99mTc-Anti-CEA Radioimmunoscintigraphy of Lung Adenocarcinoma* Thomas Leitha M.D.; Reinhard Walter, M.D.; Werner Schlick, M.D.; and Robert Dudczak, M.D.
Antk:arcinoembryonic antigen radioimmuDOscintigraphy (anti-CEA RIS) in colorectal adenocarcinoma has been reported to allow a better estimation of the local tumor extensionthan other radiologic methods. This study evaluated the clinical feasibility of a -Tc-Iabeled anti-CEA monoclonal antibody (BW431/26, Behring Institute, FRG) in II patients for stagingof primary adenocarcinoma of the lung. The primary tumor size ranged from 3 to 8 cm with a mean of 4 em. Mediastinal and hilar nodes were present in four patients, intrapulmonary metastases were present in two patients, and pleural and liver metastases were present in one patient each. The CEA levels were in the range of 2 to 265 nglml and elevated (>5 nglml) in six patients. Planar scintigraphy was performed at 6 h and 24 h post injection (pi). Analog and digitized images were interpreted by two observers. One patient was imaged twice and experienced serum sicknessdue to human anti-mouse antibodies (HAMA) after the second study, which showed marked unspeci6c tracer uptake in liver, spleen, and bone marrow, but DO speci6c uptake by the tumor and was excluded from further analysis. Visual interpretation identi6ed the primary tumor clearly in sevenpatients. Notumor imaging was observed in two patients. Two patients were classmed as having questionable imaging due to a poor separation of tumor uptake from mediastinal blool pool. The primary tumor could be clearly delineated in both
patients after comparison with the chest radiograph. Thus, the overall sensitivity for imaging of the primary tumor was 82 percent. The average targetlbackground ratio was 1.31±O.17:1 at 6 h pi, and I.30±O.16:1 at 24 h pi. Hilar and mediastinal nodes were correctly suspected in three patients, but the cardiac blood pool hampered a clear interpretation. Intrapulmonary and pleural metastases were diagnosed in all cases. The single liver metastasis was missedbecause of the high unspecif)c tracer uptake. Planar anti-CEA RIS with -Tc BW 431/26 was superior to computed tomography (CT)in one case with subtotal tumor resection. We summarize that at present, planar anti-CEA RIS with -Tc BW 431/26 cannot be advised as a routine staging procedure in adenocarcinoma of the lung, but it may be helpful in the detection of residual or recurrent (Clum 1991; 99:14-19) tumor tissue.
Tung cancer is the leading cause of cancer death in men aged 35 years or older, and the second L leading cause of cancer death in women 35 to 74 years old. I There seems to be a shift in incidence of the histologic types over the past 20 years, with a fall in the fraction of cases of epidermoid cancer and a rise in the percentage of adenocarcinomas. 2 After the tissue diagnosis oflung cancer is obtained, an appropriate staging of the patient is obligatory. The purpose of staging is to aid in selection of treatment and to estimate the probability of cure and survival. The most unfavorable anatomic prognostic factor in lung cancer is tumor spread beyond the lung, especially to the contralateral mediastinum. It has been demonstrated that tracheobronchial lymphatic metastases from the lung on one side to mediastinal lymph nodes on the opposite" and direct metastasis from the
upper lobe to the anterior mediastinum of the other side" is not an unusual course of the disease. Goldberg et al3 found a bilateral spread in the mediastinum in 60 percent of lung carcinoma of the right upper lobe and 25 percent of the left upper lobe at the time of initial diagnosis. Usually surgical intervention lacks benefit for patients with involvement of the contralateral mediastinum. Several noninvasive and invasive diagnostic procedures have been applied to exclude these patients from unnecessary surgical stress. In the majority of cases, conventional chest radiography raises the suspicion of lung cancer, but it fails to provide information about mediastinal metastasis and tumor extension if the latter is masked by atelectases, pleural effusion, or infiltrates. Indirect methods such as esophagograms, pulmonary angiograms, or azygograms are of no value." The sensitivity of computed tomography (Cf) had been investigated thoroughly for staging of lung cancer. Baron et al6 staged 82 percent correctly with cr but had 18 percent inconclusive results. An
·From the First Department of Internal Medicine and Second Department of Surgery. University of Vienna. Vienna. Austria. Reprint requests: Dr. Leitha, Lazarettgasse 14. Vienna. Austria
1090
14
CEA = carcinoembryonic antigen; RIS = radioimmUDOScintigraphy; HAMA = human anti-mouse antibodies; MR = magnetic resonance; CT= computed tomography; Mab = monoclonal antibodies; SPECT = single photon emmission computed tomography; REM = rapid eye movement; ABG = arterial blood gas; RV= residual volume; MIP = maximum inspiratory pressure; VT=tidai volume; EMG=electromyogram; EOG=electro-ocuIogram; ECG = electrocardiogram; EEG = electro encephalogram; RMS = respiratory muscle strength; IPPV = intermittent positive pressure ventilation; VC = vital capacity; COPD = chronic obstructive pulmonary disease
RadlolmmunoectiI1lphy in Lung AdenocarcInoma (1..fItha 81 aI)
ported to allow better estimation of the local tumor extension of colorectal cancer than radiographic methods. 16 In vitro data with the anti-CEA Mab BW 431/26 have indicated specific binding to adenocarcinoma of intestinal and pulmonal origin. However, in vitro data are of limited value to determine the clinical feasibility of RIS with a certain Mab, since imaging results are also inHuenced by the physical characteristics of the label attached, the labeling method, and the anatomic conditions. Whereas the experiences with anti-CEA immunoscintigraphy and secondary (metastatic) adenocarcinoma of the lung have not been encouraging, no published data, to our knowledge, are available for the detection of primary adenocarcinoma of the lung. Thus, the usefulness of the llllm'fc-labeled anti-CEA Mab BW 431/26 in patients with primary adenocarcinoma of the lung was evaluated, especially if this tracer may improve the estimation of the local tumor spread.
"unacceptably high rate of false positive results" in the mediastinum has been reported by Osborn et al." U nderwood et al8 compared cr with the results of mediastinoscopy and surgery. They found up to 36 percent of false-negative and 2 percent false-positive results. Early impressions with the nuclear magnetic resonance (MR) tomography suggested better tissue discrimination than cr. 9 Recent evaluations found a comparable sensitivity between cr and MR,IO but a higher sensitivity of the MR for hilar involvement. Because of its better spatial resolution, cr is superior in imaging bronchial abnormalities. 11 Radiologic methods are limited by the fact that abnormalities are detected by enlargement and not by alteration of tissue architecture. A lymph node enlargement of nonmalignant causes may be falsely interpreted as mediastinal tumor spread and potentially curative surgery may be missed. Radionuclide imaging methods identify abnormal tissue based on functional changes. Lung perfusion scanning in combination with conventional chest radiography has been reported to identify a subgroup of patients with a higher probability ofhilar and mediastinal lymph node involvement," but its predictive value is poor in the single patient. At present, gallium-67-eitrate scanning remains the only radionuclide imaging procedure being recommended for thoracic staging oflung cancer in clinical practice. 13 , 14 Yet, the specificity of67gallium citrate scanning is limited because of its accumulation in inHammatory tissue." Thus, an overestimation of the tumor extension may occur. The recently introduced radioimmunoscintigraphy (RIS) with monoclonal antibodies (Mab) directed against certain surface antigens of tumor cells should offer better tumor delineation. Radioimmunoscintigraphy with radiolabeled anticarcinoembryonic antigen (CEA) Mab has been re-
Patient no.
CEA, nwml
Age,
1 2 3
4 121 265
71 58 65
4
2
69
5 6 7
26 8 4
55 69 65
8 9 10
4
5 8
11
6
lbtients
Eleven nonselected patients (male:female=8:3; age: 64.5± 11.0 years) with histologically confirmed lung adenocarcinoma were included in this study. The study protocol was approved by the ethical committee of the First Department of Internal Medicine, University Clinic Vienna. Informed consent was obtained in all cases. None of the patients had undergone HIS before the first injection. Primary tumor extension and stage were determined using conventional chest radiography, chest cr, sonography, and bone scintigraphy. Histologic diagnosis was made by transbronchial biopsy, bronchial lavage, or open lung biopsy specimen. Ten patients had no tumor resection before imaging. Only patient 8 was imaged three weeb after tumor resection. Three patients (cases 3, 4, and 6) had had chemotherapy. None had chemotherapy within the last three weeb before scintigraphy. None of the patients had radiotherapy. The primary tumor ranged from 3 to 8 em in diameter with a mean of 4 cm. Mediastinal and hiIar nodes were present in four patients, intrapulmonary metastases were present
Tumor Size, cm
Leukocytes /nl
Primary Site, Lobe
5.0 4.2 4.6 9.6
Left upper Right upper Right lower Right lower
4 5 3.5 5.5
10.6 16.0 14.9
Left lower Lingula Right upper
4 8 4
52 78 82
12.0 4.5 6.0
Right middle Lingula Right lower
5 ng/ml) in six patients. The leukocyte counts ranged from 4.2 to 161nl in five and were normal in six patients. Patients' characteristics are summarized in 'Iable 1. Patient 8 initially underwent middle lobe resection under the clinical diagnosis of chronic pneumonia. Histologic study revealed a subtotally resected adenocarcinoma of the lung. The histologically and scintigraphically confirmed residual tumor was negative in cr after surgery. The patient was examined again four months after the initial study, because at this time cr had identified tumor tissue at the resection site. Acute bronchospasm occurred immediately after second tracer injection. The symptoms were terminated instantly by intravenous infusion of calcium g1uconate and glucocorticosteroids. No determination of the human anti-mouse antibody (HAMA) titer was performed in this patient before or after the first injection, but two determinations immediately before the second injection and four weeks later found a quotient of 5.6 between the two HAMA titers, which were regarded as HAMA positive.
RadiopharmaceuHcal The BW 431/26 (Behringwerke AG, Marburg) is an intact murine monoclonal IgGl antibody, which selectively binds to a specific epitope of the CEA.17 The BW 431/26 was labeled with -Tc O. according to the instructions of the manufacturer immediately before injection. Labeling efficacy was determined using a reversed phase chromatography ITLC (Gelman SG). The tracer was injected intravenously over three to five minutes. The dose was in the range from 630 to 750MBq-Tc. Scintigraphy
Thyroid blocking with perchlorate orally 30 minutes before tracer injection was performed only in the first four consecutive patients and abandoned afterward. Planar scintigraphy (SOO,OOO counts) was performed at 6 and 24 h post injection (Pi) with a large field of view gamma camera (LFOV Siemens) and stored (64 X 64, 16 bit matrix) in a dedicated computer system (DEC PDP 11134). The imaging protocol included four thoracic images (anterior-posterior [API, posterior-anterior [PAl, left lateral, right lateral) and images of the skull (AP), the abdomen (AP, PAl, and the pelvis (AP, PAl at 6 " pi. At 24 h pi thoracic images were repeated in identical positions. The imaging of the other regions was optional only in cases with diagnostic doubts after the first image. Analog and digitized scintigraphs were interpreted by two experienced investigators without the knowledge of the clinical history. A focal increased tracer accumulation was regarded as a positive result if it could be clearly separated from the blood pool oflarge vessels and the heart. Thrget/nontarget ratios were determined in the images in which the tumor was visualized best.
FIGURE 1. Conventional chest radiography in a patient with a primary adenocarcinoma in the left upper lung lobe. Radiograph of a 71-year-old patient (patient 1). The nodule (arrows) in the left upper lung lobe below the aortic knuckle was shown to represent a primary adenocarcinoma by bronchoscopy. No signs of mediastinal involvement could be indentified on conventional chest radiography or computed tomography.
Visual interpretation identified the primary tumor clearly in seven patients. Figures 1 and 2 show a 71year-old patient (patient 1) with a primary tumor in the left upper lobe. Figure 1 shows the conventional chest radiograph that visualizes the primary tumor as nodule below the aortic knuckle. The corresponding immunoscintigraph (Fig 2) 6 h after the injection of 99mTc BW 431/26 shows a focal tracer uptake in the
RESULTS
The labeling procedure of the 99mTc BW 431/26 was fast and easy. The reaction yield was more than 98 percent. All studies were of good quality and had a high count rate, thus allowing short imaging times even at 24 h after injection. No visual thyroid uptake was seen in the patients without thyroid blocking, thus indicating long-term stability of the tracer. All patients tolerated the first injection without side effects. 16
FIGURE 2. Corresponding immunoscintigraph to Figure 1: anteriorposterior thoracic projection 6 h pi of-Tc BW 431/26. The image shows high activity accumulation in the heart and the large vessels, representing the blood pool. The prominent liver activity in the right lower part of the image was shaded by scaling the image to the activity uptake of the tumor. A focal tracer uptake in the left upper lung lobe can be clearly separated from large vessels and matches the tumor in the chest radiograph. Radiolmmunosctlnigraphy in Lung Adenocarcinoma (l..8/tha et at)
left upper lung lobe that can be clearly separated from large vessels and matches the tumor in the chest radiograph. Focal tracer accumulation adjacent to the blood pool of large vessels was seen in two patients and
classified as questionable tumor imaging without the knowledge of the chest radiograph. Both tumors could be delineated clearly from large vessels and the heart in comparison with the chest radiograph. The primary tumor was missed in two cases, evidently because of poor uptake and not because of superimpositions of blood pool activity. Local tumor size in RIS was comparable with the tumor size in the chest radiograph. Hilar and mediastinal nodes were suspected in three patients and missed in one, but the blood pool of the heart and large vessels impaired a clear interpretation. However, interpretation of the posterior mediastinum was possible in the lateral images, whereas all other mediastina were masked by blood pool activity, even in the lateral projections. In one patient a supraclavicular lymph node was seen only at 6 h pi. No additional information about the tumor extent was obtained at 24 h pi. Intrapulmonary and pleural metastases were diagnosed in all two cases. One case with a single metastasis of the liver was missed because of the high nonspecific liver uptake of the antibody. Radioimmunoscintigraphy was superior to CT in one case with histologically proven subtotal resection of the primary tumor and hilar involvement. Even the comparison of presurgical and postsurgical CT failed to prove residual tumor, but RIS showed a tracer uptake reaching from the resected area to the hilus (Fig 3). Four months later, cr was repeated and in comparison with the initial images, it showed tumor tissue at the site of resection (Fig 4). Table 2 summa-
FIGURE 4. Computed tomography of patient 8, four months after tumor resection. Computed tomography in patient 8 showed no residual tumor immediately after tumor resection, whereas residual tumor tissue was confirmed by histologic study and radioimmunoscintigraphy (Fig 3). The CT (Fig 4) was repeated four months later in comparison with the initial images showed tumor tissue at the site of resection. -Tc Anti-CEA radioimmunoscintigraphy was repeated four months after tumor resection, but the patient developed serum sickness due to human anti-mouse antibodies and the images showed only unspecific tracer uptake.
FIGURE 5. Serum sickness due to the development of human antimouse antibodies (HAMA) and repeated injections of murine monoclonal antibodies: anterior-posterior thoracic projection, 6 h pi of-Tc BW 431126. The activity distribution in a patient (8) with serum sickness due to the development of HAMA after the first injection of a murine monoclonal antibody and repeated tracer injection is strikingly different from that found in normal immunescintigraphy. The usually prominent activity in the cardiac blood pool is not visible, because of the rapid clearing of immune complexes from the blood. Note the nonspecific tracer uptake in the bone marrow, presumably representing uptake of immune complexes in the reticuloendothelial system.
FIGURE 3. Immunoscintigram of patient 8, three weeks after incomplete tumor resection: anterior-posterior thoracic projection 6 h pi of -Tc BW 431/26. This patient with primary lung adenocarcinoma had a histologically confirmed residual tumor after the resection of the middle lobe. The postoperative computed tomogram failed to detect residual tumor tissue. Note the focal tracer accumulation separated from the blood pool of the heart and the pulmonary artery reaching from the site of resection to the hilus and representing positive imaging of residual tumor tissue.
CHEST 1991 1 I JANUARY, 1991
17
Table 2-Ruulla oj-Tc Anti-CEA Immunoacintigraphic Staging· Manifestations
Data Sensitivity Specificity Accuracy
+ Predictive
value - Predictive value
Primary Tumor
Pleural Intrapulmonary
Hilar Mediastinal
313 (100)
314 (75) 7n (100) 1&11 (91) 313 (100)
9111 (82) -t 9111 (82) 919 (100)
lI/11 (100) 313 (100)
-t
818 (100)
818 (100)
718
(88)
*Thble values are number of patients; numbers within parentheses are percentages. tNo data are given, because our study included no true negative cases.
rizes the results of staging. One patient (case 8) who had been imaged twice experienced serum sickness due to HAMA-antibodies after the second injection. These images (Fig 5) were clearly different from the studies without clinically evident immune reactions. They showed a prominent uptake in liver, spleen, and skeleton, presumably representing the reticuloendothelial system. The tumor, which was clearly imaged after the first injection, showed no tracer uptake. Consequently, tracer distribution was regarded as unspecific in the second study and this study was omitted from further evaluation. The average target/background ratio was 1.31±O.17:1 at 6 h pi and 1.30±O.16:1 at 24 h pi respectively. There was no statistically significant difference between the two ratios (p=O.4). Imaging results were independent from serum CEA levels and tumor stage. DISCUSSION
Radioimmunoscintigraphy with radiolabeled antiCEA Mab had already been established as a valuable tool in the diagnosis of colorectal recurrences." Its efficacy in the detection of metastases, however, was disappointing. The regional sensitivity of planar scintigraphy for secondary adenocarcinoma of the lung had been reported in the range from 14 to 50 percent, 19 depending on the features of the radiopharmaceuticals used. In our experience, the 99mTc BW 431126 identified 40 percent of the patients with lung metastases of colorectal carcinoma, but underestimated the number oflesions in all cases. 211 The results of our present study indicated superior sensitivity of the 99mTc BW 431126 for primary lung adenocarcinoma than for secondary manifestations, as 64 percent of the tumors had been clearly identified. Another 18 percent of the primary tumors, which initially had been classified as questionably positive because of poor separation from the blood pool of 18
large vessels or the heart, turned out to represent true positive tumor imaging, after comparison with the chest radiograph. Thus, the overall sensitivity for imaging of the primary tumor was 82 percent. The tumor to background contrast was comparatively lovv, however, and no significant change in the ratio was observed between 6 and 24 h pi. The reasons for the poor contrast are uncertain, but they may include a weak and probably unstable binding of the antibody to the tumor cell, since there was no change in target! background ratio between 6 and 24 h pi. The long circulation half time of intact Mab, causing high background activity, may contribute to these findings. The divergent results between primary and secondary adenocarcinoma of the lung may be due to a different antigen-expression between the two or different vascularization with subsequently different access of the labeled Mab. Radioimmunoscintigraphy provided no additional information about the intrapulmonary tumor extension compared with chest radiography, but none of the patients had atelectases, pneumonia, or severe pleural effusion, which might have hampered the radiologic tumor delineation. The single liver metastasis in our study was missed because the physiologic liver uptake of this antibody is high, thus obscuring the contrast between normal and abnormal tissue." Hilar and mediastinal tumor manifestations were suspected correctly in three of four cases, but they were classified as questionable because of a weak separation of the blood pool activity of large vessels and the heart. The physiologic uptake of the antibody in the bone marrow hampered imaging of mediastinal tumor manifestations to a lesser extent. The clinical value of 99mTc anti-CEA RIS as a noninvasive staging procedure for the diagnosis of extrapulmonary tumor spread is severely reduced by the weak tumor to background contrast in the mediastinum. However, we believe that the satisfactory imaging of intrapulmonary tumors warrants further evaluation of this method, although several problems remain to be solved. There is evidence that target to background contrast, at least with certain radiopharmaceuticals, may be increased by single photon emission computed tomography (SPECT) as it has been shown for the 131J BW 431131 and thoracic tumor manifestations." No reviewed studies are available for the 99mTc BW 431126, but first results with abdominal tumor manifestations seem promising." Consequently, further studies are needed using 99mTc BW431126 and SPECT to investigate, if this procedure allows a better interpretation of the mediastinum. The second drawback of RIS is the long circulation halftime ofintact antibodies that results in a prominent cardiac blood pool activity and may mask specific RadIoimmunosctiigraphy in Lung AdlInocan:inoma (Leitha at 111)
mediastinal uptake. These problems could be overcome by using radiopharmaceuticals labeled with isotopes with a longer physical half time (eg, lllln, 131 1), thus enabling later imaging, at the time oflower blood pool activity. Unfortunately, no sufficient data are available for other commercial Mab preparations with these isotopes and primary lung adenocarcinoma. Experience with anti-CEA RIS in colorectal cancer had shown that this method cannot replace other methods for whole body screening, especially liver sonography, but a special aspect oflung carcinoma has to be taken into consideration. Clinically occult adrenal gland metastases had been reported by Sandler et al23 in 11 of 110 patients. We had no patient in our study with adrenal tracer uptake, but none of the patients showed clinical signs of adrenal gland metastases and no further diagnosis was endeavored. It may be speculated that whole body RIS could be capable of identifying occult adrenal gland metastases without additional abdominal CT. We summarize that at present, planar anti-CEA RIS with 9llmTc BW 431/26 cannot be advised as a routine staging procedure in adenocarcinoma of the lung; however, it allows satisfactory intrapulmonary tumor delineation and may be helpful for the detection of residual or recurrent tumor tissue in the presence of changes in lung architecture or inconclusive CT. Further investigations with 9llmTc BW 431/26 and SPECT seem advisable for possible enhancement of target background contrast. REFERENCES 1 Silverberg E. Cancer statistics. CA 1984: 34:7-23 2 Vincent RG, Rickren JVv. Lane W\v, Bross I, 'ThJdta H, Houten L, et aI. The changing histopathology of lung cancer: a review of 1682 cases. Cancer 1977; 39:1647-55 3 Goldberg EM, Shapiro CM, Glicksman AS. Mediastinoscopy for assessing mediastinal spread in clinical staging of lung carcinoma. Semin Oncoll974; 1:205-15 4 Borrie J. Lung cancer survival New York: Appleton-eentryCrafts: 1965 5 Fishman NH, Bronstein MH. Is mediastinoscopy necessary in the evaluation of lung cancer? Ann Thorac Surg 1975; 20:67886 6 Baron RL, Levit RG, Sagel SS, White MJ, Roper, Margarger JP. Computed tomography in the preoperative evaluation of bronchogenic carcinoma. Radiology 1982; 145:727-32 7 Osborn DR, Korobkin M, Ravin CE, Putman CE, Wolfe WG, Sealy WC, et aI. Comparison of plain mdiogmphy, conventional tomogmphy and computed tomogmphy in detecting intmthoracic lymph node metastasis from lung carcinoma. Radiology 1982; 142:157-61
8 Underwood GH Jr, Hooper RG, Axelbaum Sp' Goodwin DW Computed tomogmphic scanning of the thorax in the staging of bronchogenic carcinoma. N Engl J Med 1979; 300:777-78 9 Cohen AM, Creviston S, liPuma JP, Bryan PJ, Lieberman J, Hsaga JR, et aI. Nuclear magnetic resonance imaging of the mediastinum and hili: early impressions of its efficacy AJR 1983; 141:1363-69 10 Poon PY, Bronskill MJ, Henkelman M, Rideout DF, Shulman HS, Weisbrod GL, et aI. Mediastinal lymph node metastases from bronchogenic carcinoma: detection with MR imaging and CI'. Radiology 1987; 162:651-56 11 Balm P, Brown K, Collins JD, Ovenfors CO, Steckel RJ. Evaluation of intmthoracic extent of lung cancer by plain chest mdiogmphy, computed tomography, and magnetic resonance imaging. Am Rev Respir Dis 1988; 137:1456-62 12 Macumber NH, Calvin]\v. Perfusion lung scan patterns in 100 patients with bronchogenic carcinoma. J Thorac Cardiovasc Surg 1976; 72:229-302 13 Little AG, DeMeester TR, MacMahon H. The staging of lung cancer. Semin Oocoll983; 10:56-70 14 Golomb HM, DeMeesterTR. Lung cancer: a combined modality approach to staging and therapy. CA 1979; 29:258-75 15 McKenna RJ, Haynie TP, Lihshitz HI, Mountain CF, McMurtrey MJ. Critical evaluation of the galIium-67 scan for surgical patients with lung cancer. Chest 1985; 87:428-31 16 De Land FH, Goldenberg DM. Diagnosis and treabnent of neoplasms with radionuclide labeled antibodies. Semin Nucl Med 1985; 15:2-11 17 Bosslet K, Liiben G, Schwarz A, Hundt E, Harthus Hp, Seiler FR. Immunhistochemicallocalization and molecular characteristics of three monoclonal antibody defined epitopes detectable on carcinoembryonic antigen (CEA). Int J Cancer 1985; 36:75 18 Henze E, Kiibel R, Waitzinger J, Biichler M, Adam WE, Beger HG. Tumor scintigmphy with 1311 anti CEA monoclonal antibodies and F(ab'). in colorectal cancer. Eur J Nucl Med 1987; 13:125-29 19 Bares R, Fass J, Truong S, Biill U, Schumpelick V. Radioimmunoszintigraphie mit SPECI': Methodik, Probleme und k1inische Erfahrung. Nucl Med 1987; 26:202-05 20 Leitha T, Baur M, Steger G, Dudczak R. Anti-eEA immunoscintigraphy in the postopemtive care of tumor patients: differentiated use of several monoclonal antibody prepamtions. Wr KIin WSchr 1990; 17:503-09 21 Oberhausen E, Steinstriisser A, Schrotter HJ. Immunscintigmphy of colorectal tumors with the monoclonal antibody BW 43l/J1. Radioaktive Isotope Klin Forsch 1986; 17:397-402 22 Bares R, Biill U, Wliller G, Fass J, Truong S, Schumpelick V. Clinical experience with single photon emission computer tomogmphy (SPECf)-mdioimmunoscintigraphy (RIS). In: Nagel, GA, Sauer R, Schreiber H\v, eds: Immunotherapy and scintigraphy of tumors with monoclonal antibodies 1988; (Aktuelle Onkologie 41) Miinchen: W Zuckschwerdt Verlag, 1988: 34-7 23 Sandler MA, Pearlberg JC, Madrazo BL, Gitschlag KF. Gross SC. Computed tomogmphic evaluation of the adrenal gland in the preopemtive assessment of bronchogenic carcinoma. Radiology 1982; 145:733-36
CHEST 199 11 1 JANUARY, 1991
19
Antk:arcinoembryonic antigen radioimmuDOscintigraphy (anti-CEA RIS) in colorectal adenocarcinoma has been reported to allow a better estimation of the local tumor extensionthan other radiologic methods. This study evaluated the clinical feasibility of a -Tc-Iabeled anti-CEA monoclonal antibody (BW431/26, Behring Institute, FRG) in II patients for stagingof primary adenocarcinoma of the lung. The primary tumor size ranged from 3 to 8 cm with a mean of 4 em. Mediastinal and hilar nodes were present in four patients, intrapulmonary metastases were present in two patients, and pleural and liver metastases were present in one patient each. The CEA levels were in the range of 2 to 265 nglml and elevated (>5 nglml) in six patients. Planar scintigraphy was performed at 6 h and 24 h post injection (pi). Analog and digitized images were interpreted by two observers. One patient was imaged twice and experienced serum sicknessdue to human anti-mouse antibodies (HAMA) after the second study, which showed marked unspeci6c tracer uptake in liver, spleen, and bone marrow, but DO speci6c uptake by the tumor and was excluded from further analysis. Visual interpretation identi6ed the primary tumor clearly in sevenpatients. Notumor imaging was observed in two patients. Two patients were classmed as having questionable imaging due to a poor separation of tumor uptake from mediastinal blool pool. The primary tumor could be clearly delineated in both
patients after comparison with the chest radiograph. Thus, the overall sensitivity for imaging of the primary tumor was 82 percent. The average targetlbackground ratio was 1.31±O.17:1 at 6 h pi, and I.30±O.16:1 at 24 h pi. Hilar and mediastinal nodes were correctly suspected in three patients, but the cardiac blood pool hampered a clear interpretation. Intrapulmonary and pleural metastases were diagnosed in all cases. The single liver metastasis was missedbecause of the high unspecif)c tracer uptake. Planar anti-CEA RIS with -Tc BW 431/26 was superior to computed tomography (CT)in one case with subtotal tumor resection. We summarize that at present, planar anti-CEA RIS with -Tc BW 431/26 cannot be advised as a routine staging procedure in adenocarcinoma of the lung, but it may be helpful in the detection of residual or recurrent (Clum 1991; 99:14-19) tumor tissue.
Tung cancer is the leading cause of cancer death in men aged 35 years or older, and the second L leading cause of cancer death in women 35 to 74 years old. I There seems to be a shift in incidence of the histologic types over the past 20 years, with a fall in the fraction of cases of epidermoid cancer and a rise in the percentage of adenocarcinomas. 2 After the tissue diagnosis oflung cancer is obtained, an appropriate staging of the patient is obligatory. The purpose of staging is to aid in selection of treatment and to estimate the probability of cure and survival. The most unfavorable anatomic prognostic factor in lung cancer is tumor spread beyond the lung, especially to the contralateral mediastinum. It has been demonstrated that tracheobronchial lymphatic metastases from the lung on one side to mediastinal lymph nodes on the opposite" and direct metastasis from the
upper lobe to the anterior mediastinum of the other side" is not an unusual course of the disease. Goldberg et al3 found a bilateral spread in the mediastinum in 60 percent of lung carcinoma of the right upper lobe and 25 percent of the left upper lobe at the time of initial diagnosis. Usually surgical intervention lacks benefit for patients with involvement of the contralateral mediastinum. Several noninvasive and invasive diagnostic procedures have been applied to exclude these patients from unnecessary surgical stress. In the majority of cases, conventional chest radiography raises the suspicion of lung cancer, but it fails to provide information about mediastinal metastasis and tumor extension if the latter is masked by atelectases, pleural effusion, or infiltrates. Indirect methods such as esophagograms, pulmonary angiograms, or azygograms are of no value." The sensitivity of computed tomography (Cf) had been investigated thoroughly for staging of lung cancer. Baron et al6 staged 82 percent correctly with cr but had 18 percent inconclusive results. An
·From the First Department of Internal Medicine and Second Department of Surgery. University of Vienna. Vienna. Austria. Reprint requests: Dr. Leitha, Lazarettgasse 14. Vienna. Austria
1090
14
CEA = carcinoembryonic antigen; RIS = radioimmUDOScintigraphy; HAMA = human anti-mouse antibodies; MR = magnetic resonance; CT= computed tomography; Mab = monoclonal antibodies; SPECT = single photon emmission computed tomography; REM = rapid eye movement; ABG = arterial blood gas; RV= residual volume; MIP = maximum inspiratory pressure; VT=tidai volume; EMG=electromyogram; EOG=electro-ocuIogram; ECG = electrocardiogram; EEG = electro encephalogram; RMS = respiratory muscle strength; IPPV = intermittent positive pressure ventilation; VC = vital capacity; COPD = chronic obstructive pulmonary disease
RadlolmmunoectiI1lphy in Lung AdenocarcInoma (1..fItha 81 aI)
ported to allow better estimation of the local tumor extension of colorectal cancer than radiographic methods. 16 In vitro data with the anti-CEA Mab BW 431/26 have indicated specific binding to adenocarcinoma of intestinal and pulmonal origin. However, in vitro data are of limited value to determine the clinical feasibility of RIS with a certain Mab, since imaging results are also inHuenced by the physical characteristics of the label attached, the labeling method, and the anatomic conditions. Whereas the experiences with anti-CEA immunoscintigraphy and secondary (metastatic) adenocarcinoma of the lung have not been encouraging, no published data, to our knowledge, are available for the detection of primary adenocarcinoma of the lung. Thus, the usefulness of the llllm'fc-labeled anti-CEA Mab BW 431/26 in patients with primary adenocarcinoma of the lung was evaluated, especially if this tracer may improve the estimation of the local tumor spread.
"unacceptably high rate of false positive results" in the mediastinum has been reported by Osborn et al." U nderwood et al8 compared cr with the results of mediastinoscopy and surgery. They found up to 36 percent of false-negative and 2 percent false-positive results. Early impressions with the nuclear magnetic resonance (MR) tomography suggested better tissue discrimination than cr. 9 Recent evaluations found a comparable sensitivity between cr and MR,IO but a higher sensitivity of the MR for hilar involvement. Because of its better spatial resolution, cr is superior in imaging bronchial abnormalities. 11 Radiologic methods are limited by the fact that abnormalities are detected by enlargement and not by alteration of tissue architecture. A lymph node enlargement of nonmalignant causes may be falsely interpreted as mediastinal tumor spread and potentially curative surgery may be missed. Radionuclide imaging methods identify abnormal tissue based on functional changes. Lung perfusion scanning in combination with conventional chest radiography has been reported to identify a subgroup of patients with a higher probability ofhilar and mediastinal lymph node involvement," but its predictive value is poor in the single patient. At present, gallium-67-eitrate scanning remains the only radionuclide imaging procedure being recommended for thoracic staging oflung cancer in clinical practice. 13 , 14 Yet, the specificity of67gallium citrate scanning is limited because of its accumulation in inHammatory tissue." Thus, an overestimation of the tumor extension may occur. The recently introduced radioimmunoscintigraphy (RIS) with monoclonal antibodies (Mab) directed against certain surface antigens of tumor cells should offer better tumor delineation. Radioimmunoscintigraphy with radiolabeled anticarcinoembryonic antigen (CEA) Mab has been re-
Patient no.
CEA, nwml
Age,
1 2 3
4 121 265
71 58 65
4
2
69
5 6 7
26 8 4
55 69 65
8 9 10
4
5 8
11
6
lbtients
Eleven nonselected patients (male:female=8:3; age: 64.5± 11.0 years) with histologically confirmed lung adenocarcinoma were included in this study. The study protocol was approved by the ethical committee of the First Department of Internal Medicine, University Clinic Vienna. Informed consent was obtained in all cases. None of the patients had undergone HIS before the first injection. Primary tumor extension and stage were determined using conventional chest radiography, chest cr, sonography, and bone scintigraphy. Histologic diagnosis was made by transbronchial biopsy, bronchial lavage, or open lung biopsy specimen. Ten patients had no tumor resection before imaging. Only patient 8 was imaged three weeb after tumor resection. Three patients (cases 3, 4, and 6) had had chemotherapy. None had chemotherapy within the last three weeb before scintigraphy. None of the patients had radiotherapy. The primary tumor ranged from 3 to 8 em in diameter with a mean of 4 cm. Mediastinal and hiIar nodes were present in four patients, intrapulmonary metastases were present
Tumor Size, cm
Leukocytes /nl
Primary Site, Lobe
5.0 4.2 4.6 9.6
Left upper Right upper Right lower Right lower
4 5 3.5 5.5
10.6 16.0 14.9
Left lower Lingula Right upper
4 8 4
52 78 82
12.0 4.5 6.0
Right middle Lingula Right lower
5 ng/ml) in six patients. The leukocyte counts ranged from 4.2 to 161nl in five and were normal in six patients. Patients' characteristics are summarized in 'Iable 1. Patient 8 initially underwent middle lobe resection under the clinical diagnosis of chronic pneumonia. Histologic study revealed a subtotally resected adenocarcinoma of the lung. The histologically and scintigraphically confirmed residual tumor was negative in cr after surgery. The patient was examined again four months after the initial study, because at this time cr had identified tumor tissue at the resection site. Acute bronchospasm occurred immediately after second tracer injection. The symptoms were terminated instantly by intravenous infusion of calcium g1uconate and glucocorticosteroids. No determination of the human anti-mouse antibody (HAMA) titer was performed in this patient before or after the first injection, but two determinations immediately before the second injection and four weeks later found a quotient of 5.6 between the two HAMA titers, which were regarded as HAMA positive.
RadiopharmaceuHcal The BW 431/26 (Behringwerke AG, Marburg) is an intact murine monoclonal IgGl antibody, which selectively binds to a specific epitope of the CEA.17 The BW 431/26 was labeled with -Tc O. according to the instructions of the manufacturer immediately before injection. Labeling efficacy was determined using a reversed phase chromatography ITLC (Gelman SG). The tracer was injected intravenously over three to five minutes. The dose was in the range from 630 to 750MBq-Tc. Scintigraphy
Thyroid blocking with perchlorate orally 30 minutes before tracer injection was performed only in the first four consecutive patients and abandoned afterward. Planar scintigraphy (SOO,OOO counts) was performed at 6 and 24 h post injection (Pi) with a large field of view gamma camera (LFOV Siemens) and stored (64 X 64, 16 bit matrix) in a dedicated computer system (DEC PDP 11134). The imaging protocol included four thoracic images (anterior-posterior [API, posterior-anterior [PAl, left lateral, right lateral) and images of the skull (AP), the abdomen (AP, PAl, and the pelvis (AP, PAl at 6 " pi. At 24 h pi thoracic images were repeated in identical positions. The imaging of the other regions was optional only in cases with diagnostic doubts after the first image. Analog and digitized scintigraphs were interpreted by two experienced investigators without the knowledge of the clinical history. A focal increased tracer accumulation was regarded as a positive result if it could be clearly separated from the blood pool oflarge vessels and the heart. Thrget/nontarget ratios were determined in the images in which the tumor was visualized best.
FIGURE 1. Conventional chest radiography in a patient with a primary adenocarcinoma in the left upper lung lobe. Radiograph of a 71-year-old patient (patient 1). The nodule (arrows) in the left upper lung lobe below the aortic knuckle was shown to represent a primary adenocarcinoma by bronchoscopy. No signs of mediastinal involvement could be indentified on conventional chest radiography or computed tomography.
Visual interpretation identified the primary tumor clearly in seven patients. Figures 1 and 2 show a 71year-old patient (patient 1) with a primary tumor in the left upper lobe. Figure 1 shows the conventional chest radiograph that visualizes the primary tumor as nodule below the aortic knuckle. The corresponding immunoscintigraph (Fig 2) 6 h after the injection of 99mTc BW 431/26 shows a focal tracer uptake in the
RESULTS
The labeling procedure of the 99mTc BW 431/26 was fast and easy. The reaction yield was more than 98 percent. All studies were of good quality and had a high count rate, thus allowing short imaging times even at 24 h after injection. No visual thyroid uptake was seen in the patients without thyroid blocking, thus indicating long-term stability of the tracer. All patients tolerated the first injection without side effects. 16
FIGURE 2. Corresponding immunoscintigraph to Figure 1: anteriorposterior thoracic projection 6 h pi of-Tc BW 431/26. The image shows high activity accumulation in the heart and the large vessels, representing the blood pool. The prominent liver activity in the right lower part of the image was shaded by scaling the image to the activity uptake of the tumor. A focal tracer uptake in the left upper lung lobe can be clearly separated from large vessels and matches the tumor in the chest radiograph. Radiolmmunosctlnigraphy in Lung Adenocarcinoma (l..8/tha et at)
left upper lung lobe that can be clearly separated from large vessels and matches the tumor in the chest radiograph. Focal tracer accumulation adjacent to the blood pool of large vessels was seen in two patients and
classified as questionable tumor imaging without the knowledge of the chest radiograph. Both tumors could be delineated clearly from large vessels and the heart in comparison with the chest radiograph. The primary tumor was missed in two cases, evidently because of poor uptake and not because of superimpositions of blood pool activity. Local tumor size in RIS was comparable with the tumor size in the chest radiograph. Hilar and mediastinal nodes were suspected in three patients and missed in one, but the blood pool of the heart and large vessels impaired a clear interpretation. However, interpretation of the posterior mediastinum was possible in the lateral images, whereas all other mediastina were masked by blood pool activity, even in the lateral projections. In one patient a supraclavicular lymph node was seen only at 6 h pi. No additional information about the tumor extent was obtained at 24 h pi. Intrapulmonary and pleural metastases were diagnosed in all two cases. One case with a single metastasis of the liver was missed because of the high nonspecific liver uptake of the antibody. Radioimmunoscintigraphy was superior to CT in one case with histologically proven subtotal resection of the primary tumor and hilar involvement. Even the comparison of presurgical and postsurgical CT failed to prove residual tumor, but RIS showed a tracer uptake reaching from the resected area to the hilus (Fig 3). Four months later, cr was repeated and in comparison with the initial images, it showed tumor tissue at the site of resection (Fig 4). Table 2 summa-
FIGURE 4. Computed tomography of patient 8, four months after tumor resection. Computed tomography in patient 8 showed no residual tumor immediately after tumor resection, whereas residual tumor tissue was confirmed by histologic study and radioimmunoscintigraphy (Fig 3). The CT (Fig 4) was repeated four months later in comparison with the initial images showed tumor tissue at the site of resection. -Tc Anti-CEA radioimmunoscintigraphy was repeated four months after tumor resection, but the patient developed serum sickness due to human anti-mouse antibodies and the images showed only unspecific tracer uptake.
FIGURE 5. Serum sickness due to the development of human antimouse antibodies (HAMA) and repeated injections of murine monoclonal antibodies: anterior-posterior thoracic projection, 6 h pi of-Tc BW 431126. The activity distribution in a patient (8) with serum sickness due to the development of HAMA after the first injection of a murine monoclonal antibody and repeated tracer injection is strikingly different from that found in normal immunescintigraphy. The usually prominent activity in the cardiac blood pool is not visible, because of the rapid clearing of immune complexes from the blood. Note the nonspecific tracer uptake in the bone marrow, presumably representing uptake of immune complexes in the reticuloendothelial system.
FIGURE 3. Immunoscintigram of patient 8, three weeks after incomplete tumor resection: anterior-posterior thoracic projection 6 h pi of -Tc BW 431/26. This patient with primary lung adenocarcinoma had a histologically confirmed residual tumor after the resection of the middle lobe. The postoperative computed tomogram failed to detect residual tumor tissue. Note the focal tracer accumulation separated from the blood pool of the heart and the pulmonary artery reaching from the site of resection to the hilus and representing positive imaging of residual tumor tissue.
CHEST 1991 1 I JANUARY, 1991
17
Table 2-Ruulla oj-Tc Anti-CEA Immunoacintigraphic Staging· Manifestations
Data Sensitivity Specificity Accuracy
+ Predictive
value - Predictive value
Primary Tumor
Pleural Intrapulmonary
Hilar Mediastinal
313 (100)
314 (75) 7n (100) 1&11 (91) 313 (100)
9111 (82) -t 9111 (82) 919 (100)
lI/11 (100) 313 (100)
-t
818 (100)
818 (100)
718
(88)
*Thble values are number of patients; numbers within parentheses are percentages. tNo data are given, because our study included no true negative cases.
rizes the results of staging. One patient (case 8) who had been imaged twice experienced serum sickness due to HAMA-antibodies after the second injection. These images (Fig 5) were clearly different from the studies without clinically evident immune reactions. They showed a prominent uptake in liver, spleen, and skeleton, presumably representing the reticuloendothelial system. The tumor, which was clearly imaged after the first injection, showed no tracer uptake. Consequently, tracer distribution was regarded as unspecific in the second study and this study was omitted from further evaluation. The average target/background ratio was 1.31±O.17:1 at 6 h pi and 1.30±O.16:1 at 24 h pi respectively. There was no statistically significant difference between the two ratios (p=O.4). Imaging results were independent from serum CEA levels and tumor stage. DISCUSSION
Radioimmunoscintigraphy with radiolabeled antiCEA Mab had already been established as a valuable tool in the diagnosis of colorectal recurrences." Its efficacy in the detection of metastases, however, was disappointing. The regional sensitivity of planar scintigraphy for secondary adenocarcinoma of the lung had been reported in the range from 14 to 50 percent, 19 depending on the features of the radiopharmaceuticals used. In our experience, the 99mTc BW 431126 identified 40 percent of the patients with lung metastases of colorectal carcinoma, but underestimated the number oflesions in all cases. 211 The results of our present study indicated superior sensitivity of the 99mTc BW 431126 for primary lung adenocarcinoma than for secondary manifestations, as 64 percent of the tumors had been clearly identified. Another 18 percent of the primary tumors, which initially had been classified as questionably positive because of poor separation from the blood pool of 18
large vessels or the heart, turned out to represent true positive tumor imaging, after comparison with the chest radiograph. Thus, the overall sensitivity for imaging of the primary tumor was 82 percent. The tumor to background contrast was comparatively lovv, however, and no significant change in the ratio was observed between 6 and 24 h pi. The reasons for the poor contrast are uncertain, but they may include a weak and probably unstable binding of the antibody to the tumor cell, since there was no change in target! background ratio between 6 and 24 h pi. The long circulation half time of intact Mab, causing high background activity, may contribute to these findings. The divergent results between primary and secondary adenocarcinoma of the lung may be due to a different antigen-expression between the two or different vascularization with subsequently different access of the labeled Mab. Radioimmunoscintigraphy provided no additional information about the intrapulmonary tumor extension compared with chest radiography, but none of the patients had atelectases, pneumonia, or severe pleural effusion, which might have hampered the radiologic tumor delineation. The single liver metastasis in our study was missed because the physiologic liver uptake of this antibody is high, thus obscuring the contrast between normal and abnormal tissue." Hilar and mediastinal tumor manifestations were suspected correctly in three of four cases, but they were classified as questionable because of a weak separation of the blood pool activity of large vessels and the heart. The physiologic uptake of the antibody in the bone marrow hampered imaging of mediastinal tumor manifestations to a lesser extent. The clinical value of 99mTc anti-CEA RIS as a noninvasive staging procedure for the diagnosis of extrapulmonary tumor spread is severely reduced by the weak tumor to background contrast in the mediastinum. However, we believe that the satisfactory imaging of intrapulmonary tumors warrants further evaluation of this method, although several problems remain to be solved. There is evidence that target to background contrast, at least with certain radiopharmaceuticals, may be increased by single photon emission computed tomography (SPECT) as it has been shown for the 131J BW 431131 and thoracic tumor manifestations." No reviewed studies are available for the 99mTc BW 431126, but first results with abdominal tumor manifestations seem promising." Consequently, further studies are needed using 99mTc BW431126 and SPECT to investigate, if this procedure allows a better interpretation of the mediastinum. The second drawback of RIS is the long circulation halftime ofintact antibodies that results in a prominent cardiac blood pool activity and may mask specific RadIoimmunosctiigraphy in Lung AdlInocan:inoma (Leitha at 111)
mediastinal uptake. These problems could be overcome by using radiopharmaceuticals labeled with isotopes with a longer physical half time (eg, lllln, 131 1), thus enabling later imaging, at the time oflower blood pool activity. Unfortunately, no sufficient data are available for other commercial Mab preparations with these isotopes and primary lung adenocarcinoma. Experience with anti-CEA RIS in colorectal cancer had shown that this method cannot replace other methods for whole body screening, especially liver sonography, but a special aspect oflung carcinoma has to be taken into consideration. Clinically occult adrenal gland metastases had been reported by Sandler et al23 in 11 of 110 patients. We had no patient in our study with adrenal tracer uptake, but none of the patients showed clinical signs of adrenal gland metastases and no further diagnosis was endeavored. It may be speculated that whole body RIS could be capable of identifying occult adrenal gland metastases without additional abdominal CT. We summarize that at present, planar anti-CEA RIS with 9llmTc BW 431/26 cannot be advised as a routine staging procedure in adenocarcinoma of the lung; however, it allows satisfactory intrapulmonary tumor delineation and may be helpful for the detection of residual or recurrent tumor tissue in the presence of changes in lung architecture or inconclusive CT. Further investigations with 9llmTc BW 431/26 and SPECT seem advisable for possible enhancement of target background contrast. REFERENCES 1 Silverberg E. Cancer statistics. CA 1984: 34:7-23 2 Vincent RG, Rickren JVv. Lane W\v, Bross I, 'ThJdta H, Houten L, et aI. The changing histopathology of lung cancer: a review of 1682 cases. Cancer 1977; 39:1647-55 3 Goldberg EM, Shapiro CM, Glicksman AS. Mediastinoscopy for assessing mediastinal spread in clinical staging of lung carcinoma. Semin Oncoll974; 1:205-15 4 Borrie J. Lung cancer survival New York: Appleton-eentryCrafts: 1965 5 Fishman NH, Bronstein MH. Is mediastinoscopy necessary in the evaluation of lung cancer? Ann Thorac Surg 1975; 20:67886 6 Baron RL, Levit RG, Sagel SS, White MJ, Roper, Margarger JP. Computed tomography in the preoperative evaluation of bronchogenic carcinoma. Radiology 1982; 145:727-32 7 Osborn DR, Korobkin M, Ravin CE, Putman CE, Wolfe WG, Sealy WC, et aI. Comparison of plain mdiogmphy, conventional tomogmphy and computed tomogmphy in detecting intmthoracic lymph node metastasis from lung carcinoma. Radiology 1982; 142:157-61
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