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Ann Thorac Surg 2007;83:1826-1830
© 2007 The Society of Thoracic Surgeons
a Department of Surgery, Division of Cardiothoracic Surgery, University of Alabama at Birmingham School of Public Health, Birmingham, Alabama
b Department of Epidemiology, University of Alabama at Birmingham School of Public Health, Birmingham, Alabama
Accepted for publication December 19, 2006.
* Address correspondence 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 Fifty-third Annual Meeting of the Southern Thoracic Surgical Association, Tucson, AZ, Nov 8–11, 2006.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsCommentDiscussionReferences |
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Methods: This is a retrospective review of a prospective database. Patients with nonsmall-cell lung cancer, a dedicated FDG-PET with the maxSUV of the primary lung tumor and FDG-avid mediastinal (N2) nodes reported (before therapy), and who underwent lymph node removal were eligible.
Results: There were 239 patients with 335 FDG-PET–positive N2 nodes at 14 different PET centers. The median ratio of the maxSUV of the lymph node to the maxSUV of the primary tumor of the pathologically proven malignant nodes was 0.58 (range, 0.32 to 1.61). Benign nodes had a median ratio of 0.40 (range, 0.21 to 1.10, p = 0.02). The median value was similar for all centers except one. Receiver operating characteristics analysis determined the optimal value of the ratio that maximized sensitivity to be 0.56 or greater (+LR 6.6, sensitivity 94%, specificity 72%).
Conclusions: The ratio of the maxSUV of the mediastinal (N2) lymph node to the maxSUV of the primary tumor in patients with nonsmall-cell lung cancer predicts mediastinal nodal pathology across different PET centers. When the ratio is 0.56 or greater, there is a 94% chance that the node is malignant. The ratio may take into account the different techniques used at different centers.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionReferences |
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Because the maxSUV of the tumor and the N2 lymph nodes is clinically significant and as there exists about a 10% to 15% difference in this value across centers, we sought a way to account for this variation and yet help clinicians who treat patients with NSCLC at different PET centers across the world. We hypothesized that a ratio between two SUV values may take this difference into account and control for it. We generated a ratio by dividing the maxSUV of the primary tumor by the maxSUV of the regional lymph node. Our hypothesis was that a ratio of these two maxSUV values, which were derived at the same time under the same FDG-PET scanning techniques, might be a universal predictor of lymph node pathology. We have called this ratio the PET predictive ratio for mediastinal N2 lymph node pathology.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionReferences |
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Radiologic Imaging
The FDG-PET/CT scans that were performed at the University of Alabama were done using an integrated PET/CT scanner (GE Discovery LS PET-CT Scanner; General Electric, Milwaukee, Wisconsin). Patients were asked to fast for 4 hours, and then subsequently received 555 MBq (15 mCi) of FDG intravenously followed by PET after 1 hour. The scans were performed from the skull base to midthigh level. The CT examination was used for attenuation correction of PET images. The scanning time for emission PET 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. The maxSUV of the primary and of each suspicious lymph node station was determined by drawing regions of interest on the attenuation-corrected FDG-PET images around it. It was then calculated by the software contained within the PET or PET/CT scanner by the formula [8]:
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Scans from other PET centers were also eligible for this study. Entry criteria used to accept other PET scan reports mandated a dedicated PET center (this excludes coincidence detection systems) and a PET report that provides the maximum standardized uptake values of the primary tumor in the lung and of the PET-positive regional N2 lymph nodes. In addition, the report had to be signed by a board-certified nuclear radiologist. If the patient was considered N2 lymph node negative by the PET or if the lymph node maxSUV was not provided, the patient was excluded from this study. Only the maxSUV was used for this study; mean and peak SUV were not used. If the patient had more than one lung nodule, the highest maxSUV of the two lung nodules was used to calculate the ratio. We have called this new ratio, which has no units, the PET predictive ratio (PPR) for mediastinal N2 lymph node pathology. It is thus calculated by:
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Procedures, Staging, and Surgery
All patients were clinically staged using the T, N, M classification system [9]. A clinical stage was assigned for the patient based on the integrated FDG-PET/CT scan results by one physician (R.J.C.). Biopsy specimens were obtained from suspicious N2, N3, or M1 areas (maxSUV > 2.5) before pulmonary resection. Mediastinoscopy was used to obtain biopsies of suspicious lymph nodes in the paratracheal area (stations 2R, 4R, 2L, 4L, and the superior part of the 7), and endoscopic transesophageal ultrasound fine-needle aspiration (EUS-FNA) was used to obtain biopsies of suspicious posterior aortopulmonary window lymph nodes (5), subcarinal (7), periesophageal (8), and inferior pulmonary ligament lymph nodes (9). Endoscopic ultrasonography was performed under conscious sedation, as previously described [10, 11].
Statistical Methods
Data were imported from the prospective database (Excel; Microsoft Corp, Seattle, Washington) into an Access database (Microsoft Corp). Receiving operator characteristics (ROC) curves were generated using SAS 9.0 (SAS Institute, Cary, North Carolina). A p value of 0.05 or less was considered to indicate a statistically significant outcome that was unlikely due to chance.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionReferences |
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Figure 1 depicts the positive predictive value for various ranges of the PPR for mediastinal lymph nodes. This figure is powerful because it allows one to predict the probability that an N2 lymph node is malignant despite where the patient had their PET performed. Figure 2 shows the ROC curves for the optimal cut-off value of the PPR to predict metastatic in a mediastinal N2 lymph node for all centers. It found that a ratio of 0.56 or greater was predictive of lymph node malignancy (+LR 6.6, sensitivity 94%, specificity 72%).
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Comment |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionReferences |
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Although SUVs are widely reported by most PET centers, there is an inherent variability in this measurement from one center to another. First, some centers report mean SUV instead of maxSUV. We prefer the max SUV because reports show that there is as much as 35% variability between different observers when the mean SUV value is used. This difference between observers when reading the same PET scan is reduced to only about 3% when the maximum SUV values are used [7]. However, the difference between maxSUVs at different PET centers remains high at 10% to 15%. Interestingly, a new value called the peak SUV has recently has been reported, but consensus on how to calculate it remains unresolved [14, 15]. The peak SUV may be determined by taking the top 5% or 10% of the hottest pixels and averaging them together. It may become the new preferred value over maxSUV in the future.
Because the formula of the maxSUV, as shown in the Methods section, is based only on the activity at a pixel, the injected dose of FDG, and the patient’s weight, one might think that there should be little to no variation across centers. However, several factors do conspire to lead to a 10% to 15% difference in this value. These factors include the well counter that is used to measure the does of FDG injected, the time between dose injection and imaging, attenuation correction variables, injected FDG that may extravasate into the subcutaneous tissue, patient muscular activity in between injection and scanning, and finally, glucose and insulin levels. These factors may vary some among institutions [16] and between one scan and another.
We hypothesized that a ratio of maxSUV values (ie, one maxSUV value divided by another) may be one way to negate these inherent differences between PET centers and standardize the measurement. That would potentially generate clinical research on PET data that was applicable to physicians using PET centers all over the world. This new ratio, which we call the PET predictive ratio for mediastinal N2 lymph nodes (or, PPR for N2 nodes), does seem to be reproducible for four centers and for the combination of 11 centers, which served as a fifth center. These data, if corroborated from other reports, may be clinically useful. The histology of N2 nodes is crucial in the treatment strategy of patients with NSCLC. This ratio may help direct the type of N2 biopsy employed. For instance, if the ratio shows the paratracheal 4R nodes has a PPR of 0.9 and the no. 8 periesophageal lymph node has a PPR of 0.5, perhaps a mediastinoscopy may be preferred over EUS-FNA. However, if the no. 8 N2 lymph node station has a PPR of 0.7 and the other N2 nodes are less, then perhaps that patient should go first for EUS-FNA.
Our future studies are analyzing other ratio values as well using the maxSUV data. For instance, perhaps the ratio of the maxSUV/cm of tumor (in the tumor’s greatest dimension on the CT scan) or the maxSUV/cm2 or cm3 may be an important way to ensure that the SUV is not just a surrogate marker for size. This ratio value (and perhaps we should use peak SUV/cm or peakSUV/cm2 in the future) may be another important value that is easily generated from PET data, and one that helps guide clinical decisions.
More data are needed from a larger number of patients and from many different centers. This preliminary report suggests that the PET positive ratio for mediastinal N2 lymph nodes has promise. It may be a predictor of N2 mediastinal lymph node pathology for different PET centers for NSCLC patients who have the maximum SUV of both their lung cancer and of regional N2 lymph nodes reported.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionReferences |
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I am glad that Cerf has moved on from air leaks, which he produced four papers, at least two presented before this Association, to the SUV, and now this is the fourth paper in the last two years on a similar subject, though it be either lung or esophagus. I think he is probably Professor of Nuclear Medicine at the University of Alabama. I know I need to be careful what I say because you remember yesterday in the pro-con debate when his opponent was already on the ground after being hit eight times, writhing in pain, pleading for mercy, Cerf says, I hate to put the dagger in, but he put it right through the heart, delivering the death knell. So I have to be careful what I say, but I will move on. But it is the collegiality of discussion at the Southern Thoracic that we are able to say such things.
This is a very well thought out study and I appreciate the author sending me the manuscript before the meeting. First, he makes several well known points in his manuscripts that the SUV is a known predictor of disease virulence, predicts response to chemotherapy, and also the potential for predicting nodal spread. He then presents a new formula called a PET predictive ratio that would take a computer to compute. I really think he wants it to be known as the Cerf ratio.
The criticism of the study is that it is carried out in 14 different centers all related to UAB. We all know that all CT-PET scanners are not the same. In addition, approximately 10 years ago, as I remember talking to Cerf, they did not even report the SUV out on PET scans at the University of Alabama. I am not sure that a PET predictive ratio at the present time really changes how we practice. Cerf, I have just a couple of questions for you.
How does the PET predictive ratio change the way you practice at the current time? If lymph nodes are greater than 1.5 cm, then it is probably gong to be biopsied by either mediastinoscopy or the new technique of fiberoptic bronchoscopy with ultrasound FNA.
In conclusion, he points to the ongoing future studies, so I know that we will have more. In his reference list, he has 18 references, and in these, nine are headed by Cerf. I know we are going to hear more from him in the future. I think he is correct in that a multi-institutional study is necessary to confirm the usefulness of the PET predictive ratio. Cerf, I think you are a great guy and you have done wonders at the University of Alabama, and I am very proud of you.
DR CERFOLIO: First of all, and I mean this in all sincerity, it is an honor for me to have Dr Miller discuss my paper. He doesn’t know it, but the only reason I am standing here today is because of Dr Miller. He took me under his wing when I first started at UAB and was a lone fish out of water, and Dr Miller introduced me to this society as well as others – he got me into the Southern, and onto the program committee so I am honored to have him as my discussant. Dr Miller, you sir can poke fun at me all you want.
To answer your questions, all of these centers were not related to UAB. These are centers all throughout Alabama, Tennessee, Florida, and other places. So I just want to make sure that is clear. These are 14 different centers. The center with the most patients however is the one integrated PET/CT center at UAB. Second, our centers have always reported the maxSUVs when we first got it – you may be confusing us with Duke that has not provided SUV data on PET scans over the past several years. We didn’t have an integrated PET/CT scanner at UAB until I think 2001. We were using one in private practice across the street and they were recording maxSUV as well.
Finally, your third question is, how does the PPR change my practice? Well, it really does change my practice. If a lymph node is enlarged on CT scan, you are right, we are going to biopsy it irrespective of the PET, but most enlarged lymph nodes are PET positive, assuming the patient has non-small cell lung cancer. So the PPR gives you a target as to what to go after first because it is most likely to be malignant. For instance, if the 4R has a PPR of 0.4, but the subcarinal #7 LN’s PPR is 0.7, then I would go to an EUS-FNA, because we have a higher accuracy of hitting the subcarinal nodes with an EUS-FNA than a mediastinoscopy and it is more likely positive than the 4R. We would go to the EUS. So it has changed my practice. Thank you.
DR DANIEL L. MILLER (Atlanta, GA): Cerf, I enjoyed your paper. It was actually the shortest presentation I think I have ever heard you give in your academic life, so I don’t know how valid the data is in this series.
The big question I have is that if you have a tumor that has an endobronchial component resulting in postobstruction pneumonia or if the tumor has a necrotic center, then you may have a falsely elevated maxSUV, which is going to drive your ratio down. Did you look at that at all, because I think you have to include the anatomical location of the tumor and its secondary effects in analyzing the maxSUV?
DR CERFOLIO: That is an important point and is true for mean SUV not maxSUV. Your comments are correct if you look at the mean SUV value of a tumor with a necrotic center, but if you look at the maxSUV, the entire middle part of that tumor could have a maxSUV of zero but you will have a pixel with a maxSUV of 11, and so you report it as an 11. So this is why radiologists have used the max over the mean, because it is more reproducible, less objective. So the maxSUV won’t be affected. Soon it will be peak SUV as I discussed during the talk.
DR BRYAN FITCH MEYERS (St. Louis, MO): Dr Cerfolio, I have one question for you. You used a ratio, but you didn’t show us that the ratio gave you any additional benefit over just using the maxSUV of the mediastinal lymph nodes. Do you have any comparison of using the ratio system that you have reported versus just a simpler maxSUV system on the same patients to show that it discriminates better?
DR CERFOLIO: We have shown in previous reports that the maxSUV of lymph nodes, and I didn’t want to re-bore anybody too much with the other stuff that we have presented nationally, that there is a very large overlap between falsely positive and truly positive mediastinal lymph nodes. The idea of a ratio was to try to decrease the false positives rates when compared to using just the absolute value and to produce a number that could be applied to patients on various PET’s all over the world. Now it is true that we did not set out to do this in this manuscript – the goal of this study was to identify a ratio and see if it was consistent between different Pet centers and it was. But we did not show the fall in the false positive rate is in this report, you are correct. One of the criticisms I have received in the past, as Dr Miller talked about me doing a lot of SUV papers, was that, well, maybe the maxSUV values I talk about are good for me, but how does it help you in Atlanta or how does it help you in St. Louis? So we wanted to do something that was going to be more applicable to people everywhere and not just isolated to the UAB PET scanner. And so that is why we did this ratio study. We could go back and look at the maxSUV of each lymph node and calculate the false positive rate compared to the false positive rate for the ratio.
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References |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionReferences |
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This article has been cited by other articles:
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  B. E. Lee, J. Redwine, C. Foster, E. Abella, T. Lown, D. Lau, and D. Follette Mediastinoscopy might not be necessary in patients with non-small cell lung cancer with mediastinal lymph nodes having a maximum standardized uptake value of less than 5.3 J. Thorac. Cardiovasc. Surg., March 1, 2008; 135(3): 615 - 619. [Abstract] [Full Text] [PDF]
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 R. J. Cerfolio and A. S. Bryant Reply Ann. Thorac. Surg., November 1, 2007; 84(5): 1798 - 1798. [Full Text] [PDF]
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