Endoscopic Ultrasound and Positron Emission Tomography for Lung Cancer Staging

Transcription

1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2006;4: Endoscopic Ultrasound and Positron Emission Tomography for Lung Cancer Staging MANDEEP S. SAWHNEY,*, ROBERT A. KRATZKE, FRANK A. LEDERLE, AMY M. HOLMSTROM, DOUGLAS B. NELSON,* and ROSEMARY F. KELLY *Section of Gastroenterology, Center for Epidemiological and Clinical Research, Minneapolis VA Medical Center, Minneapolis, Minnesota; Section of Hematology, Oncology and Transplantation, and Section of Cardiothoracic Surgery, University of Minnesota, Minneapolis, Minnesota Background & Aims: Accurate assessment of mediastinal lymph nodes is vital for optimum treatment allocation in lung cancer patients. Currently available strategies fail to identify many patients with advanced mediastinal disease, resulting in unnecessary surgery. We prospectively compared 2 promising new modalities, positron emission tomography (PET) and endoscopic ultrasound (EUS), for staging mediastinal lymph nodes. Methods: Consenting patients with lung cancer who also were suitable candidates for surgery were enrolled in the study. Patients underwent both PET and EUS. Outcomes were analyzed by surgery results or follow-up with serial imaging. Results: Seventy-two eligible patients were enrolled, and adequate data were available for 65 patients. The final diagnosis was based on tissue analysis in 59 patients and 1-year radiologic follow-up evaluation in 6 patients. PET correctly diagnosed mediastinal lymph node status in 77% of patients, and EUS fine-needle aspiration was correct in 94% of patients (P.012). The overall sensitivity, specificity, and accuracy of PET were 61%, 91%, and 77% compared with 87%, 100%, and 94% for EUS. We estimated that EUS obviated a surgical procedure in 55% (95% confidence interval, 40% 69%) of patients with radiologic evidence of mediastinal metastasis, and in 22% (95% confidence interval, 10% 41%) of patients without radiologic evidence of mediastinal metastasis. Conclusions: EUS fine-needle aspiration was more accurate than PET in staging mediastinal lymph nodes in lung cancer patients, and resulted in a substantial reduction in mediastinoscopy and thoracotomy. Lung cancer is the leading cause of cancer death for men and women in the United States. 1 Surgical lung resection is undertaken with intent to cure in localized disease, but is associated with a 5% mortality rate, 2 a 10% rate of life-threatening complications, 3 and a 50% rate of persistent pain. 4,5 Approximately 50,000 lung resections are performed each year in the United States for non-small cell lung cancer. 6 Some of these are unnecessary because they uncover extensive disease for which the procedure is not considered to be beneficial. Had the true extent of disease been known before surgery, these procedures would not have been performed. One recent series reported that 23% of patients had unresectable disease at thoracotomy; one third of these were because of malignant mediastinal lymph nodes that had been missed by preoperative staging. 7 More accurate preoperative staging could reduce unnecessary surgery. Computed tomography (CT) is the mainstay for staging the mediastinum, but its accuracy in differentiating benign from malignant mediastinal nodes is low. 8 Mediastinoscopy and mediastinotomy also are used for staging mediastinal lymph nodes, but are expensive, invasive, and associated with morbidity and mortality. 9 Positron emission tomography (PET) and endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA) have emerged as promising new modalities, and each has been shown to be superior to CT for staging mediastinal lymph nodes A substantial difference in the cost ($2385 per PET scan, and $855 per EUS FNA) and availability warrant comparative studies. 15 Several studies comparing EUS with PET have been performed, but either are retrospective or have enrolled a highly selected patient population The aim of our study was to compare prospectively EUS FNA with PET for staging mediastinal lymph nodes in a broad range of patients with lung cancer, and to assess their potential for preventing unnecessary surgical procedures. Abbreviations used in this paper: CI, confidence interval; CT, computed tomography; EUS, endoscopic ultrasound; FNA, fine-needle aspiration; PET, positron emission tomography by the American Gastroenterological Association Institute /06/$32.00 doi: /j.cgh

2 July 2006 EUS VS PET FOR LUNG CANCER STAGING 847 Methods Patients Patients with suspected or pathologically confirmed non-small cell lung cancer seen at our institution from March 2003 to May 2005 were considered for enrollment in the study. All patients had undergone a complete history, physical examination, routine blood tests, chest radiograph, and CT of the chest and upper abdomen. Consenting patients who were being considered for further diagnostic or therapeutic surgical procedures were enrolled in the study. The Minneapolis VA Institutional Review Board approved the study. All patients underwent PET and EUS. Planned surgery was deferred in patients who were found to have malignant mediastinal nodes by EUS FNA. The remaining patients underwent either mediastinoscopy or complete mediastinal lymphadenectomy at the time of thoracotomy. A few patients without EUS-FNA diagnosis of malignant mediastinal nodes nevertheless did not undergo surgery and were followed-up by serial imaging. These patients were included in the final analysis if they did not undergo any cancer therapy and if follow-up CT was available for at least 1 year after the preoperative evaluation. Procedures A PET scan of the thorax was obtained minutes after a mean intravenous injection of 18 F-flouro-deoxy-Dglucose (Eastern Isotopes; Chicago, IL; ECAT Exact; Siemens, Knoxville, TN). The transaxial 3-dimensional resolution of the scanner at 10 cm was 6.0 mm, with a count rate of 180 kilocounts/s/mci/ml. A nuclear medicine specialist interpreted the attenuated and nonattenuated images. A PET scan was considered positive if there was standard value uptake greater than 2.5 in the mediastinum. PET scans that were interpreted as intermediate positive or indeterminate were considered negative because they did not eliminate the need for further evaluation. Formal whole-body PET scans were not performed routinely. PET scan findings outside the thorax therefore were not included in the final analysis. EUS was performed using an Olympus linear-array echoendoscope GF-UC140P-AL5 (Olympus America Inc., Melville, NY). The mediastinum was imaged at 7.5 MHz ultrasound frequency. Lymph nodes imaged were characterized by size and location (American Joint Committee on Cancer designated mediastinal stations). 19 All lymph nodes, with the exception of subcarinal nodes, were considered for sampling. Subcarinal nodes were sampled if they met at least one of the following criteria: size greater than 5 mm in diameter, distinct margins, round/oval shape, or hypoechoic echotexture. EUS FNA was performed with a 22-gauge or 25-gauge needle (Echo-tip; Wilson-Cooke, Winston-Salem, NC) using standard technique. 20 Nodes contralateral to the primary lung lesion were sampled first. A pathologist provided immediate preliminary interpretation. Needle passes for aspiration were continued until a preliminary diagnosis of malignancy was made, or the pathologist was satisfied that an adequate sample representative of the lymph node had been obtained. The final decision regarding the diagnosis of malignancy or adequacy of sampling was individualized, and made by a staff pathologist. As a general rule, malignant cells or benign lymphocytes had to be present on more than 1 needle pass (ideally several needle passes) before an unequivocal diagnosis was rendered. When more than 1 lymph node was present at a station, the largest node was sampled first. Patients with enlarged mediastinal lymph nodes or uptake in the mediastinum on PET underwent mediastinoscopy before thoracotomy. A standard cervical mediastinoscopy was performed to sample lymph nodes located in the right and left high and low paratracheal mediastinum, pretracheal mediastinum, and subcarina. A left anterior mediastinotomy also was performed when access to the aortopulmonary window was needed. Patients without abnormalities in the mediastinum on CT and PET underwent thoracotomy with complete lymph node dissection. References Standard A patient was considered to have malignant mediastinal nodes if there was cytologic (obtained by EUS FNA) or histologic (node biopsy specimen obtained at surgery or core biopsy specimen via CT guidance) evidence of malignancy. A patient was considered to have benign lymph nodes if surgical biopsy examination showed benign histology. Patients also were included in the final analysis if follow-up CT, performed at least 1 year after EUS, was available for comparison. Lymph nodes that showed no change or a decrease in size over this interval were designated benign. An increase in size or number of nodes was considered evidence of malignancy for the purpose of study reporting. Data Analysis Sensitivity was calculated as a proportion of patients with malignant mediastinal nodes with a positive test result, specificity as a proportion of patients without malignant mediastinal nodes with a negative test result, accuracy as a proportion of patients with correct test results, positive predictive value as a proportion of patients with a positive test result who had malignant mediastinal nodes, and negative as a proportion of patients with a negative test result who did not have malignant mediastinal nodes. The misclassification rate was calculated as 1 overall correct fraction. A 95% confidence interval (CI) was calculated for all point estimates. The Fisher exact test was used to test for differences between categoric variables. A P value of less than.05 was considered statistically significant. Agreement between EUS FNA and PET was measured by the statistic, for which 1.0 represents perfect agreement and 0 represents the agreement expected owing to chance. On this scale, values greater than.75 are considered excellent agreement, values from.40 to.75 indicate fair to good agreement, and values less than.40 indicate poor agreement. 21 Patients with enlarged nodes on CT required further investigation, whereas patients with no evidence of mediastinal adenopathy on CT proceeded to thoracotomy. Therefore, we considered these

3 848 SAWHNEY ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 4, No. 7 Table 1. Baseline Patient Characteristics Number of patients 65 Age, y (range) 65 (49 84) Male sex 64 Race, white 64 Tumor location Right upper lobe 25 Right middle lobe 3 Right lower lobe 6 Left upper lobe 9 Left lower lobe 9 Bilateral 7 Indeterminate 11 Known lung cancer 41 Suspected lung cancer 24 groups of patients separately. Enlarged lymph nodes were defined as nodes that were 1 cm or larger in their short-axis diameter on CT. Results Seventy-two patients met entry criteria for the study. Four patients refused any further evaluation and therefore did not undergo EUS. Of these, 1 patient transferred care to another hospital, 2 patients were treated with chemotherapy or radiation therapy, and follow-up evaluation for 1 patient was not available. Three additional patients were excluded from the final analysis after having undergone EUS. Of these, 2 patients were treated with radiation and chemotherapy and therefore the final status of the lymph nodes could not be determined, and 1 patient was followed-up by serial imaging and has not yet undergone a 1-year follow-up CT scan. The remaining 65 patients constituted the study population. Baseline characteristics of these patients are shown in Table 1. All 65 patients successfully underwent PET and EUS in accordance with the study protocol. No immediate complications related to PET or EUS were noted. A staff gastroenterologist (M.S.S.) performed the EUS examinations. Conscious sedation was used, and all patients were discharged from the hospital on the same day. The number of mediastinal stations sampled by EUS was 0 in 7 patients, 1 in 23 patients, and 2 or more in 35 patients. The subcarinal mediastinum was the more commonly sampled station (n 34). A mean of 5.4 needle passes were made per node (range, 3 11). An on-site pathologist was present for all cases. Pathologic confirmation of mediastinal lymph node status was available for 59 (91%) patients. In 6 patients (9%), the final status of mediastinal lymph nodes was based on radiologic follow-up of at least 1 year. Figure 1 shows the results of EUS FNA and PET scan for study subjects. Table 2 shows the test characteristics of EUS FNA and the PET scan. EUS FNA correctly identified the mediastinal lymph node status of 61 of 65 patients, whereas PET was correct for 50 of 65 patients (accuracy, 94% vs 77%; P.01). When patients were stratified by lymph node size, EUS FNA was noted to be superior to PET for both patients with enlarged and normal-sized nodes. The most significant impact of EUS FNA was noted in 31 patients without evidence of mediastinal metastasis on CT scan. Nine of 31 patients (29%; 95% CI, 16% 47%) were found to have malignant mediastinal disease by EUS FNA. Twenty-seven patients had no evidence of abnormal mediastinal lymph nodes by both CT and PET. On EUS FNA, 6 of 27 (22%; 95% CI, 10% 41%) patients were found to have malignant mediastinal lymph nodes. Misclassification of lymph nodes occurred at a rate of 6% (95% CI, 6% 14%) by EUS FNA, and of 23% (95% CI, 17% 34%) by PET. Of the 12 mediastinal lymph nodes with false-negative PET results, 10 were noted to have metastatic non-small cell lung cancer and 2 smallcell lung cancers. Of the 3 mediastinal nodes with falsepositive PET results, 1 showed noncaseating granulomatous inflammation and the other 2 were normal. The mean size of these nodes was 12 mm (range, 6 20 mm), and the majority were located in the aortopulmonary window (4 of 15) or the subcarinal mediastinum (7 of 15). Missed diagnoses by EUS occurred in 4 patients. Lymph nodes in these patients were located in the subcarinal (n 2) and paratracheal mediastinum (n 2). For 2 patients, the abnormal lymph node was not visualized (and hence not sampled), and in 1 patient only 1 of several lymph nodes at a station was noted at surgery to be malignant. EUS FNA and PET were in agreement for mediastinal lymph node staging in 50 of 65 patients (77%), resulting in a value of.51, representing fair to good agreement. If, as is likely, all patients with either enlarged mediastinal nodes on CT scan or uptake in the mediastinum on PET would have undergone a mediastinoscopy had EUS FNA not been available, then EUS FNA obviated the need for mediastinoscopy in 21 of 38 patients (55%; 95% CI, 40% 69%). If all patients with normal mediastinum on CT and PET would have undergone a thoracotomy had EUS FNA not been available, then an unnecessary thoracotomy in 6 of 27 patients (22%; 95% CI, 10% 41%) was avoided as a result of EUS. Discussion We found EUS FNA to be an accurate and safe method for staging mediastinal lymph nodes in lung cancer patients. EUS FNA had a higher sensitivity, spec-

4 July 2006 EUS VS PET FOR LUNG CANCER STAGING 849 Figure 1. Results of EUS FNA and PET. MLN, mediastinal lymph node. ificity, and accuracy than PET. In 22% of patients, EUS FNA found evidence of mediastinal disease that had been missed by both CT and PET. A substantial reduction in the rates of mediastinoscopy and thoracotomy were attributable to EUS FNA. Several limitations of our study warrant further discussion. First, 9% of patients did not have tissue conformation of the final status of mediastinal lymph nodes. Instead, we relied on comparison with a follow-up CT obtained at least 1 year after the initial scan. This strategy has been used by several investigators, and is included in guidelines published by the American College of Chest Physicians, and is unlikely to have misclassified patients. 1,22,23 Further, only those patients who did not undergo any cancer treatment were included in the radiologic follow-up group. Second, the physician perform- Table 2. Test Characteristics of PET and EUS by Lymph Node Size Sensitivity Specificity Accuracy Positive Negative All nodes EUS 87 (78 87) 100 (93 100) 94 (86 94) 100 (90 100) 90 (83 90) PET 61 (50 67) 91 (81 97) 77 (66 82) 86 (71 95) 75 (64 75) Enlarged nodes a EUS 82 (71 82) 100 (82 100) 88 (75 88) 100 (88 100) 75 (61 75) PET 73 (61 79) 83 (61 95) 77 (61 85) 89 (74 97) 62 (46 71) Normal nodes b EUS 100 (82 100) 100 (92 100) 100 (89 100) 100 (82 100) 100 (92 100) PET 33 (14 42) 95 (88 99) 77 (64 83) 75 (32 95) 78 (72 81) NOTE. Numbers in parenthesis are 95% CIs. a Analysis limited to patients with lymph nodes 1 cmonct. b Analysis limited to patients with lymph nodes 1 cmonct.

5 850 SAWHNEY ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 4, No. 7 Table 3. Comparison of Prospective EUS Studies for Staging Mediastinal Lymph Nodes No. of patients Sensitivity Specificity Accuracy Positive Negative Gress et al, NR NR Wiersema et al, Fritscher-Ravens et al, a NR NR Fritscher-Ravens et al, a,b NR Savides and Perricone NR NR Kramer et al, NR NR 77 NR NR Annema et al, Eloubeidi et al, Caddy et al, NR, not reported. a Included patients with enlarged and normal-sized nodes. b Outcome measure was inoperable lung cancer. ing EUS was not blinded to the results of CT or PET. Prior knowledge of a suspicious lesion on imaging studies may have resulted in more diligent sampling of lymph nodes. However, the high discordance (low ) between the results of EUS FNA and either CT or PET suggests that EUS FNA results were not influenced strongly by results of previous findings. Third, nearly all patients in our study were men, reflecting the VA population seen at our institution. Fourth, our estimate of the reduction in invasive surgical procedures was calculated assuming that in the absence of EUS all patients would have undergone mediastinoscopy or thoracotomy, and therefore applies only to patients in whom a further surgical procedure is being contemplated. Fifth, PET findings outside the chest were not considered in the analysis. Gress et al 11 conducted the first prospective study of EUS FNA for lung cancer staging. In 52 lung cancer patients with enlarged mediastinal nodes, the investigators achieved a diagnostic accuracy of 96% and prompted a change in the management of 95% of patients. Table 3 lists studies that prospectively evaluated the efficacy of EUS FNA in staging mediastinal lymph nodes. These studies have focused mainly on patients with enlarged mediastinal nodes, and confirm the high diagnostic accuracy of EUS FNA in that group of patients. Three of these studies have compared EUS FNA directly with the PET scan, and similar to our study have concluded that EUS was more accurate However, unlike our study, these studies were limited to patients with positive PET scans in areas of the mediastinum that were amenable to sampling by EUS. For example, Eloubeidi et al 16 included only patients with a positive PET scan for whom the referring thoracic surgeon considered EUS to be the best staging modality. By including patients with normal-sized nodes and negative PET scan results, our study allows for a more comprehensive comparison between these 2 modalities. Overall, the positive of PET was high (89%), however, 3 of 22 patients with a positive PET scan did not have mediastinal metastasis. If pathologic conformation of the results of the PET scan had not been obtained, these patients incorrectly would have been denied a curative resection. Ten of 43 patients with no uptake in the mediastinum on PET scan were found to have mediastinal metastasis. In 8 of 10 patients, metastases were discovered preoperatively by EUS FNA, thereby avoiding unnecessary surgery. The majority of false-negative results on PET occurred for patients with normal-sized mediastinal nodes (nodes 1 cm in diameter). This was not a surprising finding because the lower limit of resolution of the PET scan is 1 cm. The sensitivity of PET for staging lung cancer patients with a normal CT scan result was only 33%, compared with 100% for EUS. Several studies have evaluated the role of EUS FNA in lung cancer patients with normal CT scan results of the mediastinum. In our study, 29% of patients with a normal mediastinal CT and 22% of patients with both normal CT and PET of the mediastinum were found to have mediastinal metastasis by EUS. In a study of 69 patients with lung cancer and normal mediastinal CT results, Wallace et al 24 found inoperable disease in 20% of patients by EUS. In another study of 79 patients, Fritscher-Ravens et al 25 found inoperable disease in 55% of patients with normal CT scan results, and in 7% of patients with both normal CT and PET results. This study allowed for inoperability to be determined by results of imaging studies. LeBlanc et al 26 found that EUS precluded surgery in 12% and influenced clinical care in 25% of lung cancer patients with radiologic localized disease. Taken together, these studies strongly suggest that EUS FNA can uncover unsuspected mediastinal disease in patients with normal imaging studies, thereby avoiding unnecessary surgery.

6 July 2006 EUS VS PET FOR LUNG CANCER STAGING 851 In conclusion, our study shows that EUS is highly accurate for staging mediastinal lymph nodes and can result in a substantial reduction in diagnostic mediastinoscopy and unnecessary thoracotomy. Patients without radiologic evidence of mediastinal metastasis also benefit from EUS. If available, EUS should play a prominent role in non-small cell lung cancer staging References 1. Alberts WM. Lung cancer guidelines. Chest 2003;123:1S 2S. 2. Handy J, Asaph J, Skokan L, et al. What happens to patients undergoing lung cancer surgery? Outcomes and quality of life before and after surgery. Chest 2002;122: Deslauriers J, Ginsberg R, Dubois P, et al. Current operative morbidity associated with elective surgical resection for lung cancer. Can J Surg 1989;32: Kalso E, Perttunen K, Kaasinen S. Pain after thoracic surgery. Acta Anaesthesiol Scand 1992;36: Dajczman E, Gordon A, Kreisman H, et al. Long-term postthoracotomy pain. 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Radiology 2001;219: Fritscher-Ravens A, Bohuslavizki K, Brandt L, et al. Mediastinal lymph node involvement in potentially resectable lung cancer: comparison of CT, positron emission tomography, and endoscopic ultrasonography with and without fine-needle aspiration. Chest 2003;123: Savides T, Perricone A. Impact of EUS-guided FNA of enlarged mediastinal lymph nodes on subsequent thoracic surgery rates. Gastrointest Endosc 2004;60: Caddy GCM, Wright G, Desmond P, et al. The accuracy of EUS- FNA in assessing mediastinal lymphadenopathy and staging patients with NSCLC. Eur Respir J 2005;25: Address requests for reprints to: Mandeep S. Sawhney, MBBS, Section of Gastroenterology (111 D), One Veterans Drive, Minneapolis, Minnesota mandeep.sawhney@med.va.gov. Supported in part by VA Clinical Science R&D Service (grant 04S- CRCOE-001 to M.S.S.).