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a Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts
b Division of Biostatistics, Indiana University School of Medicine, Indianapolis, Indiana
Accepted for publication May 28, 2009.
* Address correspondence to Dr Okereke, Department of Surgery, Section of Cardiothoracic Surgery, Indiana University School of Medicine, 545 Barnhill Dr, EH 215, Indianapolis, IN 46202 (Email: iokereke{at}iupui.edu).
Presented at the Forty-fifth Annual Meeting of The Society of Thoracic Surgeons, San Francisco, CA, Jan 26–28, 2009.
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Abstract |
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Methods: From January 2005 through June 2007, 584 consecutive patients undergoing integrated PET-CT scan for suspected lung cancer were studied. Results of integrated PET-CT scans, including the maximum SUV-T and SUV-N, were recorded. A patient was defined as having a positive PET scan if the maximum SUV (T or N) was greater than 2.5. Overall survival was documented from clinical records and the Social Security Death Index. Cox regression analysis was used to evaluate the correlation between SUV and survival.
Results: Among patients with a positive PET scan (n = 329), both SUV-T and SUV-N were predictors of survival. As maximum SUV of the primary mass increased, survival decreased (hazard ratio, 1.05; p < 0.001). As maximum SUV of locoregional lymph nodes increased, survival also decreased (hazard ratio, 1.06; p < 0.001). Furthermore, among patients with no mediastinal disease identified by PET-CT scan, increased SUV-T continued to predict poor survival (hazard ratio, 1.06; p = 0.001).
Conclusions: Local and regional maximum SUVs defined by integrated PET-CT scanning have a strong correlation with survival in patients with non–small cell lung cancer. An elevated SUV is known preoperatively and may assist clinicians in stratifying patients at increased overall risk preoperatively.
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Introduction |
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The results of PET-CT scan may also be able to stratify patients with lung cancer in terms of ultimate prognosis, as has been shown in previous studies [3–6]. Our goals were to determine whether the clinical stage, based on preoperative PET-CT scan, predicts overall outcome and to understand the correlation between standardized uptake value (SUV) and survival.
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Material and Methods |
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Outcomes
The results of the integrated PET-CT scan, including SUV-T and SUV-N, mass size, presence of lymphadenopathy by CT criteria (>1 cm in short-axis dimension), and location of positivity were recorded. Similarly, the clinical and pathologic stages were determined, using standard TNM classifications [9], in patients who underwent surgery. Survival data was obtained through electronic medical records and verified using the Social Security Death Index.
Surgical procedures were performed by 3 staff surgeons at the Beth Israel Deaconess Medical Center. Each surgical procedure was performed using either video-assisted thoracoscopic surgery or an open approach, depending on patient and tumor characteristics. Preoperative staging of the mediastinum was performed using esophageal ultrasound and endobronchial ultrasound when deemed appropriate. Mediastinal lymph node sampling and dissection were performed routinely as a part of the procedure.
Positron Emission Tomography–Computed Tomography Scan
All patients fasted for greater than 4 hours before the scan. Blood glucose levels were determined before administration of 10 Ci [18F]fluorodeoxyglucose (18FDG). Sixty minutes after administration of 18FDG, PET and CT scans were obtained from the skull base to the level of the hips. All integrated PET-CT scans were reviewed by radiologists who specialized in nuclear medicine techniques. A PET-CT scan was interpreted as positive if the maximum SUV-T or SUV-N of a study exceeded 2.5.
Images obtained from PET scan were reconstructed using standard algorithms. Abnormal 18FDG uptake was defined as areas with activity greater than in surrounding tissue and unrelated to sites with normally increased uptake of tracer (myocardium) or excretion (bladder). For the calculation of SUV, circular regions of interest (
70 pixels) were drawn on axial images adjacent to areas of increased 18FDG uptake. The SUV was calculated using the following equation:
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Statistical Analysis
Continuous variables were summarized by mean and standard error, and categorical variables were summarized by frequency and percentage. Cox proportional hazard model was used to correlate continuous independent variables with survival. The association between SUV and mortality for individual stage or grouping of stages was analyzed in combination with a Cox regression model, controlling for mass size and largest node size. The proportional hazard assumption was tested by the approach proposed by Lin and colleagues [10]. Survival functions of different populations were estimated by Kaplan-Meier estimator and compared by log-rank test. All analyses were performed by SAS 9.1 (SAS Institute Inc, Cary, NC).
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Results |
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Comment |
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Overall PET stage was seen to predict survival in our study. This finding has been seen previously [4] and is in part related to the poor overall outcome in patients identified with advanced disease, especially in patients with M1 disease [11].
Because patients with M1 disease have such guarded outcomes, we performed separate analyses of the role of SUV versus survival excluding these patients. Even after excluding patients with M1 disease, there was still a significant correlation between SUV and survival, both in the primary tumor and in locoregional lymph nodes. This correlation was also significant in the group of patients with pathologic evidence of malignant disease. Importantly, these analyses were performed adjusting for mass size to prevent potential confounding from a variable already known to be associated with worse survival. These findings are important in that they can perhaps guide treatment plan based on these values, as the SUV levels are known preoperatively.
We also thought it was important to analyze the correlation of SUV with survival within each clinical stage. Although the only individual stage with a statistically significant association of SUV and survival was for patients with PET stage II, the group of patients with no clinical evidence of disease in the mediastinum (PET stages I and II) and the group of patients with no clinical evidence of metastatic disease (PET stages I, II, and III) each had significant associations. These two groups are composed of the patients most likely to benefit from appropriate preoperative risk stratification and potential surgical resection. Whereas the long-term survival in patients identified with M1 disease is unlikely to be affected considerably, alterations in management based on SUV can potentially impact long-term outcome in patients with stage I, II, or III disease identified clinically. Many centers now use SUV primarily as an "all or none" value, with values above 2.5 considered positive and values below 2.5 considered negative. The results of this study argue that SUV should instead be used as a gradient, and higher values should potentially alter overall treatment plan. Decisions about whether to perform mediastinoscopy before resection [12], the need for adjuvant therapy [13], and the frequency of postoperative surveillance all may be affected by preoperative SUV levels.
Our study has shown that survival decreases as SUV of the primary tumor or locoregional lymph nodes increases. An important point that remains to be discovered, however, is the mechanism of failure in these patients. One potential mechanism is that tumors with higher SUV values have a more advanced stage at surgery than predicted by the preoperative PET stage, implying that as the SUV increases, accuracy decreases. Another potential mechanism is earlier local recurrence of disease, implying that tumors with higher SUV values are more locally aggressive. Yet another possible mechanism is an increased propensity for distant metastasis. Prospective studies are required to determine the absolute causes for decreased survival in patients with higher SUV values.
Although we believe that SUV should be used as a gradient, we attempted to find a cutoff value, above and below which there were significant differences in survival. We were able to achieve this both for SUV-T and SUV-N, with values of 12.5 and 9.7, respectively. We believe that these cutoff points can be useful as a reference for clinicians, and may eventually be able to be incorporated into a staging system. Further prospective studies are required, however, before this goal can be achieved. This cutoff would be especially practical in patients with no evidence of mediastinal disease preoperatively. Better ability to stratify these patients would lead to more accurate prediction of long-term outcome and more appropriate treatment preoperatively. Our results argue that patients with a high SUV would potentially profit from a more aggressive treatment plan, including mediastinoscopy before resection of the primary tumor and adjuvant chemotherapy, regardless of final pathologic results.
The goals of this study were to determine the ability of PET-CT to predict survival in patients with suspected lung cancer, and to understand which specific aspects of PET-CT were important. Preoperative PET stage does predict long-term outcome, and SUV values predict survival. Further studies are required to determine mechanisms of failure related to higher SUV values.
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Discussion |
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Second, what do we do now with the patient who is mediastinoscopy negative, but who has a tumor with an SUV of 15 and a node of 12, which would fall into your high-risk group? Should we give those patients induction chemo? Is your group starting to look at that or considering it?
DR OKEREKE: I think those are both great questions. I think the second one goes toward the heart of the relevance of this study.
To answer the first question, approximately 10% to 15% of our patients had bronchoalveolar pathology. As such, I would say that bronchoalveolar probably does not have a significant impact toward the overall results of this study. This is my approximation.
As to the second question, I think that once again the relevance of this study is, especially in mediastinal-negative patients with a very high SUV, should we do neoadjuvant strategies? I think based on this, the next study should be a prospective randomized trial looking at SUV and potentially separating patients into two groups, one with neoadjuvant and one without. I think that will be the next step.
DR MICHAEL J. LIPTAY (Chicago, IL): I enjoyed the paper very much. I have a question along similar lines when the tumor SUV is high and the hilar and mediastinal nodes are negative. Do you change your strategy at all?
Secondly, did you find in the pathologic analysis of the surgical specimens that the nodes had a higher incidence of being positive; that is, high SUV in the tumor may predict nodal positivity because it's a more aggressive tumor?
DR OKEREKE: Yes, that's a great question. In fact, that's what we investigated. It did not specifically say, and there was no statistical significance in the difference of concordance between the two in that situation. But I think that's what potentially further analysis would need to consider.
DR JOSHUA R. SONETT (New York, NY): Excellent presentation. Did you look at all at the size of the tumor relative to the SUV and quantitate SUV for the size?
So does a 1-cm tumor that throws off an SUV of 10 versus a 10-cm tumor that throws off an SUV of 10 have different clinical outcomes, as per gram of tumor the smaller tumor appears more active?
DR OKEREKE: Yes, we did. Yes, I didn't include that. The size of the tumor was correlated with survival, which is not too unexpected. Secondly, these results were independent of mass size.
DR LIPTAY: No. But did you ever think of dividing by the size of the tumor, so an SUV, like a DLCO (lung diffusing capacity for carbon monoxide), for the size of that tumor?
DR OKEREKE: Oh, I see. No, we did not.
DR LIPTAY: So a 1-cm tumor that throws off an SUV of 5 may be worse than a 5-cm tumor that throws off an SUV of 12. It may bespeak early to the bad biologic character of it, but it didn't get big enough to throw off an SUV of 12.
DR OKEREKE: No, I think that's a good point.
DR LIPTAY: But you have that data, so it might be nice for us to see it in the future.
DR PAUL DE LEYN (Leuven, Belgium): Thank you for your very nice presentation. As you know, SUV is not at all standardized. It might be standardized in one institution for one PET (positron emission tomography) scanner, but you cannot transmit the data for other PET scanners.
Can we use the data from your center to select patients for adjuvant therapy in centers with other PET scanners?
DR OKEREKE: Yes. Though it is called Standard Update Value, it's quite nonstandard across different PET scanners.
We eliminated that problem at our institution because we had a single PET-CT scanner which was used for all 584 patients. But I think trying to apply a cutoff value among different institutions may have some degree of difference.
That being said, there has been some work by Dr Cerfolio. That's one of the papers that we've referenced. His cutoff value by a different methodology was about 10. We had a cutoff value for the primary tumor of 12.5.
I think that there will be some gray area, but it still should not eliminate the possibility of trying to create some type of randomized trial looking at neoadjuvant strategies based on SUV. I think that's a great point, though.
DR SETH D. FORCE (Atlanta, GA): I have a quick question. I think that one of the previous questions may have addressed this, but I didn't see kind of a report of the accuracy of your PET imaging. And so for patients who were N1 positive by PET, what was the concordance in pathologic specimens?
DR OKEREKE: Right. N1 disease was very limited preoperatively, but I think it's a good point.
DR JONES: Did you do a multivariate analysis of SUVmax? You're saying it's a marker of a poor prognosis if it's above or below a certain number. But is it an independent predictor of a poor prognosis?
Did you look at tumor size, pathologic stage, or other kinds of histopathologic variables such as grade or lymphovascular invasion?
DR OKEREKE: To answer your question, yes and no. We did it based on mass size as well.
DR JONES: And was it a multivariate analysis?
DR OKEREKE: Yes.
DR LEDFORD POWELL (Newport Beach, CA): A quick question. I enjoyed the presentation. You actually answered a lot of questions that I had had about PET scans previously.
I did want to know whether or not you noticed a correlation between the mediastinal-negative patients that had high primary tumor SUVs and their tumor biology, meaning if they had a low SUV, did they have moderately differentiated adenocarcinoma? And if they had a higher SUV, did they have a more aggressive tumor?
And should we be considering the aggressiveness of the tumor when we're looking at whether or not these patients need to get chemotherapy?
DR OKEREKE: Yes, I think potentially, and, no, we did not notice that.
DR JEAN-FRANCOIS LEVI (Neuilly-sur-Seine, France): Did you notice if the decrease of SUV after chemotherapy is a better prognostic or not?
DR OKEREKE: No, that wasn't included in our study. No, we did not include patients who underwent neoadjuvant chemoradiation in this study.
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