Ann Thorac Surg 2003;76:861-866
© 2003 The Society of Thoracic Surgeons
Original article: general thoracic
The role of FDG-PET scan in staging patients with nonsmall cell carcinoma
Robert J. Cerfolio, MDa,g*,
Buddhiwardhan Ojha, MD, MPHb,
Ayesha S. Bryant, MSPHc,
Cynthia S. Bass, RN, MSNd,
Alfred A. Bartalucci, PhDe,
James M. Mountz, MD, PhDf
a Section of Thoracic Surgery, , Birmingham, AL, USA
b Division of Nuclear Medicine, Clinical PET, , Birmingham, AL, USA
c Department of Epidemiology, School of Public Health, , Birmingham, AL, USA
d Department of Cardio-Thoracic Surgery, , Birmingham, AL, USA
e Department of Biostatistics, School of Public Health, Birmingham, Alabama, USA
f Division of Nuclear Medicine, Nuclear Medicine and PET, University of Alabama at Birmingham, Birmingham, AL, USA
g Birmingham Veterans Administration Hospital, Birmingham, Alabama, USA
* Address reprint requests to Dr Cerfolio, Division of Cardiothoracic Surgery, University of Alabama at Birmingham, 1900 University Blvd, THT 712, Birmingham, AL 35294, USA
e-mail: robert.cerfolio{at}ccc.uab.edu
Presented at the Poster Session of the Thirty-eighth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 28–30, 2002.
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Abstract
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BACKGROUND: To assess the role of flourodeoxyglucose–positron-emission tomography (FDG-PET) scan in staging patients with nonsmall cell lung cancer (NSCLC).
METHODS: We prospectively studied 400 patients with NSCLC. Each patient underwent a computed tomography (CT) scan of the chest and upper abdomen, other conventional staging studies and had a FDG-PET scan within 1 month before surgery. All suspicious N2 lymph nodes by either chest CT or by FDG-PET scan were biopsied. Patients that were N2 and M1 negative underwent pulmonary resection and complete thoracic lymphadenectomy.
RESULTS: The FDG-PET had a higher sensitivity (71% vs 43%, p < 0.001), positive predictive value (44% vs 31%, p < 0.001), negative predictive value (91% vs 84%, p = 0.006), and accuracy (76% vs 68%, p = 0.037) than CT scan for N2 lymph nodes. Similarly, FDG-PET had a higher sensitivity (67% vs 41%, p < 0.001), but lower specificity (78% vs 88%, p = 0.009) than CT scan for N1 lymph nodes. FDG-PET led to unnecessary mediastinoscopy in 38 patients. FDG-PET was most commonly falsely negative in the subcarinal (#7) station and the aortopulmonary window lymph node (#5, #6) stations. It accurately upstaged 28 patients (7%) with unsuspected metastasis and it accurately downstaged 23 patients (6%).
CONCLUSIONS: The FDG-PET scan allows for improved patient selection. It more accurately stages the mediastinum, however there are many false positives lymph nodes and it may be more likely to miss N2 disease in the #5, #6, and #7 stations. A positive FDG-PET scan means a tissue biopsy is indicated in that location.
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Introduction
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The treatment of patients with nonsmall cell lung cancer (NSCLC) is determined by the stage. Currently, most surgeons agree that patients with metastatic cancer in the N2 lymph nodes should receive neoadjuvant therapy and, if downstaged, go on to pulmonary resection if their risks are not prohibitive. Other studies have also suggested that patients with N1 disease may also benefit from preoperative chemotherapy as well [1]. There are several prospective randomized, multi-institutional trials both in the United States and in Europe that are evaluating the use of preoperative chemotherapy for patients with N1 disease. If a survival advantage is found favoring the patients who receive preoperative chemotherapy then the identification of N1 disease before surgical resection may also change our surgical management. For these reasons we evaluated the sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), and accuracy of fluorodeoxyglucose (F-18 [FDG]) positron-emission tomography (PET) for N2, N1, and M1 disease and compared it with computed tomography (CT) imaging scans.
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Material and methods
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From May 2000 through July 2002 all patients who had an indeterminate pulmonary nodule or who had biopsy proven nonsmall lung cancer (NSCLC) were sent to a newly opened positron-emission tomography (PET) center in Birmingham, Alabama. This center features a dedicated ECAT EXACT PET scanner (CTI, Knoxville, TN). The scans were performed 60 minutes after injection of approximately 370 MBq of F-18 (FDG) intravenously. The PET scans were correlated with chest CT scans. The patients were advised not to eat or drink fluids containing calories for 4 to 6 hours before arrival at the PET center. This was confirmed with the patient before injection of the radiotracer. The scans were performed from the skull base to midthigh level.
Standard preoperative testing was performed. Patients were initially seen and examined in the University of Alabama at Birmingham (UAB) thoracic surgery clinic. In addition to CT and FDG-PET, all patients had a complete history, physical exam, and a chemistry-18 analysis. If there was an abnormality in the alkaline phosphatase an ultrasound of the liver and a bone scan was performed for further assessment. If patients complained of any new bone pain, a bone scan was performed. If patients complained of a new headache, a magnetic resonance imaging (MRI) scan of the brain was performed. Any suspicious lesion on conventional staging or on FDG-PET underwent biopsy for further evaluation.
Entry criteria into this study included a whole body FDG-PET at one center only and a CT scan both performed within 4 weeks of surgery. Patients with type 1 diabetes were excluded. Patients had either biopsied proven NSCLC before scanning or confirmed NSCLC pathologically after definitive biopsy or resection of a lymph node or nodes, or of the pulmonary mass. All patients who underwent thoracotomy and pulmonary resection had complete thoracic lymphadenectomy. A consecutive series of patients was used and prospective algorithm was used.
If either CT or FDG-PET suspected metastatic disease in any N2 station, that station was biopsied before thoracotomy. Table 1 illustrates procedures used to biopsy or remove mediastinal lymph nodes. Staging was accomplished through the recently revised TNM staging system [2]. The #2R, #4R, #2L, #4L and proximal #7 lymph nodes stations were biopsied through a mediastinoscopy. The mid and distal #7, #8 and #9 stations through a transesophageal ultrasound, and the #5 and #6 stations through a left video-assisted thoroscopy (VATS), Chamberlin, or mini-thoracotomy. If the patient was N2 positive they underwent neoadjuvant therapy, and then underwent pulmonary resection later if retesting of that same lymph node station was negative for residual cancer. FDG-PET was considered positive for an N1 or N2 lymph node if the PET report, after review with a nuclear medicine physician (J.M.M. or B.O.) and a chest CT radiologist, stated that there was hypermetabolic activity consistent with malignant disease in that numbered lymph node (characteristically defined as standard uptake value [SUV] > 2.5). All N2 stations were numbered on the reports. The only N1 nodes specifically numbered were the #10 station; the other N1 nodes (#11, #12, #13, and #14) were called intraparenchymal nodes. CT scan was considered positive if the report described a lymph node as greater than 1 cm in the short axis in a specified lymph node station.
Operations were performed in a university setting (UAB) by one general thoracic surgeon (R.J.C.). Standard operative technique was used. Nodes completely removed (not sampled) in the right chest included the #2R, #4R, #7, #8, #9, and #10R stations along with the rest of the N1 nodes contained in the part of the lung that was resected (#11, #12, #13 and #14). In the left chest the stations completely resected included #5, #6, #7, #8, #9, and #10L stations, and the rest of the N1 nodes contained in the part of the lung resected (#11, #12, #13, and #14). N1 nodes were defined as nodes #10, #11, #12, #13, and #14. N2 nodes were defined as any single digit node. Pathologic review was performed by standard techniques and immunohistochemical staining was used when appropriate.
The FDG-PET was considered to have accurately upstaged a patient when all other standard tests were negative (or not performed because the patient was asymptomatic) and the patient would have otherwise undergone thoracotomy, except the FDG-PET identified an area of metastatic disease that was previously unsuspected and later confirmed by tissue biopsy. FDG-PET was considered to have accurately downstaged a patient when another imaging modality called a lesion metastatic or suspicious for metastatic disease; the patient would have otherwise been turned down for thoracotomy, but the lesion had low metabolic activity on FDG-PET and subsequent tissue biopsies (or MRI if the bone) proved that lesion to be benign.
The diagnostic value of FDG-PET and CT scanning was compared with biopsy node assessment by calculating sensitivity, specificity, PPV, NPV, and accuracy using the formulas presented in Table 2. The results for this data have been reported in two ways. One method considers the values for the N2 and N1 lymph nodes by each patient individually (Table 3)
and the other considers the values of each node (Table 4).
The test of proportions was used to compare the sensitivity, specificity, PPV, NPV, and accuracy between FDG-PET and CT. A two-sided p value of 0.05 or less was considered as a statistically significant difference between two groups unlikely to be due to chance. The statistical analysis was performed using SAS version 8.02 (SAS Institute, Cary, NC) and EpiInfo 2002 (Centers for Disease Control, Atlanta, GA) software.
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Table 3. Overall Sensitivity, Specificity, Accuracy, Positive Predictive Value, and Negative Predictive Value for the N2 and N1 Lymph Nodes for FDG-PET and for CT Scan
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Table 4. Sensitivity, Specificity, Positive Predictive Value, Negative Predictive Value, and Accuracy by the Lymph Nodes for FDG-PET and CT Scan
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Results
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There were 400 patients (258 men and 142 women) with a median age of 66 years old (range 27 to 88 years old). The sensitivity, specificity, PPV, NPV, and accuracy for FDG-PET scans and CT scan for the N2 and N1 lymph nodes are depicted in Table 3. As illustrated in Table 3, FDG-PET has a significantly higher sensitivity, PPV, NPV, and accuracy than CT for the N2 lymph nodes. The p values for this difference are indicated in the table. Similarly, FDG-PET has a higher sensitivity, but lower specificity, for N1 lymph nodes. Table 3 considers the FDG-PET or CT scan correct if it predicted N2 or N1 disease in a patient and if the patient turned out to actually have N2 or N1 disease. It does not consider the accuracy at each station. For example, if the FDG-PET predicted the patient to have N2 disease at the #7 subcarinal lymph node station, but the patient really only had N2 disease at the #4 lower paratracheal lymph node station, the FDG-PET was considered correct for accurately predicting the presence of N2 disease. The actual accuracy at each individual lymph node station is illustrated in Table 4.
Mediastinoscopy
Table 4 demosntrates that the specificity for #4R, #4L, and #7 lymph node stations are lower than for other N2 stations. This means there were more false positives in these stations. Fifty patients had an FDG-PET scan that suggested N2 disease in the mediastinoscopically accessible lymph node stations (#2R, #2L, #4R, #4L, #7), 38 patients (76%) had falsely positive FDG-PET scans, 37 had granulomatous disease, and 1 patient had silicosis. However, 12 patients (24%) were found to have metastatic NSCLC. In addition to these 50 patients, there were 23 other patients that were true positives for N2 disease by both CT and FDG-PET scans.
Twenty-two patients (5.5%) had false negative FDG-PET for N2 disease. All had microscopic cancer in the N2 nodal stations. Nine of these patients were only positive in one N2 position and in 8 patients FDG-PET failed to detect microscopic cancer in the #7 lymph node. Two of these patients had atypical carcinoid tumors, but their primary tumors in the lung were FDG-PET positive. In 5 patients the aortopulmonary (#5 and #6) lymph nodes had metastatic cancer, and 4 of these 5 patients had large tumors that, in retrospect, obscured this area. Similarly, in 4 patients who had false negative right paratracheal (#2R and #4R) lymph nodes, 3 patients had adjacent large right upper lobe tumors.
Metastatic disease
The FDG-PET scans upstaged 28 patients (7%). The locations of these unsuspected metastases are illustrated in Table 5.
FDG-PET scans downstaged 23 patients (6%) and the locations of the suspected metastases, later proven to be benign as FDG-PET suggested, and are depicted in Table 6.
As indicated in Tables 5 and 6, FDG-PET scan is highly sensitive and specific for determining the presence or absence of malignancy in the adrenal gland, bone, and liver.
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Comment
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The exact role and cost effectiveness of FDG-PET scanning for patients with apparent resectable nonsmall cell carcinoma is still controversial. Recent reports using FDG-PET for patients with bronchogenic malignancy [3–7] have called it accurate [3], useful [4], and reliable [5]. Some conclude that it is has "better efficiency than CT scanning" [4] and "improves the rate of detection of local and distant metastases" [5]. It has also been reported to be "cost effective" [7]. However, the accuracy of FDG-PET at each individual lymph node stations has never been reported. The results of FDG-PET scans’ accuracy seem to vary. This may be secondary to where the studies were performed, what generation PET scanner was used for imaging, and how they were interpreted.
It is important for physicians to differentiate a full ring dedicated PET camera from partial ring or coincidence (hybrid) systems. In fact, apparently Medicare will only cover FDA-approved full ring or partial ring scanners, or coincidence systems that have very specific features by the end of 2003. Scans performed with gamma camera PET systems with crystals thinner than 5/8 inch will not be covered. Moreover, there remain problems with standard uptake value (SUV). Despite its name it is anything but standardized. The SUVs on different PET scanners do not necessarily equate with the SUVs on another scanner. All these issues require further study and refinement and may explain why there is a wide range of sensitivities, specificities, and accuracies reported for FDG-PET for nodal and metastatic disease.
As reported in this study, FDG-PET does not replace the need for tissue biopsies for N1 or N2 lymph nodes, or for metastatic lesions. There are false positives and negatives in all stations. However, FDG-PET did result in better patient selection before pulmonary resection. It helped target areas for biopsy and led us to find unsuspected N2 and M1 disease. Therefore our recommendation is clear. We believe an FDG-PET scan should be performed before surgical resection. Our study found a lower sensitivity and specificity for N2 nodes when compared with some other PET studies [3–22], as illustrated in Table 7.
There are several possible explanations for these findings. We may have had more false positives for lymph nodes because most of our patients were from the South and we found a high incidence of granulomatous disease. Also we used a SUV of 2.5 as our cutoff so as not to miss a cancer, but this led to more false positives. We may have had more false negatives because we did a complete thoracic lymphadenectomy and our pathologist performed immunohistochemical staining that discovered microscopic N2 disease that FDG-PET will not register as positive.
A unique finding in our study, previously unreported, is that FDG-PET may be less accurate in some lymph node stations than others. This may be true because large tumors are more likely to obscure these nodes. A newer PET-CT fusion machine may improve these blind spots. The exact clinical import of this finding is not yet fully appreciated, but surgeons may be more likely to biopsy a certain station if they know that a station is more likely to be falsely negative by FDG-PET. For example, because we found that the subcarinal #7 station is more commonly falsely negative than other N2 stations, we have a lower threshold in our practice for ordering a transesophageal ultrasound with fine needle aspirate of nodes in this station in a patient with a negative FDG-PET and CT scan with a large T2 or T3 lesion.
The FDG-PET is also valuable for detecting unsuspected M1 disease even in patients that have already had routine screening tests that were read as normal (bone scans, CT of the adrenal gland and liver, and brain scans). We found that 7% of patients had M1 disease and avoided unnecessary surgery. FDG-PET may be more sensitive in certain M1 locations just like it is in certain N2 stations [18, 19]. It seems to be quite good for lesions in the liver, adrenal gland, and bone, but not as good for the brain. Our study did not evaluate PET for the brain because our scans were done from the base of the brain downward. When an FDG-PET is positive in only one M1 station, that area requires definitive evaluation or biopsy before deferring potential curative resection to a patient with possible stage I disease.
Although currently the presence of N1 disease does not change the management in patients with NSCLC, several studies have reported that preoperative chemotherapy may be of benefit [1] and several ongoing trials are examining these questions. If these other trials also reveal a survival difference for patients with N1 disease who receive preoperative chemotherapy before surgical resection, then the accuracy of FDG-PET for N1 nodes will become important. In this trial neither FDG-PET nor CT scan predicted N1 disease well. It is possible that the new PET-CT fusion systems, with their ability to better localize hypermetabolic areas, will help differentiate N1 nodes from the primary tumor or alleviate the problem of large tumors obscuring N2 nodes [23]. Current studies are underway examining these issues.
The future is promising. We believe our data has demonstrated that surgical staging is not supplanted by FDG-PET, and tissue biopsy is mandatory before any treatment strategy. But FDG-PET helps direct those biopsies and finds unsuspected M1 disease in 7% of patients and downstages in 6% of patients. Clearly patients should not be denied any resection based on an FDG-PET scan alone, biopsies are needed. Further studies are needed to help standardize SUVs from one center to another to better define the ability of FDG-PET to accurately stage hilar and mediastinal nodes [24], and to evaluate new radiopharmaceutical agents besides FDG. Other agents must be tested like F-18 FDG, and their accuracy in staging patients with NSCLC will also need to be determined on an individual basis for each agent and at each nodal and anatomic location.
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Abstract
Introduction
