
(25)
Gould
MK
Kuschner
WG
Rydzak
CE
Maclean
CC
Demas
AN
Shigemitsu
H
, et al.  . 
Test performance of positron emission tomography and computed tomography for mediastinal staging in patients with non-small-cell lung cancer: a meta-analysis
Ann Intern Med
 , 
2003
, vol. 
139
 (pg. 
879
-
92
)
(26)
National Institute for Clinical Excellence (NICE)
Lung cancer: the diagnosis and treatment of lung cancer
Clinical Guideline No.: 24
  
NICE Web site. 2005 [cited February 25, 2005]. Available at: www.nice.org.uk/CG024NICEguideline . [Last accessed: October 25, 2007.]
(27)
Bury
T
Dowlati
A
Paulus
P
Corhay
JL
Benoit
T
Kayembe
JM
, et al.  . 
Evaluation of the solitary pulmonary nodule by positron emission tomography imaging
Eur Respir J
 , 
1996
, vol. 
9
 (pg. 
410
-
4
)
(28)
Croft
DR
Trapp
J
Kernstine
K
Kirchner
P
Mullan
B
Galvin
J
, et al.  . 
FDG-PET imaging and the diagnosis of non-small cell lung cancer in a region of high histoplasmosis prevalence
Lung Cancer
 , 
2002
, vol. 
36
 (pg. 
297
-
301
)
(29)
Imdahl
A
Jenkner
S
Brink
I
Nitzsche
E
Stoelben
E
Moser
E
, et al.  . 
Validation of FDG positron emission tomography for differentiation of unknown pulmonary lesions
Eur J Cardiothorac Surg
 , 
2001
, vol. 
20
 (pg. 
324
-
9
)
(30)
Lowe
VJ
Fletcher
JW
Gobar
L
Lawson
M
Kirchner
P
Valk
P
, et al.  . 
Prospective investigation of positron emission tomography in lung nodules
J Clin Oncol
 , 
1998
, vol. 
16
 (pg. 
1075
-
84
)
(31)
Walter
SD
Properties of the summary receiver operating characteristic (SROC) curve for diagnostic test data
Stat Med
 , 
2002
, vol. 
21
 (pg. 
1237
-
56
)
(32)
Nomori
H
Watanabe
K
Ohtsuka
T
Naruke
T
Suemasu
K
Uno
K
Evaluation of F-18 fluorodeoxyglucose (FDG) PET scanning for pulmonary nodules less than 3 cm in diameter, with special reference to the CT images
Lung Cancer
 , 
2004
, vol. 
45
 (pg. 
19
-
27
)
(33)
Nomori
H
Kosaka
N
Watanabe
K
Ohtsuka
T
Naruke
T
Kobayashi
T
, et al.  . 
11C-acetate positron emission tomography imaging for lung adenocarcinoma 1 to 3 cm in size with ground-glass opacity images on computed tomography
Ann Thorac Surg
 , 
2005
, vol. 
80
 (pg. 
2020
-
5
)
(34)
Bury
T
Paulus
P
Dowlati
A
Corhay
JL
Weber
T
Ghaye
B
, et al.  . 
Staging of the mediastinum: value of positron emission tomography imaging in non-small cell lung cancer
Eur Respir J
 , 
1996
, vol. 
9
 (pg. 
2560
-
4
)
(35)
Chin
R
Jr
Ward
R
Keyes
JW
Choplin
RH
Reed
JC
Wallenhaupt
S
, et al.  . 
Mediastinal staging of non-small-cell lung cancer with positron emission tomography
Am J Respir Crit Care Med
 , 
1995
, vol. 
152
 
Pt 1
(pg. 
2090
-
6
)
(36)
Stokkel
MP
Bakker
PF
Heine
R
Schlosser
NJ
Lammers
JW
Van Rijk
PP
Staging of lymph nodes with FDG dual-headed PET in patients with non-small-cell lung cancer
Nucl Med Commun
 , 
1999
, vol. 
20
 (pg. 
1001
-
7
)
(37)
Gupta
NC
Graeber
GM
Rogers
JS
Bishop
HA
Comparative efficacy of positron emission tomography with FDG and computed tomographic scanning in preoperative staging of non-small cell lung cancer
Ann Surg
 , 
1999
, vol. 
229
 (pg. 
286
-
91
)
(38)
Gupta
NC
Graeber
GM
Bishop
HA
Comparative efficacy of positron emission tomography with fluorodeoxyglucose in evaluation of small (<1 cm), intermediate (1 to 3 cm), and large (>3 cm) lymph node lesions
Chest
 , 
2000
, vol. 
117
 (pg. 
773
-
8
)
(39)
Saunders
CA
Dussek
JE
O’Doherty
MJ
Maisey
MN
Evaluation of fluorine-18-fluorodeoxyglucose whole body positron emission tomography imaging in the staging of lung cancer
Ann Thorac Surg
 , 
1999
, vol. 
67
 (pg. 
790
-
7
)
(40)
Pieterman
RM
van Putten
JW
Meuzelaar
JJ
Mooyaart
EL
Vaalburg
W
Koeter
GH
, et al.  . 
Preoperative staging of non-small-cell lung cancer with positron-emission tomography
N Engl J Med
 , 
2000
, vol. 
343
 (pg. 
254
-
61
)
(41)
Vesselle
H
Pugsley
JM
Vallieres
E
Wood
DE
The impact of fluorodeoxyglucose F 18 positron-emission tomography on the surgical staging of non-small cell lung cancer
J Thorac Cardiovasc Surg
 , 
2002
, vol. 
124
 (pg. 
511
-
9
)
(42)
Albes
JM
Dohmen
BM
Schott
U
Schulen
E
Wehrmann
M
Ziemer
G
Value of positron emission tomography for lung cancer staging
Eur J Surg Oncol
 , 
2002
, vol. 
28
 (pg. 
55
-
62
)
(43)
Poncelet
AJ
Lonneux
M
Coche
E
Weynand
B
Noirhomme
P
PET-FDG scan enhances but does not replace preoperative surgical staging in non-small cell lung carcinoma
Eur J Cardiothorac Surg
 , 
2001
, vol. 
20
 (pg. 
468
-
74
)
(44)
Lardinois
D
Weder
W
Hany
TF
Kamel
EM
Korom
S
Seifert
B
, et al.  . 
Staging of non-small-cell lung cancer with integrated positron-emission tomography and computed tomography
N Engl J Med
 , 
2003
, vol. 
348
 (pg. 
2500
-
7
)
(45)
Reed
CE
Harpole
DH
Posther
KE
Woolson
SL
Downey
RJ
Meyers
BF
, et al.  . 
Results of the American College of Surgeons Oncology Group Z0050 trial: the utility of positron emission tomography in staging potentially operable non-small cell lung cancer
J Thorac Cardiovasc Surg
 , 
2003
, vol. 
126
 (pg. 
1943
-
51
)
(46)
Kahn
D
Menda
Y
Kernstine
K
Bushnell
D
McLaughlin
K
Miller
S
, et al.  . 
The utility of 99mTc depreotide compared with F-18 fluorodeoxyglucose positron emission tomography and surgical staging in patients with suspected non-small cell lung cancer
Chest
 , 
2004
, vol. 
125
 (pg. 
494
-
501
)
(47)
Herder
GJ
Kramer
H
Hoekstra
OS
Smit
EF
Pruim
J
van
TH
, et al.  . 
Traditional versus up-front [18F] fluorodeoxyglucose-positron emission tomography staging of non-small-cell lung cancer: a Dutch cooperative randomized study
J Clin Oncol
 , 
2006
, vol. 
24
 (pg. 
1800
-
6
)
(48)
van Tinteren
H
Hoekstra
OS
Smit
EF
van den Bergh
JH
Schreurs
AJ
Stallaert
RA
, et al.  . 
Effectiveness of positron emission tomography in the preoperative assessment of patients with suspected non-small-cell lung cancer: the PLUS multicentre randomised trial
Lancet
 , 
2002
, vol. 
359
 (pg. 
1388
-
93
)
(49)
Viney
RC
Boyer
MJ
King
MT
Kenny
PM
Pollicino
CA
McLean
JM
, et al.  . 
Randomized controlled trial of the role of positron emission tomography in the management of stage I and II non-small-cell lung cancer
J Clin Oncol
 , 
2004
, vol. 
22
 (pg. 
2357
-
62
)
(50)
TNM: International Union Against Cancer
TNM classification of malignant tumours
 , 
1997
5th ed
New York
International Union Against Cancer
(51)
Bury
T
Barreto
A
Daenen
F
Barthelemy
N
Ghaye
B
Rigo
P
Fluorine-18 deoxyglucose positron emission tomography for the detection of bone metastases in patients with non-small cell lung cancer
Eur J Nucl Med
 , 
1998
, vol. 
25
 (pg. 
1244
-
7
)
(52)
Halter
G
Buck
AK
Schirrmeister
H
Aksoy
E
Liewald
F
Glatting
G
, et al.  . 
Lymph node staging in lung cancer using [18F]FDG-PET
Thorac Cardiovasc Surg
 , 
2004
, vol. 
52
 (pg. 
96
-
101
)
(53)
Verhagen
AF
Bootsma
GP
Tjan-Heijnen
VC
van der Wilt
GJ
Cox
AL
Brouwer
MH
, et al.  . 
FDG-PET in staging lung cancer: how does it change the algorithm?
Lung Cancer
 , 
2004
, vol. 
44
 (pg. 
175
-
81
)
(54)
Nomori
H
Watanabe
K
Ohtsuka
T
Naruke
T
Suemasu
K
Uno
K
The size of metastatic foci and lymph nodes yielding false-negative and false-positive lymph node staging with positron emission tomography in patients with lung cancer
J Thorac Cardiovasc Surg
 , 
2004
, vol. 
127
 (pg. 
1087
-
92
)
(55)
Cerfolio
RJ
Ojha
B
Bryant
AS
Raghuveer
V
Mountz
JM
Bartolucci
AA
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
, vol. 
78
 (pg. 
1017
-
23
)
(56)
Oturai
PS
Mortensen
J
Enevoldsen
H
Eigtved
A
Backer
V
Olesen
KP
, et al.  . 
Gamma-camera 18F-FDG PET in diagnosis and staging of patients presenting with suspected lung cancer and comparison with dedicated PET
J Nucl Med
 , 
2004
, vol. 
45
 (pg. 
1351
-
7
)
(57)
Halpern
BS
Schiepers
C
Weber
WA
Crawford
TL
Fueger
BJ
Phelps
ME
, et al.  . 
Presurgical staging of non-small cell lung cancer: positron emission tomography, integrated positron emission tomography/CT, and software image fusion
Chest
 , 
2005
, vol. 
128
 (pg. 
2289
-
97
)
(58)
Shim
SS
Lee
KS
Kim
BT
Chung
MJ
Lee
EJ
Han
J
, et al.  . 
Non-small cell lung cancer: prospective comparison of integrated FDG PET/CT and CT alone for preoperative staging
Radiology
 , 
2005
, vol. 
236
 (pg. 
1011
-
9
)
(59)
Pozo-Rodriguez
F
Martin de Nicolas
JL
Sanchez-Nistal
MA
Maldonado
A
Garcia de
BS
Calero-Garcia
R
, et al.  . 
Accuracy of helical computed tomography and [18F] fluorodeoxyglucose positron emission tomography for identifying lymph node mediastinal metastases in potentially resectable non-small-cell lung cancer
J Clin Oncol
 , 
2005
, vol. 
23
 (pg. 
8348
-
56
)
(60)
Bury
T
Dowlati
A
Paulus
P
Corhay
JL
Hustinx
R
Ghaye
B
, et al.  . 
Whole-body 18FDG positron emission tomography in the staging of non-small cell lung cancer
Eur Respir J
 , 
1997
, vol. 
10
 (pg. 
2529
-
34
)
(61)
Guhlmann
A
Storck
M
Kotzerke
J
Moog
F
Sunder-Plassmann
L
Reske
SN
Lymph node staging in non-small cell lung cancer: evaluation by [18F]FDG positron emission tomography (PET)
Thorax
 , 
1997
, vol. 
52
 (pg. 
438
-
41
)
(62)
Hagberg
RC
Segall
GM
Stark
P
Burdon
TA
Pompili
MF
Characterization of pulmonary nodules and mediastinal staging of bronchogenic carcinoma with F-18 fluorodeoxyglucose positron emission tomography
Eur J Cardiothorac Surg
 , 
1997
, vol. 
12
 
1
(pg. 
92
-
7
)
(63)
Marom
EM
McAdams
HP
Erasmus
JJ
Goodman
PC
Culhane
DK
Coleman
RE
, et al.  . 
Staging non-small cell lung cancer with whole-body PET
Radiology
 , 
1999
, vol. 
212
 (pg. 
803
-
9
)
(64)
Sasaki
M
Ichiya
Y
Kuwabara
Y
Akashi
Y
Yoshida
T
Fukumura
T
, et al.  . 
The usefulness of FDG positron emission tomography for the detection of mediastinal lymph node metastases in patients with non-small cell lung cancer: a comparative study with X-ray computed tomography
Eur J Nucl Med
 , 
1996
, vol. 
23
 (pg. 
741
-
7
)
(65)
Sazon
DA
Santiago
SM
Soo Hoo
GW
Khonsary
A
Brown
C
Mandelkern
M
, et al.  . 
Fluorodeoxyglucose-positron emission tomography in the detection and staging of lung cancer
Am J Respir Crit Care Med
 , 
1996
, vol. 
153
 (pg. 
417
-
21
)
(66)
Scott
WJ
Schwabe
JL
Gupta
NC
Dewan
NA
Reeb
SD
Sugimoto
JT
Positron emission tomography of lung tumors and mediastinal lymph nodes using [18F]fluorodeoxyglucose. The Members of the PET-Lung Tumor Study Group
Ann Thorac Surg
 , 
1994
, vol. 
58
 (pg. 
698
-
703
)
(67)
Scott
WJ
Gobar
LS
Terry
JD
Dewan
NA
Sunderland
JJ
Mediastinal lymph node staging of non-small-cell lung cancer: a prospective comparison of computed tomography and positron emission tomography
J Thorac Cardiovasc Surg
 , 
1996
, vol. 
111
 (pg. 
642
-
8
)
(68)
Steinert
HC
Hauser
M
Allemann
F
Engel
H
Berthold
T
von Schulthess
GK
, et al.  . 
Non-small cell lung cancer: nodal staging with FDG PET versus CT with correlative lymph node mapping and sampling
Radiology
 , 
1997
, vol. 
202
 (pg. 
441
-
6
)
(69)
Valk
PE
Pounds
TR
Hopkins
DM
Haseman
MK
Hofer
GA
Greiss
HB
, et al.  . 
Staging non-small cell lung cancer by whole-body positron emission tomographic imaging
Ann Thorac Surg
 , 
1995
, vol. 
60
 (pg. 
1573
-
81
)
(70)
Vansteenkiste
JF
Stroobants
SG
De Leyn
PR
Dupont
PJ
Verschakelen
JA
Nackaerts
KL
, et al.  . 
Mediastinal lymph node staging with FDG-PET scan in patients with potentially operable non-small cell lung cancer: a prospective analysis of 50 cases
Leuven Lung Cancer Group. Chest
 , 
1997
, vol. 
112
 (pg. 
1480
-
6
)
(71)
Wahl
RL
Quint
LE
Greenough
RL
Meyer
CR
White
RI
Orringer
MB
Staging of mediastinal non-small cell lung cancer with FDG PET, CT, and fusion images: preliminary prospective evaluation
Radiology
 , 
1994
, vol. 
191
 (pg. 
371
-
7
)
(72)
Vansteenkiste
JF
Stroobants
SG
De Leyn
PR
Dupont
PJ
Bogaert
J
Maes
A
, et al.  . 
Lymph node staging in non-small-cell lung cancer with FDG-PET scan: a prospective study on 690 lymph node stations from 68 patients
J Clin Oncol
 , 
1998
, vol. 
16
 (pg. 
2142
-
9
)
(73)
Vansteenkiste
JF
Stroobants
SG
Dupont
PJ
De Leyn
PR
De Wever
WF
Verbeken
EK
, 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?
The Leuven Lung Cancer Group. Eur J Nucl Med
 , 
1998
, vol. 
25
 (pg. 
1495
-
501
)
(74)
Albes
JM
Lietzenmayer
R
Schott
U
Schulen
E
Wehrmann
M
Ziemer
G
Improvement of non-small-cell lung cancer staging by means of positron emission tomography
Thorac Cardiovasc Surg
 , 
1999
, vol. 
47
 (pg. 
42
-
7
)
(75)
Higashi
K
Oguchi
M
Tamamura
H
Wang
XM
Yamamoto
I
Ueda
Y
, et al.  . 
Comparison of Tl SPECT FDG PET in the diagnosis of lymph node metastases from lung cancer
Jpn J Clin Radiol
 , 
1999
, vol. 
44
 (pg. 
191
-
7
)
(76)
Richter
JA
Torre
W
Gamez
C
Aramendia
JM
Crespo
A
Nicolas
A
, et al.  . 
Value of Pet-18FDG in lung cancer
Med Clin (Barc)
 , 
1999
, vol. 
113
 (pg. 
567
-
71
)
(77)
Demura
Y
Mizuno
S
Wakabayashi
M
Totani
Y
Okamura
S
Ameshima
S
, et al.  . 
Evaluation of fluorine-18-fluorodeoxyglucose whole body positron emission tomography imaging in the clinical diagnosis of lung cancer
Nihon Kokyuki Gakkai Zasshi
 , 
2000
, vol. 
38
 (pg. 
676
-
81
)
(78)
Farrell
MA
McAdams
HP
Herndon
JE
Patz
EF
Jr
Non-small cell lung cancer: FDG PET for nodal staging in patients with stage I disease
Radiology
 , 
2000
, vol. 
215
 (pg. 
886
-
90
)
(79)
Kitase
M
Hara
M
Katoh
K
Satoh
Y
Satake
M
Miyagawa
H
, et al.  . 
FDG-PET in patient with clinical T1N0 lung cancer; determination of nodal status
Jpn J Clin Radiol
 , 
2000
, vol. 
45
 (pg. 
209
-
14
)
(80)
Kubota
K
Imuran
MB
Ono
S
Akaizawa
T
Gotoh
R
Fukuda
H
, et al.  . 
Diagnostic value of whole-body positron emission tomography using fluorine-18 fluorodeoxyglucose for lung and other cancer
Jpn J Clin Radiol
 , 
2000
, vol. 
45
 (pg. 
199
-
208
[In Japanese.]
(81)
Liewald
F
Grosse
S
Storck
M
Guhlmann
A
Halter
G
Reske
S
, et al.  . 
How useful is positron emission tomography for lymphnode staging in non-small-cell lung cancer?
Thorac Cardiovasc Surg
 , 
2000
, vol. 
48
 (pg. 
93
-
6
)
(82)
Roberts
PF
Follette
DM
von Haag
D
Park
JA
Valk
PE
Pounds
TR
, et al.  . 
Factors associated with false-positive staging of lung cancer by positron emission tomography
Ann Thorac Surg
 , 
2000
, vol. 
70
 (pg. 
1154
-
9
)
(83)
Tatsumi
M
Yutani
K
Nishimura
T
Evaluation of lung cancer by 99mTc-tetrofosmin SPECT: comparison with [18F]FDG-PET
J Comput Assist Tomogr
 , 
2000
, vol. 
24
 (pg. 
574
-
80
)
(84)
Changlai
SP
Tsai
SC
Chou
MC
Ho
YJ
Kao
CH
Whole body 18F-2-deoxyglucose positron emission tomography to restage non-small cell lung cancer
Oncol Rep
 , 
2001
, vol. 
8
 (pg. 
337
-
9
)
(85)
Dunagan
D
Chin
R
Jr
McCain
T
Case
L
Harkness
B
Oaks
T
, et al.  . 
Staging by positron emission tomography predicts survival in patients with non-small cell lung cancer
Chest
 , 
2001
, vol. 
119
 (pg. 
333
-
9
)
(86)
Guan
Y
He
S
Dong
J
Value of 18F-fluorodeoxyglucose positron emission tomography imaging in staging of non-small cell lung cancer
Zhonghua Yi Xue Za Zhi
 , 
2001
, vol. 
81
 (pg. 
1180
-
3
)
(87)
Gupta
NC
Tamim
WJ
Graeber
GG
Bishop
HA
Hobbs
GR
Mediastinal lymph node sampling following positron emission tomography with fluorodeoxyglucose imaging in lung cancer staging
Chest
 , 
2001
, vol. 
120
 (pg. 
521
-
7
)
(88)
Kernstine
KH
McLaughlin
KA
Menda
Y
Rossi
NP
Kahn
DJ
Bushnell
DL
, et al.  . 
Can FDG-PET reduce the need for mediastinoscopy in potentially resectable nonsmall cell lung cancer?
Ann Thorac Surg
 , 
2002
, vol. 
73
 (pg. 
394
-
401
)
(89)
von Haag
DW
Follette
DM
Roberts
PF
Shelton
D
Segel
LD
Taylor
TM
Advantages of positron emission tomography over computed tomography in mediastinal staging of non-small cell lung cancer
J Surg Res
 , 
2002
, vol. 
103
 (pg. 
160
-
4
)
(90)
Magnani
P
Carretta
A
Rizzo
G
Fazio
F
Vanzulli
A
Lucignani
G
, et al.  . 
FDG/PET and spiral CT image fusion for medistinal lymph node assessment of non-small cell lung cancer patients
J Cardiovasc Surg (Torino)
 , 
1999
, vol. 
40
 (pg. 
741
-
8
)
(91)
Erasmus
JJ
Patz
EF
Jr
McAdams
HP
Murray
JG
Herndon
J
Coleman
RE
, et al.  . 
Evaluation of adrenal masses in patients with bronchogenic carcinoma using 18F-fluorodeoxyglucose positron emission tomography
AJR Am J Roentgenol
 , 
1997
, vol. 
168
 (pg. 
1357
-
60
)
(92)
Graeber
GM
Gupta
NC
Murray
GF
Positron emission tomographic imaging with fluorodeoxyglucose is efficacious in evaluating malignant pulmonary disease
J Thorac Cardiovasc Surg
 , 
1999
, vol. 
117
 (pg. 
719
-
27
)
(93)
Kalff
V
Hicks
RJ
MacManus
MP
Binns
DS
McKenzie
AF
Ware
RE
, et al.  . 
Clinical impact of (18)F fluorodeoxyglucose positron emission tomography in patients with non-small-cell lung cancer: a prospective study
J Clin Oncol
 , 
2001
, vol. 
19
 (pg. 
111
-
8
)
(94)
Kernstine
KH
Stanford
W
Mullan
BF
Rossi
NP
Thompson
BH
Bushnell
DL
, et al.  . 
PET, CT, and MRI with Combidex for mediastinal staging in non-small cell lung carcinoma
Ann Thorac Surg
 , 
1999
, vol. 
68
 (pg. 
1022
-
8
)
(95)
Kutlu
CA
Pastorino
U
Maisey
M
Goldstraw
P
Selective use of PET scan in the preoperative staging of NSCLC
Lung Cancer
 , 
1998
, vol. 
21
 (pg. 
177
-
84
)
(96)
Lewis
P
Griffin
S
Marsden
P
Gee
T
Nunan
T
Malsey
M
, et al.  . 
Whole-body 18F-fluorodeoxyglucose positron emission tomography in preoperative evaluation of lung cancer
Lancet
 , 
1994
, vol. 
344
 (pg. 
1265
-
6
)
(97)
Mac Manus
MP
Hicks
RJ
Ball
DL
Kalff
V
Matthews
JP
Salminen
E
, et al.  . 
F-18 fluorodeoxyglucose positron emission tomography staging in radical radiotherapy candidates with nonsmall cell lung carcinoma: powerful correlation with survival and high impact on treatment
Cancer
 , 
2001
, vol. 
92
 (pg. 
886
-
95
)
(98)
MacManus
MP
Hicks
RJ
Matthews
JP
Hogg
A
McKenzie
AF
Wirth
A
, et al.  . 
High rate of detection of unsuspected distant metastases by pet in apparent stage III non-small-cell lung cancer: implications for radical radiation therapy
Int J Radiat Oncol Biol Phys
 , 
2001
, vol. 
50
 (pg. 
287
-
93
)
(99)
Weder
W
Schmid
RA
Bruchhaus
H
Hillinger
S
von Schulthess
GK
Steinert
HC
Detection of extrathoracic metastases by positron emission tomography in lung cancer
Ann Thorac Surg
 , 
1998
, vol. 
66
 (pg. 
886
-
92
)
(100)
Toloza
EM
Harpole
L
McCrory
DC
Noninvasive staging of non-small cell lung cancer: a review of the current evidence
Chest
 , 
2003
123 Suppl
(pg. 
137S
-
46S
)
(101)
Hojgaard
L
Are health technology assessments a reliable tool in the analysis of the clinical value of PET in oncology? Who audits the auditors?
Eur J Nucl Med Mol Imaging
 , 
2003
, vol. 
30
 (pg. 
637
-
41
)
The Lung Cancer Disease Site Group would like to thank Drs Y. C. Ung, D. E. Maziak, K. Gulenchyn, and W. K. Evans and Ms Jean A. Mackay, J. A. Vanderveen, C. Lacchetti, and Mr C. A. Smith for taking the lead in drafting this systematic review. The Program in Evidence-Based Care is supported by Cancer Care Ontario (CCO) and the Ontario Ministry of Health and Long-Term Care. All work produced by the PEBC is editorially independent from its funding agencies.
Please see the Program in Evidence-Based Care section of Cancer Care Ontario's Web site for a list of current Disease Site Group members ( http://www.cancercare.on.ca/ ).