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J Thorac Cardiovasc Surg 2007;133:746-752
© 2007 The American Association for Thoracic Surgery

General Thoracic Surgery

Advances in positron emission tomography technology have increased the need for surgical staging in non–small cell lung cancer

^a Division of Cardiothoracic Surgery, University of California at Davis, Cancer Center, Sacramento, Calif
^b University of California at Davis, Cancer Center, Sacramento, Calif
^c Department of Internal Medicine, Division of Oncology, University of California at Davis, Cancer Center, Sacramento, Calif.

Read at the Thirty-second Annual Meeting of the Western Thoracic Surgical Association, Sun Valley, Idaho, June 21-24, 2006.

Received for publication June 18, 2006; revisions received October 2, 2006; accepted for publication October 24, 2006.

^_* Address for reprints: David Follette, MD, Division of Cardiothoracic Surgery, University of California at Davis, UC Davis Cancer Center, 4501 X St, Sacramento, CA 95817. (Email: david.follette{at}ucdmc.ucdavis.edu).

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Objectives: Pretreatment staging of patients with non–small cell lung cancer is critically important in determining an appropriate treatment plan. As positron emission tomography (PET) and computed tomography (CT) are proven complementary modalities in clinical staging, recent advances in PET technology have brought forth integrated PET/CT as the new standard. We tested the hypothesis that improvements in PET technology have not increased the sensitivity or specificity of PET in the staging of non–small cell lung cancer to an extent that surgical staging is no longer required.

Methods: This is a retrospective, single-institution review of 336 patients from 1995 to 2005 with biopsy-proven non–small cell lung cancer who underwent [¹⁸F] fluoro-2-deoxy-D-glucose–PET before mediastinal lymph node sampling by cervical mediastinoscopy or thoracotomy. Clinical records, histopathologic reports, and PET findings were reviewed. Data were analyzed by the Pearson ² test.

Results: Within the study population, 210 patients had routine PET and 126 had integrated PET/CT. For detecting mediastinal metastases the sensitivities of PET versus integrated PET/CT were 61.1% versus 85.7% (P < .05), specificities were 94.3% versus 80.6% (P < .001), positive predictive values were 68.8% versus 55.8%, negative predictive values were 92.1% versus 95.2%, and overall accuracy was 88.6% versus 81.7%.

Conclusions: Improvements in PET technology have increased integrated PET/CT sensitivity at the cost of significantly decreased specificity. Although it may appear that integrated PET/CT incurs fewer false negative results, the dramatic increase in false positive results reinforces the notion that integrated PET/CT should be used only as an adjunct to clinical staging and that surgical staging remains the gold standard in non–small cell lung cancer.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
Non–small cell lung cancer (NSCLC) remains the leading cause of cancer death in the United States today.¹ Given the recent advances in therapeutic options and the changing treatment algorithms, accurate pretreatment staging in NSCLC is of paramount importance in formulating an appropriate treatment plan. Patients without mediastinal lymph node disease (N0 or N1) have a better prognosis and have traditionally been treated with surgical resection alone.² Recent evidence has demonstrated a modest improvement in survival with the addition of adjuvant chemotherapy for patients with stage II or IIIA disease.^3,4 On the other hand, patients with gross mediastinal disease (N2 or N3) are commonly treated with definitive chemoradiotherapy.^5,6

Whole-body positron emission tomography (PET) with [¹⁸F] fluoro-2-deoxy-D-glucose (FDG) has rapidly become accepted as the standard noninvasive modality for staging in patients with NSCLC.^7-11 Although PET has been shown to be superior to computed tomography (CT) for staging of NSCLC, in reality PET and CT are complementary modalities whose combined diagnostic value is superior to either study alone.¹² Accordingly, technologic advances have introduced integrated PET/CT as the newest modality in the armamentarium of cancer staging.

Given the novelty of PET/CT, the number of studies comparing PET and PET/CT in NSCLC are limited, but growing. Recent studies have documented superior accuracy with integrated PET/CT over PET alone in overall staging and diagnosis of NSCLC.^13-15 However, these studies have also introduced controversy as to whether PET/CT is superior to PET for nodal staging of the mediastinum. Because of a greater than 95% negative predictive value, current practice accepts a negative PET result without the need for surgical confirmation.⁹ By contrast, a positive PET scan requires surgical confirmation because of the high false positive rate from coexistent inflammatory or infectious processes.^16-18 Practically, however, it is not infrequent that patients are treated with neoadjuvant therapy for suspected N2 disease or definitive chemoradiotherapy for N3 disease solely on the basis of a positive PET result. Previous studies showed that surgical staging was still required because of a relatively high false positive rate with PET in mediastinal staging.^16-18 We contend that integrated PET/CT also has not improved specificity to replace surgical staging as the sole diagnostic tool in NSCLC. Accordingly, the purpose of this study was to review our experience and compare the diagnostic accuracy between PET and integrated PET/CT for nodal staging in NSCLC.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
Patient Selection
A retrospective review was performed on all patients who underwent surgical mediastinal lymph node biopsy by cervical mediastinoscopy, anterior mediastinotomy, thoracotomy or a combination of these methods, between January 1995 and December 2005 on the Thoracic Surgery Service at the University of California, Davis Cancer Center. Only newly diagnosed patients with biopsy-proven NSCLC and preoperative staging PET scans were included. Patients were segregated into two study groups: standard PET versus simultaneously acquired integrated PET/CT. The PET scans were then compared with the reference standard of pathologic results to determine sensitivity, specificity, positive and negative predictive values, and accuracy. This study was approved by the Institutional Review Board at the University of California at Davis Medical Center.

PET and Integrated PET/CT Imaging
All PET studies were performed after patient fasting for a minimum of 4 hours. PET images were obtained with a dedicated PET system (ECAT EXACT 921; CTI, Knoxville, Tenn). PET/CT images were obtained with an integrated PET/CT scanner (Discovery LS; GE Medical Systems, Waukesha, Wis; or ECAT Reveal XVI; CTI, Knoxville, Tenn). Whole-body scans were obtained 30 to 60 minutes after intravenous injection of 10 to 20 mCi of FDG. For PET imaging, projection and tomographic images in the axial, coronal, and sagittal planes were reconstructed both with and without attenuation correction. For PET/CT imaging, simultaneously acquired CT data were used for attenuation correction. All studies were read by dedicated nuclear medicine physicians with a specialty in interpreting PET scan images. Clinical histories and pertinent CT scans were available for review. Intraobserver variability was not assessed. Mediastinal lymph nodes were read as positive if their activity was definitely above the surrounding mediastinal activity and not according to standard uptake values (SUV). Only patients with ipsilateral (N2) or contralateral (N3) mediastinal disease were considered to have positive results for this study.

Mediastinal Lymph Node Staging
Extended mediastinal lymph node staging was completed in all patients by cervical mediastinoscopy, anterior mediastinotomy, or thoracotomy. In patients with normal mediastinoscopy results, thoracotomy followed typically within 14 days. The results of PET and CT scanning were available to the surgeon at the time of resection. All visible and technically feasible lymph nodes were removed and were annotated according to the revised International Staging System.^19,20 Pathologic reports were reviewed to determine whether any mediastinal lymph nodes contained cancer. Only patients with pathologic disease in lymph nodes that would have been accessible by mediastinoscopy (stations 2, 4, and 7), mediastinotomy (stations 5 and 6), right thoracotomy (stations 2, 4, 7, and 9), or left thoracotomy (stations 4, 5, 6, and 9) were considered positive in this study. There were no changes in surgical routine during the study period.

Statistics
Pathologic findings served as the "gold standard." Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were calculated at the patient level. Exact binomial confidence intervals were determined for each. Comparisons between PET and PET/CT diagnostic test characteristics were made with the ² test for independent groups. Differences between the groups on demographic and baseline characteristics were assessed by the ² or t test. Statistical analysis was carried out with SAS version 9.1 for Windows (SAS Institute, Inc, Cary, NC).

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
Between January 1995 and December 2005 at the University of California, Davis Cancer Center, 629 patients underwent surgical mediastinal lymph node biopsy with an average of 4 lymph node stations sampled. Of the 293 patients excluded from this study, 269 did not have pathologic diagnosis of NSCLC, 16 patients did not have a preprocedure PET scan, 5 patients had previous staging procedures, and 3 patients did not have lymph node tissue on biopsy.

The remaining 336 patients were segregated into standard PET (n = 210) and PET/CT (n = 126). Table 1 shows the population demographics of the two patient groups. The standard PET group had 44% men and 56% women with a mean age of 65.1 years (range 32-86 years). The PET/CT group had 42% men and 58% women with a mean age of 67 years (range 37-86 years). The accuracy of mediastinoscopy in the PET group compared with the PET/CT group was 98% (50/51) and 97.7% (43/44), respectively (data not shown).

Fifty-one (24%) of 210 patients in the PET group and 44 (35%) of 126 patients in the PET/CT group underwent a mediastinoscopy followed by thoracotomy owing to node-negative disease (Table 5). The indications for mediastinoscopy in the PET versus the integrated PET/CT subgroups were a false positive PET scan (10/51, 20%, vs 19/44, 43%), a false positive CT (27/51, 53%, vs 22/44, 50%), or suggestion of either N1 disease or tumor proximity to the mediastinum (22/51, 43%, vs 17/44, 39%), respectively (P < .01) (Table 6).

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
Our results indicate that integrated PET/CT has not improved the overall accuracy of mediastinal staging in NSCLC over standard PET imaging. Improved sensitivity in the detection of N2/N3 disease with PET/CT has come at the cost of significantly worsened specificity. The drastic increase in false positive results reinforces the continued need for surgical staging in the treatment of NSCLC.

FDG-PET imaging is the most accurate noninvasive staging modality for NSCLC available today.^9,21 By using the higher rate of glycolysis in malignant cells compared with normal surrounding tissues, FDG-PET allows a physiologic assessment of tumor activity.²² Despite the high incidence of false positive results, meta-analysis of PET utility in mediastinal staging has produced a pooled sensitivity of 84% and a specificity of 89%, which compares favorably with CT (sensitivity of 57% and specificity of 82%).⁹ Although superior, the inherent limitations in anatomic precision of PET imaging have led to the evolution of combining PET imaging with CT scanning. Initial efforts using computer software to create fusion images were met with alignment difficulties from using images taken at different time points.^23,24 The advent of integrated PET/CT has made simultaneous image acquisition possible, thus ameliorating the problem.

Many studies have indicated the overall superiority of integrated PET/CT over CT alone,²⁵ PET alone,^13-15 and visually corrected or fused PET/CT^15,26,27 in NSCLC. However, with regard to nodal staging of the mediastinum in NSCLC, there does not appear to be a consensus agreement in the utility of integrated PET/CT. A review of the recent literature reveals that most studies comparing PET/CT with PET do not reach statistical significance with respect to sensitivity or specificity because of small sample size. In one of the larger series, Cerfolio and associates¹⁴ compared PET/CT with PET and showed an overall increased accuracy in both T and N staging. However, in the identification of N2 disease, increased accuracy (96% vs 93%) was a result of improved sensitivity (69% vs 62%) and came at the cost of worsened specificity (94% vs 97%), which is partly supported by our results.

Logically, this makes sense. Increased sensitivity is the result of identifying subtle lesions smaller than 2 cm, which may have been lost in the background with standard PET imaging. These lesions are now visually correlated and more easily identified with the aid of CT imaging. This, however, has not resolved the established difficulty of PET with false positive results from inflammatory or infectious diseases.^28,29

What is even more interesting was the significant impact the increased false positive results had on the types of operations performed. The PET and PET/CT groups had significantly different proportions of operations performed, which were primarily manifested by a higher rate of thoracotomy in the PET group compared with a higher rate of mediastinoscopy followed by thoracotomy in the PET/CT group. This disparity appears to be due to a significantly increased number of patients with false positive PET/CT scans, who, after a negative mediastinoscopy are able to proceed to thoracotomy. In contrast, neither a false positive CT scan, presence of N1 disease, nor tumor proximity to the mediastinum resulted in any significant difference. This striking observation highlights the increased need for surgical confirmation of a positive integrated PET/CT scan as this will allow a significant number of patients to proceed to curative resection rather than being subjected to neoadjuvant or definitive chemoradiation therapy.

This study also affirms that integrated PET/CT maintains a low false negative rate and is sufficient evidence to rule out mediastinal spread. Recent evidence has suggested that T2 tumors are more likely to harbor occult N2 disease in patients with clinical stage I disease.³⁰ However, owing to a limited sample size, this study was not able to affirm or deny those findings. Thus, although the spatial resolution with integrated PET/CT is much improved from standard PET, detection of subcentimeter lymph nodes may still pose an obstacle in ruling out metastatic disease.

Finally, the future of pretreatment staging in NSCLC is rapidly changing. As recent trials using adjuvant platinum-based chemotherapy in patients with early-stage NSCLC have shown significantly improved survival,^3,4 trials are now investigating the use of similar therapy in the neoadjuvant setting. The real impact of this will be felt in the increased need to more accurately stage the disease before therapy. Although not addressed in this study, PET/CT has been shown to be more accurate in segregating patients with N0 versus N1 disease.¹⁴ However, the high false positive rate in PET/CT will still mandate confirmation of N1 disease. Emerging invasive technologies, such as the use of fine needle aspiration with endoscopic ultrasound and endobronchial ultrasound are still being evaluated and may have significant benefit in confirming N1 disease. Suggestion has even been made that these technologies will supplant the utility of mediastinoscopy in the future.^31,32 More likely, however, will be the future development of multimodality staging algorithms to address the changing treatment algorithms in NSCLC. Until then, the current evidence still supports the continued use of mediastinoscopy as the gold standard for confirmation of mediastinal disease in NSCLC.³³

	References

Top Abstract Introduction Patients and Methods Results Discussion References

 

1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, et al. Cancer statistics, 2006. CA Cancer J Clin 2006;56:106-130.[Medline]
   
2. Smyth WR. Treatment of stage I and II non-small-cell lung cancer. Cancer Control 2001;8:318-325.[Medline]
   
3. Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C, et al. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 2005;352:2589-2597.[Medline]
   
4. Pisters KM. Adjuvant chemotherapy for non-small-cell lung cancer—the smoke clears. N Engl J Med 2005;352:2640-2642.[Medline]
   
5. Rosell R, Felip E. Role of multimodality treatment for lung cancer. Semin Surg Oncol 2000;18:143-151.[Medline]
   
6. Spasova I, Petera J, Hytych V. The role of neoadjuvant chemotherapy in marginally resectable or unresectable stage III non–small cell lung cancer. Neoplasma 2002;49:189-196.[Medline]
   
7. Cerfolio RJ, Bryant AS, Ojha B, Eloubeidi M. Improving the inaccuracies of clinical staging of patients with NSCLC: a prospective trial. Ann Thorac Surg 2005;80:1207-1214.[Abstract/Free Full Text]
   
8. Birim O, Kappetein AP, Stijnen T, Bogers AJ. Meta-analysis of positron emission tomographic and computed tomographic imaging in detecting mediastinal lymph node metastases in non–small cell lung cancer. Ann Thorac Surg 2005;79:375-381.[Abstract/Free Full Text]
   
9. Toloza EM, Harpole L, McCrory DC. Noninvasive staging of non–small cell lung cancer: a review of the current evidence. Chest 2003;123:137-146.
   
10. Reed CE, Harpole DH, Posther KE, Woolson SL, Downey RJ, Meyers BF, et al. Results of the American College of Surgeons Oncology Group Z0050 Trial: the utility of positron emission tomography in staging potentially operable non–small cell lung cancer. J Thorac Cardiovasc Surg 2003;126:1943-1951.[Abstract/Free Full Text]
    
11. Von Haag DW, Follette DM, Roberts PF, Shelton D, Segel LD, Taylor TM. Advantages of positron emission tomography over computed tomography in mediastinal staging of non–small cell lung cancer. J Surg Res 2002;124:250-258.
    
12. Hustinx R, Benard F, Alavi A. Whole body FDG-PET imaging in the management of patients with cancer. Semin Nucl Med 2002;32:35-46.[Medline]
    
13. Lardinois D, Weder W, Hany TF, Kamel EM, Korom S, Seifert B, et al. Staging of non–small cell lung cancer with integrated positron-emission tomography and computed tomography. N Engl J Med 2003;348:2500-2507.[Medline]
    
14. Cerfolio RJ, Ojha B, Bryant AS, Raghuveer V, Mountz JM, Bartolucci AA. The accuracy of integrated PET-CT compared with dedicated PET alone for the staging of patients with nonsmall cell lung cancer. Ann Thorac Surg 2004;78:1017-1023.[Abstract/Free Full Text]
    
15. Halpern BS, Schiepers C, Weber WA, Crawford TL, Fueger BJ, Phelps ME, et al. Presurgical staging of non–small cell lung cancer: positron emission tomography, integrated positron emission tomography/CT, and software image fusion. Chest 2005;128:2289-2297.[Medline]
    
16. Roberts PF, Follette DM, Von Haag DW, Park JA, Valk PE, Pounds TR, et al. Factors associated with false-positive staging of lung cancer by positron emission tomography. Ann Thorac Surg 2000;70:1154-1160.[Abstract/Free Full Text]
    
17. Takamochi K, Yoshida J, Murakami K, Niho S, Ishii G, Nishimura M, et al. Pitfalls in lymph node staging with positron emission tomography in non–small cell lung cancer patients. Lung Cancer 2005;47:235-242.[Medline]
    
18. Gonzalez-Stawinski GV, Lemaire A, Merchant F, O’Halloran E, Coleman RE, Harpole DH, et al. A comparative analysis of positron emission tomography and mediastinoscopy in staging non–small cell lung cancer. J Thorac Cardiovasc Surg 2003;126:1900-1904.[Abstract/Free Full Text]
    
19. Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest 1997;111:1710-1717.[Medline]
    
20. Mountain CF, Dresler CM. Regional lymph node classification for lung cancer staging. Chest 1997;111:1718-1723.[Medline]
    
21. Kelly RF, Tran T, Holmstrom A, Murar J, Segurola RJ. Accuracy and cost effectiveness of [18F]-2-fluoro-deoxy-D-glucose–positron emission tomography scan in potentially resectable non–small cell lung cancer. Chest 2004;125:1413-1423.[Medline]
    
22. Vansteenkiste JF. PET scan in the staging of non–small cell lung cancer. Lung Cancer 2003;42:S27-S37.[Medline]
    
23. Aquino SL, Kuester LB, Muse VV, Halpern EF, Fischman AJ. Accuracy of transmission CT and FDG-PET in the detection of small pulmonary nodules with integrated PET/CT. Eur J Nucl Med Mol Imaging 2006;33:692-696Epub 2006 Mar 3.[Medline]
    
24. Townsend DW, Carney JP, Yap JT, Hall NC. PET/CT today and tomorrow. J Nucl Med. 2004;45:4S-14S.[Abstract/Free Full Text]
    
25. Shim SS, Lee KS, Kim BT, Chung MJ, Lee EJ, Han J, et al. Non–small cell lung cancer: prospective comparison of integrated FDG PET/CT and CT alone for preoperative staging. Radiology 2005;236:1011-1019.[Abstract/Free Full Text]
    
26. Metser U, Golan O, Levine CD, Even-Sapir E. When is integrated positron emission tomography/computed tomography more accurate than side-by-side interpretation of positron emission tomography and computed tomography?. J Comput Assist Tomogr 2005;29:554-559.[Medline]
    
27. Krishnasetty V, Fischman AJ, Halpern EL, Aquino SL. Comparison of alignment of computer-registered data sets: combined PET/CT versus independent PET and CT of the thorax. Radiology 2005;237:635-639.[Abstract/Free Full Text]
    
28. Vansteenkiste JF. FDG-PET for lymph node staging in NSCLC: a major step forward, but beware of the pitfalls. Lung Cancer 2005;47:151-153.[Medline]
    
29. Passlick B. Mediastinal staging. Lung Cancer 2004;45:S85-S87.
    
30. Toloza EM, Meyers, BF, Mackie-McCall L, Reed, CE, Putnam JB. Prevalance of mediastinal metastases and sensitivity of mediastinoscopy in potentially operable non–small cell lung cancer screned by computerized tomography and positron emission tomography. J Thorac Cardiovasc Surg. In press.
    
31. Annema JT, Versteegh MI, Veselic M, Voigt P, Rabe KF. Endoscopic ultrasound guided FNA in the diagnosis and staging of lung cancer and its impact on surgical staging. J Clin Oncol 2005;23:8357-8361.[Abstract/Free Full Text]
    
32. Sawhney MS, Kratzke RA, Lederle FA, Holmstrom AM, Nelson DB, Kelly RF. Endoscopic ultrasound and positron emission tomography for lung cancer staging. Clin Gastroenterol Hepatol 2006;4:846-851Epub 2006 May 6.[Medline]
    
33. Rusch VW. Mediastinoscopy: an endangered species?. J Clin Oncol 2005;23:8283-8285.[Free Full Text]
    

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Derek von Haag Royce Calhoun David Follette Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lee, B. E. Articles by Follette, D. Search for Related Content PubMed PubMed Citation Articles by Lee, B. E. Articles by Follette, D. Related Collections Mediastinum