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Journal of Clinical Oncology, Vol 24, No 21 (July 20), 2006: pp. 3333-3339 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.05.6341 Prospective Comparative Study of Integrated Positron Emission Tomography-Computed Tomography Scan Compared With Remediastinoscopy in the Assessment of Residual Mediastinal Lymph Node Disease After Induction Chemotherapy for Mediastinoscopy-Proven Stage IIIA-N2 Non–Small-Cell Lung Cancer: A Leuven Lung Cancer Group Study
From the Department of Thoracic Surgery, Department of Nuclear Medicine, Department of Radiology, and Department of Pneumology, University Hospitals Leuven, Gasthuisberg Leuven, Belgium Address reprint requests to Paul De Leyn, MD, PhD, Department of Thoracic Surgery, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium; e-mail: Paul.Deleyn{at}uz.kuleuven.ac.be
PURPOSE: Mediastinal restaging after induction therapy for non–small-cell lung cancer remains a difficult and controversial issue. The goal of this prospective study was to compare the performance of integrated positron emission tomography (PET) –computed tomography (CT) and remediastinoscopy in the evaluation of mediastinal lymph node metastasis after induction chemotherapy. PATIENTS AND METHODS: Thirty consecutive stage IIIA-N2 non–small-cell lung cancer patients surgically treated at our institution were entered onto this prospective study. N2 disease was proven by cervical mediastinoscopy, at which a mean number of 3.8 lymph node levels were biopsied. After completion of induction chemotherapy, the mediastinum was reassessed by integrated PET-CT and remediastinoscopy. All patients underwent thoracotomy with attempted complete resection and systematic nodal dissection. RESULTS: PET-CT showed no evidence of nodal disease (N0) in 13 patients, Hilar nodal disease (N1) disease in three patients, and residual mediastinal disease (N2) in 14 patients. Remediastinoscopy was positive in only five patients. The preinduction involved lymph node level could be accurately re-evaluated in 18 patients. This was not the case in the other 12 because of extensive fibrosis and adhesions. In 17 patients, persistent N2 disease was found at thoracotomy. The sensitivity, specificity, and accuracy of PET-CT were 77%, 92%, and 83%, respectively. These parameters for remediastinoscopy were 29%, 100%, and 60%, respectively. Sensitivity (P < .0001) and accuracy (P = .012) were significantly better for PET-CT. CONCLUSION: After a thorough staging mediastinoscopy, postinduction remediastinoscopy had a disappointing sensitivity because of adhesions and fibrosis. Integrated PET-CT yielded a better result than that obtained in previous studies with side-by-side PET and CT images.
Although the optimal treatment of patients with stage IIIA-N2 non–small-cell lung cancer (NSCLC) is still under investigation, there may be a role for surgery following induction treatment in patients with downstaging of mediastinal lymph nodes (LNs) and complete resection.1-4 Mediastinal restaging after induction chemotherapy or chemoradiotherapy for NSCLC remains a difficult and controversial issue. Positron emission tomography (PET) scanning is accurate in primary LN staging,5 but the available results after induction treatment are less convincing. In a prospective multicenter study, the sensitivity of PET in the detection of residual mediastinal LN disease after induction chemotherapy was only 50%.6 Remediastinoscopy offers the advantage of providing histologic evidence of the mediastinal LN status, but it is technically challenging because of fibrosis and adhesions after prior mediastinoscopy and induction treatment. Only a few centers have reported their experience with remediastinoscopy. A sensitivity of 70% to 73% was obtained.7,8 The aim of this prospective study was to compare the performance of remediastinoscopy and integrated PET–computed tomography (CT) in the evaluation of mediastinal LN metastasis after induction chemotherapy.
Cohort Assembly From April 2002 to April 2005, all consecutive stage IIIA-N2 NSCLC patients with surgical treatment at our institution who fulfilled the inclusion criteria were entered in this prospective study with informed consent. Stage IIIA-N2 was certified by mediastinoscopy, including inspection and sampling of the left and right upper paratracheal nodes (levels 2L and 2R on the Mountain-Dressler map), left and right lower paratracheal nodes (levels 4L and 4R), and subcarinal nodes (level 7). Patients received three to four courses of cisplatin-based induction chemotherapy (mostly cisplatin + gemcitabine). No patients received induction radiotherapy. Patients with response or stable disease on CT scan were considered for thoracotomy.
PET-CT Acquisition PET-CT images were acquired 75 minutes after the intravenous administration of fluorodeoxyglucose (FDG) 4.5 MBq/kg. Patients were scanned from the groin to the head in the arms-up position. Single-section, whole-body, spiral CT (85 mAs, 130 kV, slice thickness 5 mm, table feed 12 mm/rotation) was performed after 120 mL of a contrast agent that contained 300 mg iodine/mL (Xenetix 300; Guerbet, Sulzbach, Germany) was intravenously injected using an automated injector (1.6 mL/sec, scan delay 100 seconds). A limited breath-hold technique was used to avoid motion-induced artifacts in the area of the diaphragm. On completion of the CT portion, the PET data (5 minutes/bed position) were acquired in 3-D mode. CT images were reconstructed using conventional-filtered back-projection at 3.4-mm axial intervals to match the slice separation of the PET data. Both attenuation-corrected PET images (using the CT data) and nonattenuation-corrected images were reconstructed using an ordered subsets expectation-maximization algorithm.
PET-CT Image Analysis The nuclear medicine physician (S.S.) and chest radiologist (W.D.) interpreted the integrated and software-fused PET-CT. For this purpose, only focal uptake that projected onto an LN was considered positive for residual nodal involvement. Areas of focal uptake not confined to nodes (eg, vascular structures, calcified plaques) were considered benign. Suspect nodal regions were recorded on the Mountain-Dressler map,9 and the nodal status was defined as N0-1 or N2-3.
Remediastinoscopy
Thoracotomy
Statistics The sensitivity, specificity, accuracy, and predictive values of CT and PET were calculated using the standard definitions. The relative accuracy of PET-CT versus remediastinoscopy was compared by a McNemar test for correlated proportions.
Thirty patients were included in a 3-year period between April 2002 and April 2005 (Table 1). The mean age was 64 years (range, 45 to 75 years). Most tumors (73%) were located in the upper lobes. Two-thirds of tumors were right-sided. Pathology revealed squamous cell carcinoma in 17 patients and adenocarcinoma in 13. In all patients, N2 disease was confirmed by mediastinoscopy. The mean number of LN levels biopsied was 3.8 (range, 3 to 5). Subcarinal LNs were biopsied in all 30 patients. One-third of patients had multilevel N2 disease; subcarinal LNs were positive in 50% of patients.
Accuracy of CT Alone, PET Alone, and PET-CT in Restaging The accuracy of CT alone in restaging mediastinal LN disease was 60%, the accuracy of PET alone was 70%, and that of PET-CT was 83% (Table 2). PET-CT fusion images mainly resulted in improved specificity. In three patients with N2-3 disease on PET scan, fusion images showed that FDG uptake was in a thickened pleura after previous talc usage for a contralateral pneumothorax, in normal vascular structure (Fig 1), or in brown fatty tissue. In one patient, PET-CT images detected N2 disease by demonstrating that a moderate uptake of FDG was in a necrotic LN (Fig 2).
Remediastinoscopy Remediastinoscopy was scheduled 4 weeks after completion of induction chemotherapy. The mean time interval between the first mediastinoscopy and remediastinoscopy was 106 days (range, 83 to 129 days). The mean operative time for remediastinoscopy was 53 minutes (range, 40 to 70 minutes). No intraoperative complications occurred during remediastinoscopy. The mean number of levels biopsied at remediastinoscopy was 3.6 (range, 0 to 5). The preinduction involved LN levels could be evaluated by remediastinoscopy in 18 patients; this was not the case in the other 12 because of extensive fibrosis and adhesions (Table 3). Thoracotomy revealed that the subcarinal level was not adequately biopsied in 20 patients (67%).
Thoracotomy Because no N3 disease was found at remediastinoscopy, thoracotomy with attempted complete resection and LN dissection was performed in all patients (Table 3). No resection was performed in one patient with adenocarcinoma of the right middle lobe. His remediastinoscopy was negative, but persistent, multilevel N2 disease was found at thoracotomy, and the planned pneumonectomy for central transfissural disease was aborted. A complete resection (R0) could be achieved in 22 patients (73%), but resection was incomplete in seven patients (four R1 and three R2). PET-CT showed persistent residual mediastinal disease in six of seven patients with incomplete resection (Table 4). The four R1 resections had positive mediastinal LNs, which were shown by PET-CT scan.
No mortality occurred in the hospital. The mean hospital stay was 11.6 days (standard deviation, 6.9 days). Ten patients developed postoperative complications. The most frequent postoperative complication, occurring in six patients, was respiratory infection; prolonged ventilation and intensive care (> 48 hours) were required in two. Other complications were atrial fibrillation (n = 4) and pulmonary embolus (n = 1).
Comparative Accuracy: Persistent N2 Disease After Induction Chemotherapy
Remediastinoscopy was positive in only five patients. At thoracotomy, all positive mediastinal LNs were within the normal reach of classical mediastinoscopy. In 12 patients, remediastinoscopy was false-negative (Table 5). In three patients, only small microscopic tumor deposits were found at pathologic examination, whereas, in two others, thoracotomy revealed that the LN level concerned was not adequately biopsied, because it was encapsulated in a firm fibrotic capsule. In the other seven patients with false-negative remediastinoscopy findings, severe fibrosis and adhesions impeded biopsy of the previously involved LN level. Consequently, the sensitivity of PET-CT for the detection of residual mediastinal LN disease after induction chemotherapy was 77%, the specificity was 92%, and the accuracy was 83%; negative and positive predictive values were 75% and 93%, respectively. The figures for remediastinoscopy were 29%, 100%, 60%, respectively, and negative and positive predictive values were 52% and 100%, respectively. Sensitivity (P < .0001) and accuracy (P = .012) were significantly better for PET-CT. Comparison of PET-CT and resectability results was useful. In 16 patients with a PET-CT negative for residual mediastinal LN disease, complete resection was achieved in 15. One resection was incomplete because of positive peribronchial tissue at the bronchial margin. However, of the 14 patients with positive nodes at PET-CT, only eight had complete resection (P = .018).
Primary surgery for mediastinoscopy-proven N2 NSCLC is unrewarding—the 5-year survival rate is less than 10%.16 Small randomized studies have suggested that the prognosis can be improved by adding cisplatin-based induction chemotherapy.17,18 A favorable outcome can be expected, particularly in patients with downstaging of the mediastinal nodes and complete resection.1-4 Because our experience with FDG-PET in the assessment of mediastinal LN metastasis after induction chemotherapy15 was inferior to the one achieved in baseline staging,19 we hypothesized that tissue sampling by means of remediastinoscopy would improve sensitivity. To our knowledge, this is the first prospective protocol evaluating the performance of integrated PET-CT in the restaging of the mediastinal LNs after induction treatment for N2 NSCLC and also the first prospective comparison of PET-CT and remediastinoscopy. Much to our surprise, and in contrast with the study hypothesis, the results of remediastinoscopy were quite disappointing, but integrated PET-CT performed better than in our previous experience with PET in visual comparison with CT. Many prospective series and six meta-analyses have reported the superiority of FDG-PET versus CT in primary staging of the mediastinal LNs.5,20-24 After induction therapy, PET still performs better than CT, but its accuracy is not as good as that for initial staging. The studies that have evaluated this question are quite heterogeneous, both in methods and in results (Table 6). First, some studies were prospective, and others were retrospective. Second, in most studies, only a subgroup of patients had mediastinoscopy-proven N2 disease before induction treatment. Third, some studies reported on patients with chemotherapy induction, others on a mixed population with chemotherapy or chemoradiotherapy induction, and some on patients with only chemoradiotherapy. Radiotherapy has been associated with false-positive findings because of postradiation inflammatory reactions. Overall, the sensitivity in the detection of residual mediastinal LN disease was between 50% and 67% (with an outlier of 20%), and the specificity was between 61% and 100%. This rather low sensitivity may result from small residual tumor nests that are surrounded by fibrosis and are more difficult to detect. On the basis of these results, we could not recommend PET after induction therapy as a reliable indicator of surgical resection in patients with mediastinal clearance nor as a means of avoiding thoracotomy in those with persistent mediastinal LN disease.30
The current study results are clearly better than in previous reports. In 1997, we identified the lack of anatomic information about PET and the improved interpretation when PET images and CT images are viewed side by side.31 Current fusion scanners now acquire superimposed PET and CT images. This new tool has been evaluated recently in the primary staging of NSCLC, and integrated PET-CT yielded additional information compared with visual correlation of images.32 In this postinduction study, we analyzed mediastinal PET findings more sensitive compared with chemotherapy-naive patients and with previous studies.6,19 Even a slight increase of uptake above mediastinal bloodpool activity was considered positive. Therefore, PET alone sensitivity was 71%. However, because of physiologic uptake of FDG in mediastinal structures, specificity could only be maintained by fusion imaging. Remediastinoscopy offers the advantage of providing histological evidence of mediastinal LN status after induction therapy. Only a few small series have been reported. Mateu-Navarro et al7 reported on 24 patients in a 5-year period, 12 of whom had a positive remediastinoscopy. In the 12 patients with negative remediastinoscopy, thoracotomy with nodal dissection identified five false-negative cases (sensitivity, 70%). In the series of Van Schil et al,8 on a total of 27 patients in a 7-year period, the results were comparable (sensitivity, 73%). Pitz et al33 reported on 15 patients who had remediastinoscopies after induction chemotherapy for stage IIIB NSCLC. Because of fibrosis and adhesions, incomplete or no biopsies were obtained in six patients (40%). The other nine patients had adequate remediastinoscopy, which was positive in two and negative in seven patients. In the latter seven patients, remediastinoscopy was false negative at subsequent thoracotomy in two patients. The authors concluded that remediastinoscopy was disappointing because of incompleteness or false-negative findings. In our series, remediastinoscopy was positive in only five patients and false-negative in 12 cases; this yielded a sensitivity of 29% and an accuracy of 60%. The reasons for the differences among studies are speculative. First, previous studies were retrospective and covered longer treatment intervals, but our trial had a prospective design open for all consecutive cases. Second, the performance of mediastinoscopy for initial staging of NSCLC is largely variable.34 In our study, all mediastinoscopies consisted of a thorough exploration with LN biopsies of all mediastinal nodal levels reachable by cervical mediastinoscopy, which led to an average of 3.8 LN levels biopsied. In the series that report a higher sensitivity for remediastinoscopy, no data exist on the thoroughness (eg, the number of LN levels biopsied) of the first mediastinoscopy. We believe that a more extensive initial mediastinoscopy will result in more adhesions and fibrosis, causing remediastinoscopy to be more difficult and inaccurate. Finally, in our series, one-third of patients had multilevel LN disease, which was present in only three of 26 patients in the series of Mateu-Navarro et al7 and was not reported in the series of Van Schil et al.8 Accurate evaluation of multilevel LN disease may be more demanding at remediastinoscopy. A limitation of the present study is that correlative studies on pretreatment or post-treatment PET scans are not possible, because only two-thirds of patients had their pretreatment scan in our hospital. Future studies should determine the possible correlation between decrease of standardized uptake value in the primary tumor and downstaging on PET-CT and final pathology. In conclusion, our study shows the difficulty of performing thorough remediastinoscopy and the disappointing sensitivity of postinduction remediastinoscopy that results from adhesions and fibrosis, which impede the reach to concerned LN stations, especially in the subcarinal space. Because the results of remediastinoscopy were disappointing in our study, we consider the role of remediastinoscopy in restaging after induction chemotherapy investigational. Other techniques that provide histological confirmation (endoscopic ultrasound-fine needle aspiration or transbronchial needle aspiration) should be investigated in baseline or post-treatment staging. Integrated PET-CT yields better results than those obtained in previous studies with separate PET and CT images. As a result, sensitivity and accuracy in assessing LN downstaging were significantly better for PET-CT than for remediastinoscopy. Moreover, the positive predictive value of PET-CT for persistent mediastinal LN metastasis and for the risk of an incomplete resection was high. Our study indicates that PET-CT may be useful in determining the operability after induction chemotherapy for N2 disease. Our results should be confirmed by other studies; mature survival analyses are required.
The authors indicated no potential conflicts of interest.
Presented in part at the 11th World Conference on Lung Cancer of the International Association for the Study of Lung Cancer, Barcelona, Spain, July 3-6, 2005. Author's disclosure of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
1 cm, the LN was considered positive. 
