PET, CT, and MRI With Combidex for Mediastinal Staging in Non-Small Cell Lung Carcinoma

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1 PET, CT, and MRI With Combidex for Mediastinal Staging in Non-Small Cell Lung Carcinoma Kemp H. Kernstine, MD, PhD, William Stanford, MD, Brian F. Mullan, MD, Nicholas P. Rossi, MD, Brad H. Thompson, MD, David L. Bushnell, MD, Kelley A. McLaughlin, RN, and Jeffrey A. Kern, MD Division of Cardiothoracic Surgery, Department of Internal Medicine, and Department of Radiology, The University of Iowa College of Medicine, Iowa City, Iowa Background. To determine the relative utility of positron emission tomography (PET), computed tomography (CT), and magnetic resonance imaging with Combidex (MRI-C) in the non-invasive staging of non-small cell lung cancer (NSCLC) mediastinal lymph nodes (MLN), we compared the three tests individual performance with surgical mediastinal sampling. In contrast to prior studies, cytology was not used. Methods. The MLN were evaluated using PET and CT in 64 NSCLC patients. MRI-C was performed in 9 of these patients. MLN with a PET standard uptake value greater than or equal to 2.5, or greater than 1 cm in the short axis by CT or lack of MRI-C signal change were considered positive for metastatic disease. All MLN were sampled and subjected to standard pathologic analysis. PET, CT, and MRI-C scans were interpreted blinded to the histopathological results. Sensitivity, specificity, and accuracy for each scan type to appropriately stage MLN was determined using pathologic results as the standard. Results. Thirty patients had stage I disease, 8 stage II, 9 stage IIIA, 7 stage IIIB, and 10 stage IV. Two-hundredand-thirty MLN were sampled. Sixteen patients had metastatic mediastinal disease. Compared to the pathological results, PET, CT, and MRI-C had a sensitivity, specificity, and accuracy of 70%, 86%, 84%; 65%, 79%, 76%; 86%, 82%, and 83%, respectively. PET and MRI-C were statistically more accurate than CT (p < 0.001). In cases where PET and CT did not identify MLN involvement with NSCLC, 8% (2/25) were pathologically positive. Conclusions. PET and MRI-C are statistically more accurate than CT. However, the differences are small and may not be clinically relevant. No technique was sensitive or specific enough to change the current recommendation to perform mediastinoscopy for MLN staging in NSCLC. (Ann Thorac Surg 1999;68: ) 1999 by The Society of Thoracic Surgeons In non-small cell lung cancer (NSCLC), prognosis and treatment planning are influenced by the presence of mediastinal lymph node (MLN) metastases. Currently, surgical biopsy has the greatest accuracy, but is expensive and has associated morbidity and mortality [1, 2]. Thus, techniques, such as computed tomography (CT), have been developed and are used to noninvasively determine MLN involvement. CT can determine the size of MLNs allowing assessment of pathological enlargement. In several studies, nodes larger than 1 cm in the transverse axis have been often involved with metastatic disease and, using these criteria, CT has a sensitivity and specificity to detect tumor NSCLC involvement of 55% to 80%, and 65% to 85%, respectively; with an accuracy of 65% to 85% [3 13]. Operable patients with N2 disease, stage IIIA (T1 2, N2), appear to be best served with neoadjuvant therapy, including preoperative chemotherapy and randomized Presented at the Poster Session of the Thirty-fifth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, Jan 25 27, Address reprint requests to Dr Kernstine, Division of Cardiothoracic Surgery, The University of Iowa Hospitals and Clinics, Room 1616B JCP, 200 Hawkins Dr, Iowa City, IA ; trials have shown a 3 to 5 times greater survival with neoadjuvant therapy than with surgery alone [14, 15]. Dependent upon the CT node criteria for accepting a node as malignant, CT will incorrectly categorize 20% to 45% of patients; patients who would, otherwise, have benefited from preoperative therapy. Not only that, 15% to 30% of patients would have false-positive results and would be inappropriately treated with chemotherapy. Thus, CT designated lymph node size, alone, does not sufficiently select patients for NSCLC treatment. Positron emission tomography (PET) is a new scan technology that is being used to stage MLN. A tracer, 2-( 18 F)fluoro-2-deoxy-D-glucose, is actively taken up by all tissues, but to a greater degree by cells with high metabolic activity such as tumor or infection/ inflammation [16 17]. The use of PET to evaluate malignancy in solitary pulmonary nodules is gaining acceptance, and several medical centers have reported an accuracy of 90% to 97%. The utility of PET to stage the mediastinum is also being studied. For MLN involved with metastatic NSCLC, the sensitivity was 76% to 100%, and the specificity was 81% to 100%; in many of the studies this was superior to CT [18]. PET may also have the added benefit of identifying malignancy elsewhere 1999 by The Society of Thoracic Surgeons /99/$20.00 Published by Elsevier Science Inc PII S (99)

2 Ann Thorac Surg KERNSTINE ET AL 1999;68: MEDIASTINAL STAGING WITH PET, CT, AND MRI 1023 within and outside the thorax [19]. However, due to high background metabolic activity (and therefore tracer uptake), it has limitations in the heart, liver, and brain and may not be sufficient for selecting patients for preoperative chemoradiotherapy. Realizing the deficiencies of CT and PET to stage the MLN, magnetic resonance imaging (MRI) has also been evaluated. Like CT, MRI defines mediastinal anatomy. However in prior studies that did not use contrastenhancement, MRI did not appear better than CT in staging MLN [20 21]. These studies have all been performed without contrast-enhancement which may not take full advantage of MRI capability. Recently, in an attempt to improve the MLN staging by MRI, an ultrasmall superparamagnetic biodegradable iron-oxide particle covered with a low molecular weight dextran, Combidex (Advanced Magnetics Inc, Princeton, NJ), has been developed and used in clinical trial investigations. The contrast material is phagocytized by the normal reticuloendothelial (RE) system. Thus, normal MLN with an intact RE system will readily absorb the contrast material, while malignancy-involved MLN will not [22]. Combidex shortens the T2 relaxation times, thus decreasing the signal intensity. MRI with Combidex contrastenhancement (MRI-C) should then demonstrate both anatomical detail, and functional status of an MLN. To determine the relative clinical utility of these tests in comparison to standard surgical MLN biopsy, we performed a retrospective analysis of a cohort of patients. Material and Methods From August, 1995 to August, 1998, potentially resectable NSCLC patients were enrolled in a prospective analysis of PET and CT to stage NSCLC. Patients were excluded if they were younger than 21 years of age, pregnant, or had uncontrolled diabetes mellitus. The initial evaluation included a complete history and physical examination; blood, urine, and cardiac analyses; spirometry, chest radiography, and chest CT utilizing 1 cm sections from the thoracic inlet to the adrenals. Patients found to have lung lesions that were suspicious for malignancy were offered the opportunity to participate in a University of Iowa approved (May 4, 1995) protocol. Later, an additional test, MRI-C, was added to stage these patients, a part of a national multicenter prospective trial assessing MRI-C to stage CT-discovered MLN (additional University of Iowa approval, February 25, 1997). After completion of these imaging tests, surgical biopsy was performed. No cytological-aspirated specimens were accepted for analysis. Radiologic Imaging CT. A Toshiba 5 Express or Imatron Electron Beam C150 scanner (Toshiba, Omaha, NE) was used to obtain 1-cm slice contrast-enhanced (150 cc intravenous contrast) images (Figs 1, 2A, 2B) from the thoracic inlet to the adrenal glands during a single breath hold. The CT interpretations were performed by readers who were blinded to the histopathological results. A MLNdiameter greater than 1 cm in the short-axis was considered suspicious for metastatic involvement. PET. PET images (Figs 1, 2) were obtained using a GE4096 Plus, whole body PET scanner. A set of 15 transverse tomographic slices with a 9.75 cm actual field of view was obtained. The spatial resolution in the X, Y, and Z axes was 6.5 mm full-width-half-maximum. The studies were performed in the fasting state and images were obtained 40 to 60 minutes after the intravenous injection of 10 mci of fluorodeoxyglucose (FDG). Four to five continuous positions were used to create electronically linked images from the angle of the mandible to the umbilicus. Coronal, sagittal, and transverse plane tomographic images were generated with and without attenuation correction and viewed on computer monitor. Standardized Uptake Values (SUV) were calculated for all FDG collections that were visually considered to be abnormal. FDG was produced by a Nuclear Interface FDG synthesizer using a modified (Hamacher, Uppsala, Sweden) nucleophilic fluorination method. The SUV was calculated for the primary tumor as well as any abnormal areas within the scanned region. The SUV represents the amount of radioactivity in the area of interest adjusted by the patient s weight and dose of FDG injected corrected for the radioactive tracer decay [18]. The nodal regions were estimated according to the American Thoracic Society criteria (ATS statement 1983) and then grouped into ipsilateral, N2 nodes, or contralateral, N3 nodes. An SUV of greater than or equal to 2.5 was considered positive for metastasis. MRI-C. This study was a part of a multicenter trial to investigate the use of a new dextran-coated superparamagnetic biodegradable iron compound, Combidex. The patients who were included in this study were required to be greater than 18 years of age, non-pregnant, and a candidate for mediastinoscopy or thoracotomy. Unacceptable patients included lactating females, patients with pacemakers or cerebral aneurysm clips, patients on chemotherapy or receiving radiation therapy within 30 days of study, a history of hemachromatosis, recipient of contrast agent administered within 24 hours of study, or biopsy-proven small-cell carcinoma. Multiplanar GRASS and T1 and T2 sequences were obtained from the thoracic inlet to below the hilum before and after IV administration of 2.6 mg Fe/kg Combidex. The patients were restudied 24 to 36 hours after contrast injection. The MR images (Figs 2C 2F) were evaluated for changes in signal intensity and lymph node architecture, and the results were compared with the histologic results. Lack of signal change was considered positive for metastatic involvement. Surgical Staging Surgeons were aware of the results of CT, PET, and MRI-C test results. Cervical and anterior mediastinoscopy were performed for histological sampling [23]. In 6 cases, the patients had a thoracotomy without mediastinoscopy. In one of these 6, biopsy of the contralateral hilar MLN was done through the ipsilateral thorax.

3 1024 KERNSTINE ET AL Ann Thorac Surg MEDIASTINAL STAGING WITH PET, CT, AND MRI 1999;68: Fig 1. Demonstration of mediastinal adenopathy by PET and CT. The top two images show the primary lung mass using lung and mediastinal CT windows. The three PET images on the left show uptake of 18 FDG in the primary mass (top), anterior mediastinal lymph nodes (middle), and left hilar and subcarinal nodes (bottom). The images on the right are the corresponding CT images.

4 Ann Thorac Surg KERNSTINE ET AL 1999;68: MEDIASTINAL STAGING WITH PET, CT, AND MRI 1025 Fig 2. Demonstration of MLN metastasis by CT as compared with MRI-C. (A, B) Two separate levels of a CT scan performed on a single patient. There are three lymph nodes present, two in the right paratracheal area (A, arrows), and a third in the left hilar/paratracheal area (B, arrow). (CD) MR images at the transverse level, as in Figure 2A. (C) A pre-mri-c T2-weighted image demonstrating the nodes seen in Figure 2A (4R nodes). In comparison, Figure 2D is the post-mri-c T2-weighted image demonstrating the same nodes and showing a decrease in signal on this post-dose T2-weighted image indicating that these nodes are benign. (E, F) Images at similar MRI transverse thoracic level as seen on the CT in Figure 2B. (E) A pre-mri-c T1 image demonstrating the suspicious node. Comparing it to the post-mri-c T1-weighted image, Figure 2F shows no change. This node would be considered malignant.

5 1026 KERNSTINE ET AL Ann Thorac Surg MEDIASTINAL STAGING WITH PET, CT, AND MRI 1999;68: Statistical Analysis The sensitivity, specificity, and accuracy were calculated for each of the 3 diagnostic tests using the surgical MLN biopsy results as the standard. For analysis, the ATS nodal stations were grouped into N2 and N3 depending upon the side of the primary lesion. Thus, each patient would have a maximum of 2 MLN groups entered for the analysis. A 2 -test was performed to determine statistical differences. Results There were 87 potential candidates for this trial. Eight patients were unable to participate: 4 refused consent, 2 were unable to lie flat on the PET exam table, and 2 had uncontrolled diabetes mellitus. There were 15 patients who were found to have lung lesions that were not NSCLC: four metastatic lesions and eleven granulomatous/inflammatory. These 23 patients were excluded from analysis and the remaining were able to undergo surgical biopsy. There were 64 patients enrolled in the study (41 males and 23 females) with a mean age of 65 plus or minus 9 years with the age ranging from 33 to 77 years. There were thirty-five adenocarcinomas, twentyone squamous cell carcinomas, four large cell carcinomas, and four unspecified NSCLC. The surgical biopsies were taken by the following techniques: Thirty-eight cervical mediastinoscopies, fourteen cervical/anterior mediastinoscopies, six mediastinoscopy/thoracotomies, and six thoracotomies only (in one, contralateral nodes were biopsied from the ipsilateral thorax). There were no complications associated with PET, MRI-C, or surgical biopsy. The final staging is as follows: 30 patients had stage I, 8 had stage II, 9 had stage IIIA, 7 had stage IIIB, and 10 had stage IV. There were 230 mediastinal lymph node stations that were sampled (ATS Nodal Map). These were grouped into N2 or N3 for each patient depending upon the side of the primary cancer. No N1 nodes were included. Because we did not acquire contralateral nodal tissue in 6 patients (one cervical mediastinoscopy and five thoracotomies), there were 122 N (64 patients) used in the PET and CT analysis, and 18 N (9 patients) for the MRI-C analysis. There were a total of 16 patients that had positive mediastinal disease (25%). For PET and CT, there were 20 N (16%) that were true-positives, and for MRI-C, 7 (39%). The results of mediastinal imaging can be found in Table 1. Nine of the 64 patients had an MRI-C performed as well as a PET and CT. There were 18 N available for evaluation in this group. PET correctly identified mediastinal involvement in 14 of 20 N (sensitivity, 70%); CT correctly identified metastatic involvement in 13 of 20 N (sensitivity, 65%), and MRI-C correctly identified 6 of 7 (sensitivity, 86%). PET was appropriately negative for cancer in 89 of 104 N (specificity, 86%), where CT correctly identified 82 of 104 (specificity, 79%) and MRI-C, 9 of 11 N (specificity, 82%). There were no statistical differences in the sensitivity and specificity for CT, PET, or Table 1. PET, CT, and MRI-C Comparison Modality (Patients) MRI-C. However, PET and MRI-C was more accurate than CT ( p 0.001). In addition, PET identified six suspicious areas (4/64 patients, 6%) outside the thorax; one bone and five others. Four of these were confirmed by biopsy and the remaining two were considered falsepositive. Surgical resection was performed in the remaining 2 patients and the location of their peripheral metastases is still being followed. If both PET and CT were negative for mediastinal malignancy, the false-negative rate was 8% (2/25 nodal stations). The same analysis was not performed for MRI-C, as the trial was not designed to screen the NSCLC group, but designed to screen and correctly identify the metastatic MLN. As stated, for the PET, CT, and MRI-C analysis, we did not use the ATS nodal stations. Instead, we grouped the nodal stations into N2 and N3 depending upon the side, right or left, of the primary tumor. For example, for a right-sided lesion, the right paratracheal and subcarinal regions would be grouped together as N2, separately from the left paratracheal region or N3. By doing so, for PET, we avoided the error incurred when a single nodal group emission would overshadow adjacent nodal stations, especially in cases where the SUV for MLN were high. The SUV for adjacent histologically-negative nodes might be inappropriately elevated on the PET scan, because of the emission-artifact, leading to a falsepositive in adjacent nodal stations. We felt that the SUV within an entire nodal group, N2 or N3, was more important for clinical purposes, rather than the individual nodal stations. Furthermore, not all the patients had the same number of nodal stations biopsied and we did not wish to introduce bias into the comparisons by having some patients who had a relatively large number of nodal stations sampled. Patients with a greater number of nodal groups sampled would have greater influence on the final analysis and make the final results less generalizable. Comment Percent (N) Sensitivity Specificity Accuracy PET vs Path (64) 70 (14/20) 86 (89/104) 84 (102/122) CT vs Path (64) 65 (13/20) 79 (82/104) 76 (93/122) MRI-C vs Path (9) 86 (6/7) 82 (9/11) 83 (15/18) Surgical biopsy was considered the standard by which the three MLN screening tests were compared: PET, CT, and MRI-C. Sixty-four patients had both a PET and CT performed; 9 had an additional MRI-C. There were 128 nodal groups possible (N2 or N3 designated as N). Six patients had only one nodal station biopsied. Thus, there were 122 N analyzed for PET and CT, and 18 N analyzed for MRI-C. For the different screen modalities, the table compares the sensitivity, specificity, and accuracy. By 2 analysis, both PET and MRI-C were more accurate than CT ( p 0.001). There have now been nine studies that compared mediastinal lymph node staging between PET and CT [24 32]. Six of these prospectively compared PET to CT. PET mediastinal staging was statistically superior to CT stag-

6 Ann Thorac Surg KERNSTINE ET AL 1999;68: MEDIASTINAL STAGING WITH PET, CT, AND MRI 1027 ing in four, and similar in two. This report has similar histopathological types and percentage of patients with mediastinal metastases. However, this report compares these modalities with MRI-C. In this study, PET accuracy was superior to CT, but the sensitivity and specificity were not. Other patient factors may be important for determining whether PET should be used and influence the interpretation of the PET results. However, there were insufficient patients to allow us to draw conclusions about these factors; tumor cell type, tumor location (eg, right versus left, lobe of primary, medial versus peripheral), and histological grade or stage played a role in determining the accuracy for any of these tests. From the data, both PET and CT would have under-staged approximately 30% of the nodal regions and over-staged approximately 20%. As with many of the prior studies, the number of positive nodal stations were too few, making it difficult to prove statistical significances between the different modalities, PET, CT, and MRI-C. Furthermore, the 5% sensitivity improvement noted for PET over CT would not be clinically sufficient to avoid surgical staging. When clinicians consider the available tests to stage the mediastinum in NSCLC patients, CT, PET, MRI-C or mediastinoscopy/thoracoscopy, is it critical to determine with what sensitivity, specificity, and accuracy do they feel comfortable? Basically, dependent upon the results of the noninvasive tests, there are three scenarios where patients would not receive optimal care: (1) incorrectly staging IIIB (false-positive N3), denying any surgical intervention or curative attempt; (2) incorrectly staging I or II (false-negative N2), denying them the benefit of preoperative chemotherapy; or (3) incorrectly staging IIIA (false-positive N2), giving preoperative chemotherapy unnecessarily. These errors will result in poorer survival, increased morbidity, and increased cost of care. Cervical and parasternal mediastinoscopy as well as thoracoscopy are safe and have accuracy rates of 92% or better [21]. To deny even a single patient the possibility of a curative attempt for most surgeons is untenable. As we grapple with the rising health care costs, we must recognize the economical necessity of performing noninvasive testing. An acceptable false-positive and false-negative rate remains to be determined. There is a role for these noninvasive tests and we should not discard them. Further trials should be performed. CT is very important to a thoracic practice and would be difficult to replace. PET adds to this information in the following ways: (1) demonstration of malignancy in the primary suspicious lesion; (2) estimation of the biological activity of the primary lesion; (3) demonstration of metastases in the thorax, including the mediastinum; (4) demonstration and location of metastases outside the thorax; (5) evaluation of the response to therapy; and (6) evaluation for recurrent cancer [18]. The precise details of how PET contributes to each of these remains to be determined and is to be investigated in a large multicenter trial now being planned. Alternative PET tracers and positron emitters such as xylose and choline are also being studied and may be superior in some types of malignancies. Further investigation is ongoing. In our study, rather than relying on cytopathology, which many PET-CT studies have used in the past, we felt that we would more accurately evaluate the use of PET, CT, and MRI-C by performing rigorous surgical biopsy. Cytology obtained by CT-guided transcutaneous biopsy or transtracheal/transesophageal, with or without endoscopic ultrasound-guided biopsy, is less likely to give the precise anatomical location of the biopsy or supply an adequate amount of tissue to provide sufficient certainty to institute a care plan for a given patient. Mediastinoscopy, thoracoscopy, and ipsilateral thoracotomy should better estimate the sensitivity, specificity, and accuracy of CT, PET, and MRI-C. Some have suggested an anatomico-metabolic scan, using CT and PET, as part of the routine evaluation of the lung cancer patient. Five patients (8%) in our study had false-negative N2 disease and would have been inappropriately treated with surgery alone, without having had preoperative chemotherapy, had a PET not been performed. Furthermore, as in many prior studies, PET identified 6 patients (9%) who were suspicious for metastases outside the thorax. Four of these patients (8%) had their extra-thoracic metastases confirmed by surgical biopsy or fine-needle aspiration. The remaining 2 are still being followed clinically for recurrent disease in the PET-identified suspicious areas. Thus, there is a small subset of patients that do not have clinical or CT evidence of inoperable disease, but who would be poorly served with surgical resection and could receive systemic therapy early. Whether in the chest or extra-thoracic, histological confirmation is necessary to direct care at this point, not solely relying on the PET or CT findings. At this point, although MRI-C is statistically more accurate than CT, too few cases were examined to draw a definitive conclusion as to its overall efficacy. PET, however, appears promising. The clinical relevance for the use of these tools for the evaluation of, and to follow the treatment in, NSCLC patients may have great benefit. However, PET and CT do not provide sufficient information to avoid surgical evaluation of the mediastinum in NSCLC patients. References 1. Cybulsky IJ, Bennett WF. Mediastinoscopy as a routine outpatient procedure. Ann Thorac Surg 1994;58: Bonadies J, D Agostino RS, Ruskis AF, Ponn RB. Outpatient mediastinoscopy. J Thorac Cardiovasc Surg 1993;106: Mentzer SJ, Swanson SJ, DeCamp MM, Bueno R, Sugarbaker DJ. Mediastinoscopy, thoracoscopy, and videoassisted thoracic surgery in the diagnosis and staging of lung cancer. Chest 1997;112(suppl 4): Van Schil PEY, Van Hee RHGG, Schoofs ELG. 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