ATS
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
 QUICK SEARCH:   [advanced]


     


This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Author home page(s):
Robert James Cerfolio
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Cerfolio, R. J.
Right arrow Articles by Eloubeidi, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cerfolio, R. J.
Right arrow Articles by Eloubeidi, M.

Ann Thorac Surg 2005;80:1207-1214
© 2005 The Society of Thoracic Surgeons


Original article: General thoracic

Improving the Inaccuracies of Clinical Staging of Patients with NSCLC: A Prospective Trial

Robert James Cerfolio, MD, FACS a , * , Ayesha S. Bryant, MD, MSPH b , Buddhiwardhan Ojha, MD, MPH c , Mohammad Eloubeidi, MD d

a Section of Thoracic Surgery, University of Alabama at Birmingham Birmingham, Alabama and Division of Cardiothoracic Surgery, Department of Surgery, Birmingham Veterans Administration Hospital, Birmingham, Alabama
b Department of Epidemiology, University of Alabama at Birmingham School of Public Health, Birmingham, Alabama
c Division of Nuclear Radiology, University of Alabama at Birmingham, Birmingham, Alabama
d Division of Gastroenterology, University of Alabama at Birmingham, Birmingham, Alabama

Accepted for publication April 5, 2005.

* Address reprint requests to Dr Cerfolio, Division of Cardiothoracic Surgery, University of Alabama at Birmingham, 1900 University Blvd, THT 712, Birmingham, AL. 35294 (Email: robert.cerfolio{at}ccc.uab.edu).

Presented at the Forty-first Annual Meeting of The Society of Thoracic Surgeons, Tampa, FL, Jan 24–26, 2005.


    Abstract
 Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Discussion
 References
 
BACKGROUND: Clinical stage affects the care of patients with nonsmall cell lung cancer.

METHODS: This is a prospective trial on patients with suspected resectable nonsmall cell lung cancer. All patients underwent integrated positron emission tomographic scanning and computed tomographic scanning, and all suspicious metastatic sites were investigated. A, T, N, and M status was assigned. If N2, N3 and M1 were negative, patients underwent thoracotomy and complete thoracic lymphadenectomy.

RESULTS: There were 383 patients. The accuracy of clinical staging using positron emission tomographic scanning and computed tomographic scanning was 68% and 66% for stage I, 84% and 82% for stage II, 74% and 69% for stage III, and 93% and 92% for stage IV, respectively. N2 disease was discovered in 115 patients (30%) and was most common in the subcarinal lymph node (30%). Unsuspected N2 disease occurred in 28 patients (14%) and was most common in the posterior mediastinal lymph nodes (subcarinal, 38%; posterior aortopulmonary, 15%). It was found in 9% of patients who were clinically staged I (58% in the posterior mediastinal lymph nodes) and in 26% of patients clinically staged II (86% in posterior mediastinal lymph nodes).

CONCLUSIONS: Despite integrated positron emission tomographic scanning and computed tomographic scanning, clinical staging remains relatively inaccurate for patients with nonsmall cell lung cancer. Recent studies suggest adjuvant therapy for stage Ib and II nonsmall cell lung cancer; thus the impact on preoperative care is to find unsuspected N2 disease. Unsuspected N2 disease is most common in posterior mediastinal lymph nodes inaccessible by mediastinoscopy. Thus one should consider endoscopic ultrasound fine-needle aspiration, especially for patients clinically staged as I and II, even if the nodes are negative on positron emission tomographic scanning and computed tomographic scanning.


    Introduction
 Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Discussion
 References
 
Lung cancer is responsible for more cancer deaths than the next three most common cancers combined. In particular, nonsmall cell lung cancer (NSCLC) accounts for approximately 75% to 85% of all newly diagnosed lung cancers [1]. Treatment of NSCLC depends on stage. The best tests for assessing the clinical stage are the computed tomographic (CT) scan and dedicated positron emission tomographic (PET) scan using 2-dexoy-2-18F–flouro-D-glucose (FDG-PET). These tests often detect suspicious areas of metastases that should be further investigated with other tests such as a bone scan, ultrasound, and magnetic resonance imaging. Procedures that biopsy these sites, such as mediastinoscopy, endoscopic ultrasound fine-needle aspiration (EUS-FNA) and ultrasound-guided biopsy of the liver are mandatory. However, despite all these sophisticated tests and even the use of integrated FDG-PET/CT scanning, which we have shown to be superior to dedicated FDG-PET scanning in the staging of patients with NSCLC [2], the pathologic stage often differs from the predicted clinical stage [2–5].

We decided to prospectively assess the accuracy of the predicted clinical stage and compare it with the actual pathologic stage; we also wanted to see at which stage it most commonly fails. We specifically addressed each separate lymph node station and assessed how many patients could have their care improved by having more accurate clinically staging. Until the ongoing studies that examine the use of neoadjuvant therapy for the early stages of NSCLC (ie, stages Ib and II) are completed, the current standard of care is to use surgical resection followed by adjuvant chemotherapy. Thus, for now it is only the discovery of unsuspected N2 or M1 disease that alters preoperative treatment. The EUS-FNA is a noninvasive procedure that affords biopsies of posterior mediastinal (N2) lymph nodes at locations 5, 7, 8, and 9 [6]. It is highly accurate in these nodal stations [7, 8]. We also evaluated the potential impact that the EUS-FNA would have if it had been performed on all patients prior to pulmonary resection.


    Patients and Methods
 Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Discussion
 References
 
Patient Selection
Patients who presented to one surgeon (RJC) between September 2002 and August 1, 2004 with an indeterminate pulmonary nodule or a biopsy proven NSCLC and underwent integrated FDG-PET/CT scanning at our institution and CT scanning were eligible to participate in this study. Patients were excluded if they were less than 19 years of age, had a history of type I diabetes, or received preoperative chemotherapy or radiation. All patients were clinically staged using the T, N, and M classification system [9]. A stage was given for each patient based on the FDG-PET/CT scan, which was read by a nuclear radiologist, and based on the CT scan, which as read by a chest radiologist.

Radiologic Imaging
The FDG-PET/CT scans were performed on an integrated PET/CT scanner (GE Discovery LS PET/CT Scanner, Milwaukee, WI). Patients were asked to fast for 4 hours and then subsequently received 555 MBq (15mCi) of FDG intravenously followed by PET scanning after 1 hour. The scans were performed from the skull base to mid-thigh level. The computed tomography examination was used for attenuation correction of PET images. The scanning time for positron emission tomography was 5 minutes per bed position. Iterative reconstruction with CT attenuation correction was performed. The most recent CT scan of the chest was also available for visual correlation. Maximum standard uptake value (maxSUV) of the primary lymph node and of each suspicious lymph node station was determined by drawing regions of interest on the attenuation corrected FDG-PET/CT images around it. It was then calculated by the software contained within the PET or PET/CT scanner by the formula [10]:


{1207.0500620X.si4}

in which C = activity at a pixel within the tissue defined by the regions of interest, and ID = injected dose per kg of patients body weight (w). The maximum standard uptake value (maxSUV) within the selected regions of interest was used exclusively throughout this study.

Procedures, Staging, and Surgery
Patients were meticulously staged. All suspicious N2, N3, or M1 areas (maxSUV > 2.5) were biopsied prior to pulmonary resection. Mediastinoscopy was used to biopsy suspicious lymph nodes in the paratracheal area (stations 2R, 4R, 2L, and 4L), and endoscopic transesophageal ultrasound was used to biopsy suspicious posterior aorta-pulmonary window nodes (5), subcarinal (7), peri-esophageal (8) and inferior pulmonary ligament nodes (9). Endoscopic ultrasound (EUS) was performed under conscious sedation as previously described [7], and these were all performed by a single experienced endosonographer (MAE) (> 2,500 EUS procedures). A radial echoendoscope (GF-UM130 [Olympus America, Melville, NY]) was first used to evaluate the presence or absence of a lymphadenopathy. Once a suspicious lymph node was identified (the endosonographic criteria for malignant lymph node involvement was previously described [11]), the radial echoendoscope was removed and a curvilinear echoendoscope (Olympus UC-30P or UCT 140, Melville, NY) was inserted. The EUS-FNA of the target lesions by the PET/CT scans and the CT scans was performed as previously described [12]. EUS-FNAs were preformed using a 22-gauge adjustable length Echotip needle (Wilson-Cook Inc, Winston Salem, NC). Cytological diagnosis of the aspirated lesion was reported as either positive for metastatic cancer or negative. The endosonographer (MAE) was blinded to the CT scan report and to the FDG-PET/CT scan report. In general, nodes targeted as abnormal by these modalities were biopsied, but if they could not be located by EUS, then they were not biopsied.

Patients with suspected M1 disease in the liver, adrenal, or contralateral lung underwent definitive biopsy to prove or disprove M1 cancer. If the bone or brain was suspected to harbor metastases, magnetic resonance imaging was considered the standard reference. If patients had biopsy proven N3 or M1 disease the stage was recorded but they were not resected. If there was no evidence of N2 or higher disease, patients underwent thoracotomy, pulmonary resection, and complete thoracic lymphadenectomy. Pathologic review was performed by standard techniques and immunohistochemical staining was used when appropriate. The pathologic stage was assessed using the international staging system [9].

A patient was defined as having unsuspected N2 disease if neither the FDG-PET/CT scan nor the CT scan suggested any cancer in any of the N2 nodes (clinically called N2 negative) but the patient had pathologic proof of metastatic NSCLC cancer in at least one N2 node. The University of Alabama at Birmingham's institutional review board approved both this prospective trial and the electronic prospective database used for this study.

Statistical Methods
Data was stored using an Access database (Microsoft, Seattle, WA) and analyzed using EpiInfo (Centers for Disease Control, Atlanta, GA) and the SAS program, version 9.0 (SAS, Cary, NC). Efficacy (ie, sensitivity, specificity, positive predicted value, negative predicted value and accuracy) was determined for CT scanning and FDG-PET/CT scanning using the pathology or biopsy results as the gold standard. Standard definitions were used to calculate these parameters [13]. Table 1 depicts how the true positives, true negatives, false positives, and false negatives for the clinical stage were defined for calculation of the efficacy. It also shows how the percentage for unsuspected N2 disease was calculated. The binomial approximation test was used to compare efficacy.


View this table:
[in this window]
[in a new window]
 
Table 1. Definition of Variables Used to Compute Efficacy of Clinical Stage (An Example Is Given for Patients Clinically Staged as Stage I)
 

    Results
 Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Discussion
 References
 
Patient Characteristics and Overall Staging
There were 383 patients (227 men) with primary nonsmall cell lung cancer. The patient characteristics for these patients are shown in Table 2. As shown in Figure 1, 184 of the 383 patients (48%) were clinically staged as N2 positive and 199 (52%) were staged as N2 negative. Eighty-seven patients were pathologically confirmed to have N2 disease, and 97 of the patients were found to be false positives on clinical staging modalities. Twenty-eight patients (14%) had unsuspected N2 disease. Table 3 shows the efficacy of clinical staging based on FDG-PET/CT scans and CT scans stratified by stage.


View this table:
[in this window]
[in a new window]
 
Table 2. Patient Characteristics (N = 383)
 


View larger version (21K):
[in this window]
[in a new window]
 
Fig 1. Patient stratification flow chart. (CT = computed tomographic; NSCLC = nonsmall cell lung cancer; PET-CT = positron emission tomographic-computed tomographic.)

 

View this table:
[in this window]
[in a new window]
 
Table 3. Efficacy of Clinical Staging
 
N2 Disease
There were a total of 234 N2 positive lymph nodes in the 115 patients with N2 disease. Thirty-four of these lymph nodes were unsuspected in the 28 patients who had unsuspected N2 disease. Figure 2 shows the distribution of these nodes in the previously described 87 and 28 patients. The most common location is the subcarinal (7) lymph node (32% of all positive N2 nodes), followed by the paratracheal (4R) nodes (21% of all positive N2 nodes). N2 disease was confirmed by mediastinoscopy in 46 patients, by EUS-FNAs in 34, by transbronchial biopsy in 7, and by thoracotomy in 28.



View larger version (31K):
[in this window]
[in a new window]
 
Fig 2. The distribution of N2 disease by lymph node (LN) stations in the 115 patients. Some patients had N2 disease in more than one N2 location. One patient had unsuspected N2 disease in the station 1 lymph node not shown in this figure.

 
Unsuspected N2 disease was found in 28 patients (14%). Table 4 shows the N2 nodal distribution and histology of these patients based on the lobar location of the primary cancer. Table 5 shows that the most common location for unsuspected N2 disease. It was in the posterior mediastinal lymph nodes (those nodes accessible by EUS-FNA, 58% for the 12 patients clinically staged as I and 86% for the 14 patients clinically staged as II). The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of clinical staging by FDG-PET/CT for each nodal station is depicted in Table 6.


View this table:
[in this window]
[in a new window]
 
Table 4. N2 Nodal Distribution and Histology of the 26 Patients Clinically Staged as Stage I or II With Unsuspected N2 Disease Based on the Lobar Location of the Primary Tumor
 

View this table:
[in this window]
[in a new window]
 
Table 5. Number and Percent of the 28 Patients With Unsuspected N2 Disease and in the Posterior Mediastinal Lymph Nodes By Stage
 

View this table:
[in this window]
[in a new window]
 
Table 6. Efficacy of the FDG-PET/CT Scan for Each N2 Nodal Station a
 
Standard Uptake Value
Figure 3 shows the median value and the range of the maxSUV for each N2 lymph nodes grouped by regions. It illustrates the considerable overlap between true positive and false positive values.



View larger version (18K):
[in this window]
[in a new window]
 
Fig 3. The median maximum standard uptake value (maxSUV) (with range) of the mediastinal lymph node that were true positives (dashed darker line) and false positives (solid lighter line) grouped by lymph nodes stations.

 
Interestingly, the median maxSUV of the primary tumor in the lung for the 12 patients with clinically staged I disease who had unsuspected N2 disease was 8.1 compared with 3.7 for the other 128 patients clinically staged as I who were N2 negative (p = 0.048). Similarly, the median maxSUV of the primary tumor in the lung for the 14 patients with clinically staged II disease who had unsuspected N2 disease was 9.5 compared with 5.0 for the other 36 patients clinically staged as II who were N2 negative (p = 0.05).


    Comment
 Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Discussion
 References
 
Despite the addition of the FDG-PET scan and integrated FDG-PET/CT scans, the clinical stage of patients with NSCLC only correctly predicts the actual stage (the positive predictive value) in approximately 50% of the patients. In addition, we found a relatively low accuracy for both FDG-PET/CT and CT scan in this prospective study at each stage. Toloza and colleagues [14] in 2003 reported similar findings for CT scans. They found computed tomography to have a sensitivity of only 57% and a specificity of 82% for metastatic disease in the mediastinum despite improvements in CT scan resolution. In addition, computed tomography has been shown to have low negative and positive predictive values for direct tumor invasion into the chest wall or mediastinal structures (T3 and T4 involvement) [15]. The low accuracy of FDG-PET has been reported by us in two previous prospective trials [2, 16] as well as by Reed and colleagues [17] in a multi-institutional trial in 2004. The real question is how often does this inaccurate staging adversely affect patient care?

The answer to that question depends partially on one's belief of what the best treatment of lung cancer is for each stage. In this study we found the clinical stage to be incorrect most often in patients with stage II (N1 disease). For now the standard of care for these patients is surgery. We believe that non-completed multi-institutional trials that are evaluating the use of neoadjuvant therapy for stage Ib and N1 stage II disease will show a benefit for preoperative chemotherapy or chemoradiotherapy in these patients. If these early (unpublished) data are proven true, this difference between clinical stage and pathologic stage will become even more important in the preoperative management of patients with NSCLC. The use of endobronchial ultrasound-guided transbronchial needle aspiration of N1 nodes may become a critical part of preoperative staging [18].

However, for now the standard of care for patients with N1 disease is surgery alone followed by adjuvant chemotherapy. Thus, only N2 or M1 disease will change the preoperative care. Most surgeons search carefully for M1 disease prior to surgery. The FDG-PET or FDG-PET/CT is the standard of care for many of us, and in addition, some order brain magnetic resonance imaging and bone scans as a routine. Thus we are left with enhancing our ability to preoperatively diagnosis N2 disease as a means to improve treatment outcomes.

In this study the most common locations for N2 disease were found to be the subcarinal (7) lymph node station and the lower right paratracheal (4R) station. The most common locations for unsuspected N2 disease were the subcarinal and aorta-pulmonary window stations. The N2 node that is involved may be dependent on the lobar location of the primary tumor, and this is a topic of future study for us, but in this report we do not have enough data for further analysis.

Mediastinoscopy: Staging Upper and Lower Paratracheal Lymph Nodes
Mediastinoscopy is a safe and accurate technique to prove or disprove metastatic NSCLC in the paratracheal (2R, 2L, 4R, and 4L lymph nodes). Although one can often get to the proximal or top part of the subcarinal lymph node by mediastinoscopy, the body of the node (where the vast majority of the cancer was discovered in this study) is not accessible by mediastinoscopy. EUS-FNA is the best method available to assess the entire subcarinal lymph node. Some physicians use it to biopsy the 4R as well, but we have not had that experience. There are many surgeons who perform mediastinoscopy on all patients who have NSCLC. If this had been our standard practice, we would have discovered unsuspected N2 disease in 5 of the 28 patients (assuming a 100% accuracy of mediastinoscopy at all paratracheal stations). However, a few physicians order EUS-FNA on all patients.

The EUS-FNA: Staging Of Posterior Mediastinal Lymph Nodes
EUS-FNA is the best way to obtain cytological confirmation from the 5, 7, 8, and 9 stations. Wallace and colleagues [19] in 2004 showed that 1 in 5 patients have unsuspected N2 disease in the EUS-FNA accessible posterior mediastinal lymph nodes. However, they used CT scan only in that study, and patients did not undergo FDG-PET. Because we have shown EUS-FNA to be both safe and 97% accurate [7] and Savides and Perricone [8] in 2004 reported a similar accuracy of 98% for EUS-FNA for N2 nodes, the addition of EUS in all patients has the potential to significantly lower the incidence of unsuspected N2 disease. One limitation is that EUS-FNA is not available at all centers.

Role of the MaxSUV of the Primary Nonsmall Lung Cancer
A sub-analysis of the 12 patients clinically staged as I who had unsuspected N2 disease and the 14 patients staged as II who had N2 disease shows a greater incidence of adenocarcinoma as compared with other NSCLC types. Moreover, their median maxSUV was higher than those who were truly negative. Perhaps the maxSUV of the primary (> 10) may serve as a guide to help identify those patients who are at greater risk of N2 disease and for those patients who we should more carefully search for it (routine mediastinoscopy and EUS-FNA) prior to resection. We have shown that the maxSUV of the primary itself is a predictor of nodal involvement and survival [20].

Role of the MaxSUV of the Mediastinal Lymph Nodes
This is the first series to show the accuracy of the individual N2 lymph node stations for FDG-PET/CT scans based on the maxSUV of each node. In two of our previous studies, one with 400 patients that evaluated dedicated PET [2] and the other with 129 patients that evaluated integrated PET/CT scans [2], we reported the efficacy at each lymph node station. The findings (accuracy) in those studies were remarkably similar to the results we found in this study. However, the likelihood of finding metastatic cancer in a node based on the maxSUV level for each node has never been reported. In this report we found that as the median maxSUV was higher in those patients with true positive nodes compared with those with false positive nodes. However, as seen in Figure 3, patients can have a maxSUV of greater than 12 in the 4R node, 9 in the 5 node, and 8 in the 7 node, and yet have benign nodes. Thus, false positives are not uncommon with very high maxSUV values. Therefore, histologic confirmation of any suspicious mediastinal lymph node is absolutely mandatory, and treatment decisions can not be made based on the maxSUV on FDG-PET/CT scans alone.

In conclusion, we have shown that the clinical stage, despite the use of integrated FDG-PET/CT scans differs from the pathologic stage in many patients, especially in those with predicted early staged NSCLC. The most common location for N2 disease is the subcarinal lymph node and the lower right paratracheal lymph node. The most common location for unsuspected N2 disease occurs in the posterior mediastinal lymph nodes, especially the subcarinal area. This may be dependent on the lobar location of the primary. Because EUS-FNA has been shown to be a safe, minimally invasive, and accurate technique to biopsy these posterior mediastinal lymph nodes, we suggest it be considered as a routine staging procedure for patients who are clinically staged as I or II or for those with a high maxSUV of the primary, or for both. A prospective trial is needed to evaluate the role of routine EUS-FNA and mediastinoscopy in patients that have FDG-PET/CT scans and CT scans that are normal for mediastinal nodes. This prospective trial has already been approved by the institutional review board at the University of Alabama at Birmingham and is well underway at our institution.


    Discussion
 Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Discussion
 References
 
DR JOHN R. ROBERTS (Nashville, TN): Rob, that's an excellent work and I really think that you've shed some light on some of the difficulty of those of us who are working in the histoplasmosis belt and how positron emission tomographic (PET) scans are not nearly as accurate as they are for perhaps the rest of the country.

The main question I had is that you are supporting using endoscopic ultrasound (EUS) for those stations. You could also use thoracoscopy, especially in those patients that you've already put to sleep for a mediastinoscopy, and it would allow you to identify pleural mets and some other findings that you can't pick up on EUS. I wondered if you would comment about the possible use of that modality.

DR CERFOLIO: That is a good point and of course we do video-assisted thoracoscopic surgery (VATS) as well. I told you EUS-fine-needle aspiration (FNA) is probably best for the No. 7, but thoracoscopy has a lot of advantages of stages, but not just for some nodes—for other areas as well. You're able to look at a pleural space to rule out M1 implants—if there's a fluid collection, you're able to tap it and maybe get more accurate cytology than thoracentesis allows, as we have published in an article last year in Chest. It also allows you to better assess the T, tumor status, as T2 or T3, although that rarely changes what we're going to do. We also didn't mention Wang needle biopsy, which is another way to get to No. 7's, but it doesn't get to 8 or 9. So I think if you are going to be doing a general anesthetic for mediastinoscopy, it may make sense, in some patients, to go ahead and do a thoracoscopy, although there's added time in the OR and added expense and more incisions. Plus some nodes are more difficult to assess because the tumor is in the way and then the VATS is more involved. EUS-FNA, which does not require a general anesthetic or any incisions, I think gives you a bigger bang for your buck because you're able to look at more stations with less invasiveness and cost.

DR DAVID H. HARPOLE, JR (Durham, NC): That's a very nice review of your continued prospective data collection.

I just have a couple of questions. First of all, in your mediastinoscopy, obviously the level 5 nodes were certainly involved and suspicious in a lot of cases. Do you do an extended mediastinoscopy or an anterior mediastinoscopy on patients with left upper lobe lesions to evaluate those?

Secondly, obviously the Japanese have written a lot about this, but you have a pretty good data set here. Can you use this collection of information to kind of give us a better prediction for right upper lobe, where you would want to look first, and left upper lobe, where do you want to look first? I think that's where this will have real value. I would be a little surprised if an apical right lung lesion would map down to the level 9 lymph node occasionally, but you would certainly have information to guide us.

DR CERFOLIO: Thanks Dave, those are great points. We didn't want to throw in too much data into one paper and we always tried to stay focused and answer one specific question at a time, but certainly we have mapped out the distribution of the lymph nodes based on the location of the primary tumor. And you're right, that right upper lobe tumor is going to metastasize to a 4R much more commonly than an 8 or 9. So for that patient we would recommend a mediastinoscopy over an EUS. That's part of the cost analysis that we are studying and hope to deliver in a few years.

As for your other question about extended mediastinoscopy—the short answer is no—I do not do it. I'm chicken, or as I prefer to think about it I am smart. I think that mediastinoscopy is the most dangerous operation I do and certainly the most dangerous operation I teach, and so I do not do any extended mediastinoscopy.

DR HARPOLE: Or Chamberlains?

DR CERFOLIO: Left VATS has supplanted Chamberlain in my practice for the 5 and 6 station. I rarely if ever do a Chamberlain now. As discussed before, I do left VATS to look at the pleura, assess the tumor, and I can most times get to the 5 and especially the 6 nodes very well. Of course, there is a controversy about those nodes acting like N1 nodes in LUL tumors as well—we treat them as N2.

DR FRANK C. DETTERBECK (Chapel Hill, NC): I certainly enjoyed your presentation. I think we need to be sophisticated in how we interpret the data. If you look at PET scanning for distant disease, I think there are a lot of studies that show that if you have a clinical stage I tumor, the chance you're going to actually find distant disease that is a met is less than 5% with PET, whereas if you have clinical stage III disease, you have about a 25% to 30% chance of finding it. You didn't really give us that number, but I would be curious as to what it was in your experience, how often you found distant disease. I also think the same applies for intrathoracic staging if you have central tumors or if you have an N1 tumor. We've got lots of data based on computed tomography (CT) that you have about a 25% to 30% chance of finding unsuspected mets. You found the same thing with PET. We've sort of looked at PET as being the answer, but we've never really looked at it with subsets of patients. So I think it's great that you reported at least that one subset, and I would encourage you to report further subsets, central versus peripheral tumors, to help us get a better idea about PET.

Finally, a word of caution: Although you are recommending EUS, it is really EUS in the face of having done a mediastinoscopy for many of your patients, so that the unsuspected disease was there because we already did a mediastinoscopy in the other locations. And the other thing about EUS is that although the data for EUS suggests that it is a very accurate test, still in most of the centers the EUS is done for enlarged nodes and most of the data that's out there is for enlarged nodes, and whether we're going to be just as accurate in ruling out N2 disease in these unsuspected areas when the nodes are not enlarged I think is not quite as clear, and so I'd be curious to hear your thoughts about that.

DR CERFOLIO: You have raised many excellent points and I'll briefly answer them. I'll group your first two questions and answer them in one. The first two questions were about trying to look at risk factors for peripheral lesions and looking at the role of PET for clinically staged I patients. We have a very important paper coming out in the Journal of CTVS in March or April of this year that shows that the maxSUV of the primary tumor on FDG-PET is a more important predictor of pathologic stage, recurrence and survival than the current TNM staging classification—so that value may be a more important preoperative factor than whether it is peripheral, whether it's central, whether it's adeno, whether it's squamous. It tells you the biological aggressiveness of a tumor in a host, and it doesn't get better than that. So I think when I have a high maxSUV, in our paper it was greater than 10, even if the patient is clinically staged I and small and peripheral, you better look for M1 disease, because you're more likely to find it. So I disagree with your point somewhat and that 5% you quoted might not be applicable to a subset of patients with clinically stage I disease.

The last point is really that EUS-FNA does not replace mediastinoscopy—and we categorically agree—it does not assess the paratracheal nodes well. Mediastinoscopy should still be performed, and the question is should EUS be performed routinely as well. There is a study quoted in our paper that shows that EUS may have a role in patients with normal sized nodes by CT, but PET was not used in that paper—they found unsuspected N2 disease in 1 in 5 patients in that study. And there's a learning curve. We've sent over 900 patients for EUS. You have to have an experienced guy. The only way to get experience is to start sending him cases. Finally, the real future we think, may lie in ultrasound-guided transbronchial biopsies of N1 and N2 nodes.

DR MALCOLM M. DECAMP (Boston, MA): Great series.

I have a specific technical question. You did lymphadenectomy to confirm the positive predictive value of these. I have a specific question about left upper lobe tumors and how you're getting L2 and L4 after doing a left upper lobectomy so that you really have a handle on the occult metastatic disease for that particular subgroup of patients.

DR CERFOLIO: Mack, that's a great question—and you are right—we do not get the 2L's via left thoracotomy. The only way to get them is via mediastinoscopy. But the 4L's I really do get in most all patients, except for obese ones.

DR JACK A. ROTH (Houston, TX): A high percentage of your patients underwent mediastinoscopy. How often did you uncover occult N3 disease in these patients?

DR CERFOLIO: I do not have that number—I will have to go back and look at the stats—but it is not that common, I would say only about 5%.


    References
 Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Discussion
 References
 

  1. Ihde DC, Minna JD. Non-small cell lung cancer: part I. Biology, diagnosis and staging Curr Probl Cancer 1991;15:61-104.[Medline]
  2. Cerfolio RJ, Buddhiwardhan O, Bryant AS, et al. The accuracy of integrated PET/CT compared with dedicated PET alone for the staging of patients with non-small cell lung cancer Ann Thorac Surg 2004;78:1017-1023.[Abstract/Free Full Text]
  3. Antoch G, Stattaus J, Nemat AT, et al. Non-small cell lung cancerdual modality PET/CT in preoperative staging. Radiology 2003;229:525-533.
  4. Lardinois D, Weder W, Hany TF, et al. Staging of non-small cell lung cancer with integrated positron emission tomography and computed tomography N Engl J Med 2003;348:2500-2507.[Abstract/Free Full Text]
  5. Aquino SL, Asmuth JC, Alpert NM, et al. Improved radiologic staging of lung cancer with 2-[18]-flouro-2-deoxy-D-glucose-positron emission tomography and computed tomography registration J Comput Assist Tomogr 2003;27:479-484.[Medline]
  6. Hawes RH, Gress F, Kesler KA, Cummings OW, Conces Jr DJ. Endoscopic ultrasound versus computed tomography in the evaluation of the mediastinum in patients with non-small-cell lung cancer Endoscopy 1994;26:784-787.[Medline]
  7. Eloubeidi MA, Cerfolio RJ, Chen VK, et al. Endoscopic ultrasound-guided fine needle aspiration of mediastinal lymph nodes in patients with suspected lung cancer after positron emission tomography and computed tomography scans Ann Thorac Surg 2005;79:263-268.[Abstract/Free Full Text]
  8. Savides TJ, Perricone A. Impact of EUS-guided FNA of enlarged mediastinal lymph nodes on subsequent thoracic surgery rates Gasterointest Endosc 2004;60:340-346.
  9. Mountain CF. Revisions in the International Systems for Staging Lung Cancer Chest 1997;111:1710-1717.[Abstract/Free Full Text]
  10. Nabi HA, Zubeldia JM. Clinical applications of F18-FDG in oncology J Nucl Med Technol 2002;30:3-9.[Abstract/Free Full Text]
  11. Catalano MF, Sivak MV, Rice T, Gragg LA, Van Dam J. Endosonographic features predictive of lymph node metastasis Gastrointest Endosc 1994;40:442-446.[Medline]
  12. Gress FG, Savides TJ, Sandler A, et al. Endoscopic ultrasonography, fine-needle aspiration biopsy guided by endoscopic ultrasonography, and computed tomography in the preoperative staging of non-small-cell lung cancera comparison study. Ann Intern Med 1997;127:604-612.[Abstract/Free Full Text]
  13. Beck J. Likelihood ratiosanother enhancement of sensitivity and specificity. Arch Pathol Lab Med 1986;110:685-686.[Medline]
  14. Toloza EM, Harpole L, McCrory DC. Noninvasive staging of non-small cell lung cancera review of the current evidence. Chest 2003;123:137S-146S.[Abstract/Free Full Text]
  15. Detterbeck FC, Jones DR, Parker LA. Intrathoracic stagingIn: Detterbeck FC, Rivera PM, Socinski MA, et al. editors. Diagnosis and treatment of lung cancer. an evidence-based guide for the practicing clinician. Philadelphia, PA: Saunders; 2001. pp. 73-93.
  16. Cerfolio RJ, Ohja B, Bryant AS, et al. The role of FDG-PET scan in staging patients with nonsmall cell carcinoma Ann Thorac Surg 2003;76;:861-866.[Abstract/Free Full Text]
  17. Reed CM, Posther KE, Woolson SL, et al. Results of the American College of Surgeons Oncology Group Z0050 trialthe utility of positron emission tomography in staging potentially operable non-small cell lung cancer. J Thor Cardiovasc Surg 2003;126:1945-1951.
  18. Yasufuku K, Chiyo M, Sekine Y, et al. Real-time endobronchial ultrasound guided transbronchial needle aspiration of mediastinal and hilar lymph nodes Chest 2004;126:122-128.[Abstract/Free Full Text]
  19. Wallace MB, Ravenel J, Block MI, et al. Endoscopic ultrasound in lung cancer patients with a normal mediastinum on computed tomography Ann Thorac Surg 2004;77:1763-1768.[Abstract/Free Full Text]
  20. Cerfolio RJ, Bryant AS, Ohja B, et al. The maximum standardized uptake values (SUV) on pet of a non-small cell lung cancer predicts stage, recurrence and survival J Thor Cardiovasc Surg 2005(publication pending).



This article has been cited by other articles:


Home page
Ann. Thorac. Surg.Home page
R. J. Cerfolio, L. Maniscalco, and A. S. Bryant
The Treatment of Patients with Stage IIIA Non-Small Cell Lung Cancer From N2 Disease: Who Returns to the Surgical Arena and Who Survives
Ann. Thorac. Surg., September 1, 2008; 86(3): 912 - 920.
[Abstract] [Full Text] [PDF]


Home page
Ann. Thorac. Surg.Home page
R. J. Cerfolio and A. S. Bryant
Survival of patients with unsuspected N2 (stage IIIA) nonsmall-cell lung cancer.
Ann. Thorac. Surg., August 1, 2008; 86(2): 362 - 366.
[Abstract] [Full Text] [PDF]


Home page
Ann. Thorac. Surg.Home page
R. J. Cerfolio, A. S. Bryant, and L. M. Maniscalco
A nondivided intercostal muscle flap further reduces pain of thoracotomy: a prospective randomized trial.
Ann. Thorac. Surg., June 1, 2008; 85(6): 1901 - 1906.
[Abstract] [Full Text] [PDF]


Home page
Ann. Thorac. Surg.Home page
A. S. Bryant and R. J. Cerfolio
Differences in outcomes between younger and older patients with non-small cell lung cancer.
Ann. Thorac. Surg., May 1, 2008; 85(5): 1735 - 1739.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Respir. Crit. Care Med.Home page
A. Ernst and S. P. Gangadharan
A Good Case for a Declining Role for Mediastinoscopy Just Got Better
Am. J. Respir. Crit. Care Med., March 1, 2008; 177(5): 471 - 472.
[Full Text] [PDF]


Home page
J. Thorac. Cardiovasc. Surg.Home page
R. J. Cerfolio and A. S. Bryant
Is palpation of the nonresected pulmonary lobe(s) required for patients with non-small cell lung cancer? A prospective study.
J. Thorac. Cardiovasc. Surg., February 1, 2008; 135(2): 261 - 268.
[Abstract] [Full Text] [PDF]


Home page
Ann. Thorac. Surg.Home page
B. D. Vincent, E. El-Bayoumi, B. Hoffman, P. Doelken, J. DeRosimo, C. Reed, and G. A. Silvestri
Real-Time Endobronchial Ultrasound-Guided Transbronchial Lymph Node Aspiration
Ann. Thorac. Surg., January 1, 2008; 85(1): 224 - 230.
[Abstract] [Full Text] [PDF]


Home page
JNMHome page
D. Hellwig, T. P. Graeter, D. Ukena, A. Groeschel, G. W. Sybrecht, H.-J. Schaefers, and C.-M. Kirsch
18F-FDG PET for Mediastinal Staging of Lung Cancer: Which SUV Threshold Makes Sense?
J. Nucl. Med., November 1, 2007; 48(11): 1761 - 1766.
[Abstract] [Full Text] [PDF]


Home page
Ann. Thorac. Surg.Home page
R. J. Cerfolio and A. S. Bryant
When is it Best to Repeat a 2-Fluoro-2-Deoxy-D-Glucose Positron Emission Tomography/Computed Tomography Scan on Patients with Non-Small Cell Lung Cancer Who Have Received Neoadjuvant Chemoradiotherapy?
Ann. Thorac. Surg., October 1, 2007; 84(4): 1092 - 1097.
[Abstract] [Full Text] [PDF]


Home page
Ann. Thorac. Surg.Home page
R. J. Cerfolio, A. S. Bryant, and M. A. Eloubeidi
Accessing the Aortopulmonary Window (#5) and the Paraaortic (#6) Lymph Nodes in Patients With Non-Small Cell Lung Cancer
Ann. Thorac. Surg., September 1, 2007; 84(3): 940 - 945.
[Abstract] [Full Text] [PDF]


Home page
ChestHome page
G. A. Silvestri, M. K. Gould, M. L. Margolis, L. T. Tanoue, D. McCrory, E. Toloza, and F. Detterbeck
Noninvasive Staging of Non-small Cell Lung Cancer: ACCP Evidenced-Based Clinical Practice Guidelines (2nd Edition)
Chest, September 1, 2007; 132(3_suppl): 178S - 201S.
[Abstract] [Full Text] [PDF]


Home page
ChestHome page
F. C. Detterbeck, M. A. Jantz, M. Wallace, J. Vansteenkiste, and G. A. Silvestri
Invasive Mediastinal Staging of Lung Cancer: ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition)
Chest, September 1, 2007; 132(3_suppl): 202S - 220S.
[Abstract] [Full Text] [PDF]


Home page
ThoraxHome page
F. C Detterbeck
Evolution and science, progress and change
Thorax, August 1, 2007; 62(8): 654 - 655.
[Full Text] [PDF]


Home page
Ann. Thorac. Surg.Home page
R. J. Cerfolio and A. S. Bryant
Predictors of Survival and Disease-Free Survival in Patients With Resected N1 Non-Small Cell Lung Cancer
Ann. Thorac. Surg., July 1, 2007; 84(1): 182 - 190.
[Abstract] [Full Text] [PDF]


Home page
J. Thorac. Cardiovasc. Surg.Home page
R. J. Downey, T. Akhurst, M. Gonen, B. Park, and V. Rusch
Fluorine-18 fluorodeoxyglucose positron emission tomographic maximal standardized uptake value predicts survival independent of clinical but not pathologic TNM staging of resected non-small cell lung cancer
J. Thorac. Cardiovasc. Surg., June 1, 2007; 133(6): 1419 - 1427.
[Abstract] [Full Text] [PDF]


Home page
Ann. Thorac. Surg.Home page
R. J. Cerfolio and A. S. Bryant
Ratio of the Maximum Standardized Uptake Value on FDG-PET of the Mediastinal (N2) Lymph Nodes to the Primary Tumor May Be a Universal Predictor of Nodal Malignancy in Patients With Nonsmall-Cell Lung Cancer
Ann. Thorac. Surg., May 1, 2007; 83(5): 1826 - 1830.
[Abstract] [Full Text] [PDF]


Home page
J. Thorac. Cardiovasc. Surg.Home page
B. E. Lee, D. von Haag, T. Lown, D. Lau, R. Calhoun, and D. Follette
Advances in positron emission tomography technology have increased the need for surgical staging in non-small cell lung cancer
J. Thorac. Cardiovasc. Surg., March 1, 2007; 133(3): 746 - 752.
[Abstract] [Full Text] [PDF]


Home page
J. Thorac. Cardiovasc. Surg.Home page
R. J. Cerfolio
Reply to the Editor
J. Thorac. Cardiovasc. Surg., January 1, 2007; 133(1): 276 - 277.
[Full Text] [PDF]


Home page
J. Thorac. Cardiovasc. Surg.Home page
A. S. Bryant and R. J. Cerfolio
The clinical stage of non-small cell lung cancer as assessed by means of fluorodeoxyglucose-positron emission tomographic/computed tomographic scanning is less accurate in cigarette smokers
J. Thorac. Cardiovasc. Surg., December 1, 2006; 132(6): 1363 - 1368.
[Abstract] [Full Text] [PDF]


Home page
ChestHome page
R. J. Cerfolio, A. S. Bryant, and M. A. Eloubeidi
Routine Mediastinoscopy and Esophageal Ultrasound Fine-Needle Aspiration in Patients With Non-small Cell Lung Cancer Who Are Clinically N2 Negative: A Prospective Study
Chest, December 1, 2006; 130(6): 1791 - 1795.
[Abstract] [Full Text] [PDF]


Home page
ChestHome page
R. J. Cerfolio, A. S. Bryant, E. Scott, M. Sharma, F. Robert, S. A. Spencer, and R. I. Garver
Women With Pathologic Stage I, II, and III Non-small Cell Lung Cancer Have Better Survival Than Men
Chest, December 1, 2006; 130(6): 1796 - 1802.
[Abstract] [Full Text] [PDF]


Home page
Ann. Thorac. Surg.Home page
A. S. Bryant, S. J. Pereira, D. L. Miller, and R. J. Cerfolio
Satellite Pulmonary Nodule in the Same Lobe (T4N0) Should Not Be Staged as IIIB Non-Small Cell Lung Cancer
Ann. Thorac. Surg., November 1, 2006; 82(5): 1808 - 1814.
[Abstract] [Full Text] [PDF]


Home page
Ann. Thorac. Surg.Home page
A. S. Bryant and R. J. Cerfolio
The maximum standardized uptake values on integrated FDG-PET/CT is useful in differentiating benign from malignant pulmonary nodules.
Ann. Thorac. Surg., September 1, 2006; 82(3): 1016 - 1020.
[Abstract] [Full Text] [PDF]


Home page
Ann. Thorac. Surg.Home page
R. J. Cerfolio and A. S. Bryant
Maximum Standardized Uptake Values on Positron Emission Tomography of Esophageal Cancer Predicts Stage, Tumor Biology, and Survival
Ann. Thorac. Surg., August 1, 2006; 82(2): 391 - 395.
[Abstract] [Full Text] [PDF]


Home page
Ann. Thorac. Surg.Home page
A. S. Bryant, R. J. Cerfolio, K. M. Klemm, and B. Ojha
Maximum Standard Uptake Value of Mediastinal Lymph Nodes on Integrated FDG-PET-CT Predicts Pathology in Patients with Non-Small Cell Lung Cancer
Ann. Thorac. Surg., August 1, 2006; 82(2): 417 - 423.
[Abstract] [Full Text] [PDF]


Home page