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Scintigraphic Evaluation of Patients with Lung Carcinoma
Scintigraphic Evaluation of Patients with Lung Carcinoma* Philip O. Alderson, M.D. t
Datients with lung carcinoma can benefit in several ways from radionuclide studies (Table 1). The major role of the studies is to detect the presence or extent of the primary disease, but newer applications also are having an impact on determinations of prognosis and evaluation of therapy. The various scintigraphic approaches include direct evaluation of pulmonary ventilation and perfusion via the lung scan; evaluation of metastatic disease and opportunistic infections by gallium citrate (&7Ga) scintigraphy; evaluation for distant metastases by liver, bone, brain, or other organ scans; and additional applications, such as localization of hemoptysis by technetium 99m (W"Tc) red blood cell lung imaging or evaluation of cardiac function by gated blood pool studies in patients receiving certain types of cardiotoxic chemotherapy. This summary of scintigraphy in patients with lung carcinoma addresses the utility of these various approaches.
I
VENTILATION-PERFUSION LUNG SCINTIGRAPHY
The major role of ventilation-perfusion (V-P) scintigraphy in patients with lung carcinoma is to provide a quantitative preoperative estimate of the physiologic effects of tumor resection on the patient's pulmonary function. Considerable disability may result from hypercarbia and chronic ventilatory insufficiency if the patients postoperative FEV. is less than 0.8 L. I .I To avoid disabling surgery, the contribution of the involved lung to the overall function must be known. Conventional spirometry provides information about global cardiopulmonary function, but its measurements cannot provide the regional specificity of V-P scintigraphy. Differential bronchospirometry with temporary catheter occlusion of the pulmonary arteries initially was used to predict postoperative lung function in patients undergoing pneumonectomy, but it was expensive, had low patient compliance, and could not provide detailed regional information. The good correlation between differential bronchospirometry and xenon radiospirometry prompted the use of xenon in predictions of postoperative FEV I and FVC in patients undergoing pneumonectomy," Subsequently, the quantitative differential perfusion scan also was found to be accurate in predicting postoperative lung function," presumably due to a close relationship between unilateral ventilation and perfusion in the patients with lung cancer who were studied. Before quantitative radionuclide scans are performed, every pneumonectomy patient should have a measurement of total pulmonary function. If the FEV I is greater than 50% ofFVC and is greater than 2 L, the maximum voluntary ventilation is greater than 50% of predicted, and the ratio of residual volume to total lung capacity is less than 50%, the *From Columbia-Presbyterian Medical Center, New York. tProfessor of Radiology and Director; Division of Nuclear Medicine.
patient is a reasonable candidate for surgery. Then, the relationship of this overall function to the lung to be resected can be determined by scintigraphy. Surgery usually is not performed if a postoperative FEV I of less than 0.8 L is predicted after pneumonectomy," Split function studies are carried out by summing the activity of each lung in anterior and posterior views. The postoperative function is predicted by multiplying the preoperative value by the ratio of the counts in the remaining lung to the total lung activity. Where pneumonectomy is avoidable, segmental resection or lobectomy has become the surgical procedure of choice. The operative mortality of lobectomy is approximately the same as for pneumonectomy, but the 5-year survival is higher after lobectomy. Most studies have reported the use of scintigraphic techniques before pneumonectomy, although efforts are now being directed toward the prediction of postlobectomy lung function. For example, where resections involved more than 3 segments, Ali and associates" found that predicted FEV. and FVC correlated well with postoperative values. Segmental and lobar analyses present problems related to anatomic overlap of lobes and to changes associated with atelectasis and compensatory hyperinflation. Regional quantification may be performed best using the lateral and oblique images, given that the lobar separation is more readily defined in these views. Although the interlobar planes are not as well defined in the posterior oblique views, they are less affected by counts from the opposite lung. Although the optimum method for extracting lobar data is not established, an average of the lobar counts obtained from the lateral and oblique views may be a reasonable compromise between the conflicting goals of optimum lobar separation and avoidance of contralateral activity. Given the difficulty of obtaining quantitative xenon venTable l-Radionuclicle Imaging in Lung Cancer Lung scan Split function analysis preoperative/postoperative Evaluation of radiotherapy effects Gallium 67 scan Mediastinal spread Distant metastases Diagnose opportunistic infections Other scans Liver (metastases, SVC syndrome) Bone (metastases, HPO, etc) Bleeding (hemoptysis) Gated blood pool scans (LVfunction during chemotherapy) Future Labeled antibody imaging Lymphoscintigraphy
CHEST I 89 I 4 I APRIL, 1988 I Supplement /
2458
tilation measurements in multiple views, 8lmKr scintigraphy and aerosol inhalation studies provide attractive alternatives for estimating lobar ventilation. Krypton-81m imaging has been found to permit quantification of both regional ventilation and lobar ventilation/perfusion ratios. 7Irregular areas of interest are drawn to separate lobar regions in either 8lml(r studies or perfusion images. Care must be taken to include as few extralobar counts as possible. The percentage of global function contributed by the selected lobe is determined as the ratio of counts in that lobe to total counts in the lung. The predicted postlobectomy FEVl may be determined as in the split function study, te. by multiplying the preoperative FEVl by the lobar percentages of the ventilation or perfusion of the remaining lung. All this effort may be counterbalanced, however, by the fact that a pneumonectomy often must be performed even when a more limited resection was planned preoperatively. Thus, a conservative approach would be to do a "split lung" rather than lobar scintigraphic calculation to predict postoperative function based on the "worst case" assumption of a pneumonectomy. Scintigraphic V-P studies also can provide important qualitative and quantitative information about patients who were not candidates for tumor resection, but instead had pulmonary radiotherapy. It is well known that exposure of the lungs to ionizing radiation in therapeutic dose ranges (4,500-6,750 rad integral doses at midlung depth) causes decreased perfusion to the irradiated lung as well as decreased ventilation.f" This is true whether ventilation is assessed with 133Xe, 81m1(r, or radioaerosols and occurs after exposure of the lungs to conventional eoCo gamma rays or to higher ••quality" types of irradiation such as 15 meV fast neutrons. The severity of the radiation-induced pulmonary changes is clearly dose-dependent and requires substantially less neutron radiation to produce the same effect as a higher dose of gamma photons. The adverse changes in perfusion in animal studies have usually occurred within 3 months of the completion of a fractionated exposure, without significant later recovery. In animal studies there has been little individual variation with respect to the response to exposure. In the clinical setting, therefore, V-P scans can be used to provide serial assessments of the impact of certain dose levels of lung radiotherapy on a regional (ie, port-based) basis and serve as an aid to determine whether higher dose therapy can be tolerated. Radionuclide scans have not been useful in early tumor detection or in predicting the likelihood of tumor resectability." Pulmonary scintigraphy is generally too nonspecific to assess the presence or extent of lung carcinoma. Perfusion defects caused by lung carcinoma are mixed with numerous defects caused by regional alveolar hypoxia and are indistinguishable in most patients. This is an especially common problem in patients at risk for lung carcinoma, because chronic bronchitis and emphysema are extremely common in smokers. Further, some central tumors fail to cause the expected large perfusion deficits. Mediastinal and hilar involvement, for example, were unsuspected scintigraphically in 50% of affected patients in one series. 11 Although V-P studies may allow tumor localization in a small number of patients with abnormal sputum cytology results and normal chest radiographs, no specific patterns have been found that would predict tumor histology from regional ventilation or
"""'C
2485
perfusion patterns.10 GALLIUM-67 SCINTIGRAPHY
Detection of metastatic tumor is the most important potential role of 67Ga scintigraphy in the management of carcinoma of the lung." A reliable, noninvasive means of detecting metastatic tumor and determining its distribution at the time of initial presentation would be enormously helpful in planning therapy, since the extent of metastasis has a profound effect on the rate of survival. Patients with primary carcinoma of the lung who have no detectable spread to lymph nodes at the time of surgery have approximately a 30% chance of surviving 5 years. Patients with metastases to peribronchial or ipsilateral hilar nodes have only a 12%5-year survival rate. When patients have metastatic carcinoma of the lung in mediastinal lymph nodes, contralateral hilar nodes, or cervical nodes, the 5-year survival rate drops to 3%.
The detectability of metastases in the hilum and mediastinum by 67Ga scintigraphy has been investigated extensively, but the reported results have varied depending on the criteria used to define abnormality (Table 2). Waxman and associates" found that unilateral uptake in the mediastinum or a pulmonary hilum was highly specific (94%)but relatively insensitive (66%)for metastatic tumor, whereas abnormal uptake anywhere in the hila or mediastinum also was sensitive (96%), but less specific (56%). Bilateral hilar uptake alone was neither sensitive (30%) nor specific (59%) for metastatic tumor: Alazraki and associates" observed a sensitivity of 100% and a specificity of 71% in the detection of mediastinal metastasis. As a result, they proposed that 87Ga scintigraphy be used as a screening test prior to mediastinoscopy in patients without radiographic evidence of mediastinal metastasis. They suggested that a patient whose primary tumor is detectable by 67Ga scintigraphy be spared mediastinoscopy and referred directly for thoracotomy if the scan fails to show abnormal mediastinal activity. They also proposed that a patient with abnormal mediastinal activity or a primary lesion that is undetectable by scanning undergo mediastinoscopy before thoracotomy. Fosburg and associates" suggested a similar strategy. In contrast, DeMeester et all6.17 suggested
Table i-Gallium 67 Detection ofHilar and/or Mediastinal MetiJ8tGtJes From Lung Carcinoma· Authors
n
Sensitivity
Specificity
DeMeester et al
0.75
Lesk et al Fosburg et al Waxman et al
47 25 34 70 50
0.83 0.71 0.67
Neumann et al Lunia et al
38 75
Alazraki et al
1.00
0.89 0.88 O.96t 0.66* 0.301 0.55 0.92
0.86 O.56t 0.94* 0.59§ 0.63 0.70
*From Turner D. Ga-67 scintigraphy in malignant disease. In Alderson PO, ed., Nuclear Radiology. 3rd ed. Washington, DC: American College of Radiology, 1983; 458. Used with permission. tUptake in mediastinum and/or hilum (any site). *Unilateral hilar or mediastinal uptake. IBilateral hilar uptake. IV Wor1d Conference on LungCancer
that mediastinoscopy should be undertaken for the detection of metastasis only if the scan of the mediastinum is negative. In their series, abnormal mediastinal uptake of 87Ga was associated with a 90% probability of disease in that location, while there was a 33% chance of mediastinal disease in a patient with a negative study. Neumann and associates" found 87Ga scintigraphy to be neither sensitive nor specific enough to warrant its use as a substitute for mediastinoscopy. Despite the con8icting results reported by various groups regarding mediastinal and hilar accumulation of 87Ga in patients with carcinoma of the lung, it is apparent that abnormal uptake of 87Ga in the mediastinum increases the probability that mediastinal metastases are present. DeMeester et al18•17believe that whole body 87Ga scintigraphy is helpful in the identification ofclinically occult metastasis of lung carcinoma outside the thorax. In their series, 87Ga accumulation by both the primary tumor and an extrathoracic site indicated a 90% probability that the extrathoracic site was a metastasis. Furthermore, they suggested that the scan could be used as a guide for biopsy confirmation ofoccult metastasis. They also observed that routine scintigraphy of the liver and skeleton and cr scans of the brain added little to whole body 87Ga scintigraphy in the preoperative evaluation of patients without symptoms referrable to those organs. In their series, 87Ga scintigraphy demonstrated almost all occult metastases detected by other imaging techniques, as well as additional metastases to the adrenal glands, kidneys, and the diaphragm. An additional role for 81Ga scintigraphy is in detection of opportunistic pulmonary infections in patients undergoing chemotherapy. Gallium 67 has been shown to provide earlier detection of Pneumocysti8 carinii pneumonia (PCP) than chest radiographs or other approaches, 18 and should be considered for early patient evaluation if infection is suspected. The findings, of course, are nonspecific. Widespread pulmonary accumulation of 87Ga has been seen in a variety of inflammatory, iatrogenic, and idiopathic disorders, including AIDS, radiation pneumonitis (the active stage 1-2 weeks postexposure), idiopathic pulmonary fibrosis, sarcoidosis and after certain types of chemotherapy (eg, bleomycin). Most of these disorders are associated with chest roentgenographic abnormalities, whereas opportunistic infections often cause no roentgenographic changes early in their course. Leukocytes labeled with WIn also may be able to detect these early pulmonary infections but also are attracted to the lung by many noninfectious processes. At this time, WIn leukocytes do not seem to offer a clear advantage over 87Ga in evaluation of opportunistic infections.
Other Current Applications Liver, brain, and bone scans are potentially valuable adjuncts to the detection and management of distant metastases from lung carcinoma. The radionuclide brain scan has been supplanted by brain CT in most institutions, but still is a sensitive means for detecting metastatic disease when cr is unavailable. 18 The liver scan is nearly as sensitive as abdominal CT in detecting metastases, ao and it is readily available, easily tolerated, and relatively inexpensive. Radionuclide emission tomography (SPECT) of the liver further improves the resolution of the technique and, thus, its ability to detect small or deep metastases. 11.11 However, nearby organs such as
the adrenals are not visualized by either type of liver scintigraphy. The secondary effects of pathology elsewhere can be seen occasionally, however; as illustrated by the utility of the liver scan in detecting and assessing the effects of the superior vena cava (SVC) syndrome. When lung cancer causes SVC obstruction, chest wall collaterals carry How to the umbilicus and retrograde to the portal area. When the undiluted colloid particles reach the portal region, they are taken up by the liver and create an anterior hot spot. Radionuclide angiography over the chest during the colloid injection can demonstrate the pathway of the collateral Bow. The bone scan remains the most sensitive imaging test for detecting skeletal. metastases, which are seen in approximately 40% of patients who present with small cell carcinoma of the lung but in fewer than 10% of those presenting with other histologic varieties. Bone scans also may reveal the effects of cancer-associated abnormalities such as pulmonary osteoarthropathy, wherein areas of increased periosteal activity are seen in distal portions of the extremities. The scan also can detect polymyositis, or other paraendocrine abnormalities (eg, hyperparathyroidism). The strategies for employing bone scans and other conventional scintigraphic tests in patients with lung carcinoma are controversial and varied, but most suggest that routine screening of asymptomatic patients by multiorgan imaging is not warranted. Other scintigraphic studies that may benefit patients with lung carcinoma include utilization of UhtTc-Iabeled RBCs to localize the source of recurrent hemoptysis." "Bleeding" scans are able to detect extremely slow bleeding in the abdomen, where the site is surrounded by more background activity than in the lung. Thus, these studies should be even more effective in the lung. The drawback to these scans is that active bleeding must occur at some point during the course of the study. The utilization of gated blood pool scanning to evaluate ventricular function in patients who receive doxorubicin (Adriamycin) as one of their chemotherapeutic agents also is of interest. There is clear dose-related cardiotoxicity with Adriamycin that can be evaluated effectively by obtaining a series of gated blood pool scans and evaluating serial changes in the left ventricular ejection fraction (EF).14 When the baseline EF falls more than 10 points or to a resting value of less than 50%, cardiotoxicity should be considered. If Adriamycin therapy is withdrawn early enough, the cardiotoxic changes seem reversible. Thus, baseline and serial blood pool studies should be obtained at regular intervals in lung cancer patients who receive total adriamycin doses of approximately 300 mg/m" or more. FUTURE STUDIES
1\vo types of nuclear medicine studies that have been used
to evaluate other types of tumors have potential applications in patients with lung cancer: The first, Iymphoscintigraphy, relies on the injection of labeled microcolloid particles into tissue in the lymph drainage area of the organ of interest. 15 The radionuclide then is transported through the appropriate lymphatic channels and is trapped within sinusoids or actively phagocytized within lymph nodes. This process permits visualization of draining lymph nodes over a severalhour period following injection. Normal nodes accumulate activity, but nodes involved by tumor are not visualized. CHEST / 89 / 4 / APRIL, 1988 / Supplement
2478
Variations in lymph node anatomy and drainage patterns make interpretation of the studies somewhat difficult. However, experienced observers seem to be providing accurate interpretations in patients with breast carcinoma." Application of this technique to lung cancer have been reported, i6 but further work is needed to determine its true potential. The second new radionuclide technique with great potential in patients with lung carcinoma is that of using radiolabeled antibodies for tumor detection and, perhaps, therapy.21.28 Early experiences with labeled antibodies for tumor detection have raised several questions. These include whether radionuclides of iodine or other agents such as WIn will be optimum for labeling, whether whole antibodies or fragments of antibodies should be labeled, whether imaging can commence soon after injection or must be delayed for several days, whether allergic reactions to monoclonal antibodies are a significant clinical problem, and whether labeled antibodies can be used for tumor therapy as well as for lesion detection. The lung is relatively free from several sources of typical background activity (eg, bowel, urinary system, liver), so high tumor-to-background activity ratios should be possible following intravenous administration of the radiolabeled antibody. Work now is progressing with other tumors such as melanoma, but should be able to be extended to lung cancel: Theoretically, this would allow more sensitive detection and staging of lung cancer than possible by any other methods. If so, methods for patient selection will be needed, since monoclonal antibody imaging studies are not likely to be used for ee screening," REFERENCES 1 Olsen G, Block A, Swenson E, etal. Pulmonary function: evaluation of lung resection candidate: a prospective study. Am Rev Respir Dis 1975; 111:379-85 2 Williams CD, Brenowitz JB. "Prohibitive" lung function and major surgical procedures. Am J Surg 1976; 132:763-69 3 Kristersson S, Lindell SE, Svesnberg L. Prediction of pulmonary function loss due to pneumonectomy using 133-Xe radiospirometry. Chest 1972; 62:694-98 4 Wernly JA, DeMeester TR, Kirchner et ale Clinical value of quantitative ventilation-perfusion lung scans in the surgical management of bronchogenic carcinoma. J Thorac Cardiovasc Surg 1980; 80:535-39 5 Block AJ, Olsen GN. Preoperative pulmonary function testing. JAMA 1976; 235:257-61 6 Ali MK, Mountain CF, Ewer MS, et ale Predicting loss of pulmonary function after pulmonary resection for bronchogenic carcinoma. Chest 1980; 77:337-41 7 Ciofetta G, Silverman M, Hughes JMB. Quantitative approach to the study of regional lung function in children using krypton 81m. Br J Radioll980; 53:950-54 8 Alderson PO, Bradley E~ Mendenhall KG, et ale Radionuclide evaluation of pulmonary function following hemithorax irradiation of normal dogs with Co-6O or fast neutrons. Radiology 1979; 130:425-33 9 Bradley E~ Alderson PO, Deye JA, et ale Effects offraetionated doses of fast neutrons and photons on the normal canine lung: RBE values obtained by radionuclide studies. Int J Radiat Oncol 1979; 5:197-207
n:
2488
10 KatzRD, Alderson PO, Tockman MS, etal. Ventilation-perfusion lung scanning in patients with early lung carcinoma. Radiology 1981; 141:171-78 11 Lipscomb DJ, Pride NB. Ventilation and perfusion scans in the preoperative assessment of bronchial carcinoma. Thorax 1977; 32:720-25 12 Turner DA. Ga-67 scintigraphy in malignant disease. In: Alderson PO, ed. Nuclear radiology. 3rd ed. Washington, DC: American College of Radiology, 1983:456-59 13 Waxman AD, Julian ~ Komiako M, Brachman MB, Tamasescu DE, Wolfstein R, et ale Gallium uptake in hilar and mediastinal structures in patients with pulmonary tumors: the significance of location and cell type on sensitivity and specificity. J Nucl Med 1979; 20:645-52 14 Alazraki N~ Ramsdell JW, Taylor A, Friedman PJ, Peters RM, Tlsi G M. Reliability of gallium scan chest radiography compared to mediastinoscopy for evaluating mediastinal spread in lung cancer. Am Rev Respir Dis 1978; 117:415-20 15 Fosburg RG, Hopkins GB, Kan MK. Evaluation of the mediastinum by gallium-67 scintigraphy in lung cancer. J Thorac Cardiovasc Surg 1979; 77:76-82 16 DeMeester TR, Beckerman C, Joseph JG, Toscano MS, Golomb H, Bitran J, et al. Gallium-67 scanning for carcinoma of the lung. J Thorac Cardiovasc Surg 1976; 72:699-708 17 DeMeester TR, Golumb HM, Kirchner ~ Rezai-Zadeh K, Bitran JD, Streeter DL, et ale The role of gallium-67 scanning in the clinical staging and preoperative evaluation of patients with carcinoma of the lung. Ann Thorac Surg 1979; 28:451-64 18 Levenson SM, Warren RD, Richman SD, Johnston GS, Chabner BA. Abnormal pulmonary gallium accumulation in P carlnii pneumonia. Radiology 1976; 119:395-98 19 Alderson PO, Gado MH, Siegel BA. Computerized cranial tomography and radionuclide imaging in the detection of intracranial mass lesions. Semin Nucl Med 1977; 7:161-73 20 Alderson PO, Adams D~ McNeil BJ, et ale Computed tomography, ultrasound, and scintigraphy of the liver in patients with colon or breast carcinoma: a prospective comparison. Radiology 1983; 149:225-30 21 Keyes JW Jr, Singer D, Satterlee W, Kolff ~ Harkness BA. Liver-spleen studies with the rotating gamma camera: utility of tomography. Radiology 1984; 153:537-41 22 Brendel AJ, Leccia F, Drouillard J, et ale SPEC( planar scintigraphy and transmission computed tomography: a comparison of accuracy in diagnosing focal hepatic disease. Radiology 1984; 153:527-32 23 Winzelberg GG, Wholey MH, Jarmlowski CA, Sachs M, Weinberg JH. Patients with hemoptysis examined by Tc-99m sulfur colloid and Tc-99m labelled red blood cells. Radiology 1984; 153:523-56 24 Alexander J, Dainiak N, Berger H, Goldman L, Johnstone D, Reduto L, et ale Serial assessment of doxorubicin cardiotoxicity With quantitative radionuclide angiocardiography. N Eng} J Med 1979; 300:278-83 25 Markisz JA, McNeil BI. Lymphoscintigraphy. In: Alderson PO, ed. Nuclear radiology. 3rd ed. Washington, DC: American College of Radiology, 1983; 466-75 26 Bethune DCG, Mulder DS, Chiu RCJ. Endobronchiallymphoscintigraphy. J Thorac Cardiovasc Surg 1978; 76:446-52 27 Goldenberg DM. Tumor imaging with monoclonal antibodies. J Nucl Med 1983; 24:360-62 28 Halpern SE, Dillman RO, Witzum KF, et al, Radioimmunodetection of melanoma utilizing In-III96.5 monoclonal antibody: a preliminary report. Radiology 1985; 155:493-99
IV WorldConference on Lung Cancer
Datients with lung carcinoma can benefit in several ways from radionuclide studies (Table 1). The major role of the studies is to detect the presence or extent of the primary disease, but newer applications also are having an impact on determinations of prognosis and evaluation of therapy. The various scintigraphic approaches include direct evaluation of pulmonary ventilation and perfusion via the lung scan; evaluation of metastatic disease and opportunistic infections by gallium citrate (&7Ga) scintigraphy; evaluation for distant metastases by liver, bone, brain, or other organ scans; and additional applications, such as localization of hemoptysis by technetium 99m (W"Tc) red blood cell lung imaging or evaluation of cardiac function by gated blood pool studies in patients receiving certain types of cardiotoxic chemotherapy. This summary of scintigraphy in patients with lung carcinoma addresses the utility of these various approaches.
I
VENTILATION-PERFUSION LUNG SCINTIGRAPHY
The major role of ventilation-perfusion (V-P) scintigraphy in patients with lung carcinoma is to provide a quantitative preoperative estimate of the physiologic effects of tumor resection on the patient's pulmonary function. Considerable disability may result from hypercarbia and chronic ventilatory insufficiency if the patients postoperative FEV. is less than 0.8 L. I .I To avoid disabling surgery, the contribution of the involved lung to the overall function must be known. Conventional spirometry provides information about global cardiopulmonary function, but its measurements cannot provide the regional specificity of V-P scintigraphy. Differential bronchospirometry with temporary catheter occlusion of the pulmonary arteries initially was used to predict postoperative lung function in patients undergoing pneumonectomy, but it was expensive, had low patient compliance, and could not provide detailed regional information. The good correlation between differential bronchospirometry and xenon radiospirometry prompted the use of xenon in predictions of postoperative FEV I and FVC in patients undergoing pneumonectomy," Subsequently, the quantitative differential perfusion scan also was found to be accurate in predicting postoperative lung function," presumably due to a close relationship between unilateral ventilation and perfusion in the patients with lung cancer who were studied. Before quantitative radionuclide scans are performed, every pneumonectomy patient should have a measurement of total pulmonary function. If the FEV I is greater than 50% ofFVC and is greater than 2 L, the maximum voluntary ventilation is greater than 50% of predicted, and the ratio of residual volume to total lung capacity is less than 50%, the *From Columbia-Presbyterian Medical Center, New York. tProfessor of Radiology and Director; Division of Nuclear Medicine.
patient is a reasonable candidate for surgery. Then, the relationship of this overall function to the lung to be resected can be determined by scintigraphy. Surgery usually is not performed if a postoperative FEV I of less than 0.8 L is predicted after pneumonectomy," Split function studies are carried out by summing the activity of each lung in anterior and posterior views. The postoperative function is predicted by multiplying the preoperative value by the ratio of the counts in the remaining lung to the total lung activity. Where pneumonectomy is avoidable, segmental resection or lobectomy has become the surgical procedure of choice. The operative mortality of lobectomy is approximately the same as for pneumonectomy, but the 5-year survival is higher after lobectomy. Most studies have reported the use of scintigraphic techniques before pneumonectomy, although efforts are now being directed toward the prediction of postlobectomy lung function. For example, where resections involved more than 3 segments, Ali and associates" found that predicted FEV. and FVC correlated well with postoperative values. Segmental and lobar analyses present problems related to anatomic overlap of lobes and to changes associated with atelectasis and compensatory hyperinflation. Regional quantification may be performed best using the lateral and oblique images, given that the lobar separation is more readily defined in these views. Although the interlobar planes are not as well defined in the posterior oblique views, they are less affected by counts from the opposite lung. Although the optimum method for extracting lobar data is not established, an average of the lobar counts obtained from the lateral and oblique views may be a reasonable compromise between the conflicting goals of optimum lobar separation and avoidance of contralateral activity. Given the difficulty of obtaining quantitative xenon venTable l-Radionuclicle Imaging in Lung Cancer Lung scan Split function analysis preoperative/postoperative Evaluation of radiotherapy effects Gallium 67 scan Mediastinal spread Distant metastases Diagnose opportunistic infections Other scans Liver (metastases, SVC syndrome) Bone (metastases, HPO, etc) Bleeding (hemoptysis) Gated blood pool scans (LVfunction during chemotherapy) Future Labeled antibody imaging Lymphoscintigraphy
CHEST I 89 I 4 I APRIL, 1988 I Supplement /
2458
tilation measurements in multiple views, 8lmKr scintigraphy and aerosol inhalation studies provide attractive alternatives for estimating lobar ventilation. Krypton-81m imaging has been found to permit quantification of both regional ventilation and lobar ventilation/perfusion ratios. 7Irregular areas of interest are drawn to separate lobar regions in either 8lml(r studies or perfusion images. Care must be taken to include as few extralobar counts as possible. The percentage of global function contributed by the selected lobe is determined as the ratio of counts in that lobe to total counts in the lung. The predicted postlobectomy FEVl may be determined as in the split function study, te. by multiplying the preoperative FEVl by the lobar percentages of the ventilation or perfusion of the remaining lung. All this effort may be counterbalanced, however, by the fact that a pneumonectomy often must be performed even when a more limited resection was planned preoperatively. Thus, a conservative approach would be to do a "split lung" rather than lobar scintigraphic calculation to predict postoperative function based on the "worst case" assumption of a pneumonectomy. Scintigraphic V-P studies also can provide important qualitative and quantitative information about patients who were not candidates for tumor resection, but instead had pulmonary radiotherapy. It is well known that exposure of the lungs to ionizing radiation in therapeutic dose ranges (4,500-6,750 rad integral doses at midlung depth) causes decreased perfusion to the irradiated lung as well as decreased ventilation.f" This is true whether ventilation is assessed with 133Xe, 81m1(r, or radioaerosols and occurs after exposure of the lungs to conventional eoCo gamma rays or to higher ••quality" types of irradiation such as 15 meV fast neutrons. The severity of the radiation-induced pulmonary changes is clearly dose-dependent and requires substantially less neutron radiation to produce the same effect as a higher dose of gamma photons. The adverse changes in perfusion in animal studies have usually occurred within 3 months of the completion of a fractionated exposure, without significant later recovery. In animal studies there has been little individual variation with respect to the response to exposure. In the clinical setting, therefore, V-P scans can be used to provide serial assessments of the impact of certain dose levels of lung radiotherapy on a regional (ie, port-based) basis and serve as an aid to determine whether higher dose therapy can be tolerated. Radionuclide scans have not been useful in early tumor detection or in predicting the likelihood of tumor resectability." Pulmonary scintigraphy is generally too nonspecific to assess the presence or extent of lung carcinoma. Perfusion defects caused by lung carcinoma are mixed with numerous defects caused by regional alveolar hypoxia and are indistinguishable in most patients. This is an especially common problem in patients at risk for lung carcinoma, because chronic bronchitis and emphysema are extremely common in smokers. Further, some central tumors fail to cause the expected large perfusion deficits. Mediastinal and hilar involvement, for example, were unsuspected scintigraphically in 50% of affected patients in one series. 11 Although V-P studies may allow tumor localization in a small number of patients with abnormal sputum cytology results and normal chest radiographs, no specific patterns have been found that would predict tumor histology from regional ventilation or
"""'C
2485
perfusion patterns.10 GALLIUM-67 SCINTIGRAPHY
Detection of metastatic tumor is the most important potential role of 67Ga scintigraphy in the management of carcinoma of the lung." A reliable, noninvasive means of detecting metastatic tumor and determining its distribution at the time of initial presentation would be enormously helpful in planning therapy, since the extent of metastasis has a profound effect on the rate of survival. Patients with primary carcinoma of the lung who have no detectable spread to lymph nodes at the time of surgery have approximately a 30% chance of surviving 5 years. Patients with metastases to peribronchial or ipsilateral hilar nodes have only a 12%5-year survival rate. When patients have metastatic carcinoma of the lung in mediastinal lymph nodes, contralateral hilar nodes, or cervical nodes, the 5-year survival rate drops to 3%.
The detectability of metastases in the hilum and mediastinum by 67Ga scintigraphy has been investigated extensively, but the reported results have varied depending on the criteria used to define abnormality (Table 2). Waxman and associates" found that unilateral uptake in the mediastinum or a pulmonary hilum was highly specific (94%)but relatively insensitive (66%)for metastatic tumor, whereas abnormal uptake anywhere in the hila or mediastinum also was sensitive (96%), but less specific (56%). Bilateral hilar uptake alone was neither sensitive (30%) nor specific (59%) for metastatic tumor: Alazraki and associates" observed a sensitivity of 100% and a specificity of 71% in the detection of mediastinal metastasis. As a result, they proposed that 87Ga scintigraphy be used as a screening test prior to mediastinoscopy in patients without radiographic evidence of mediastinal metastasis. They suggested that a patient whose primary tumor is detectable by 67Ga scintigraphy be spared mediastinoscopy and referred directly for thoracotomy if the scan fails to show abnormal mediastinal activity. They also proposed that a patient with abnormal mediastinal activity or a primary lesion that is undetectable by scanning undergo mediastinoscopy before thoracotomy. Fosburg and associates" suggested a similar strategy. In contrast, DeMeester et all6.17 suggested
Table i-Gallium 67 Detection ofHilar and/or Mediastinal MetiJ8tGtJes From Lung Carcinoma· Authors
n
Sensitivity
Specificity
DeMeester et al
0.75
Lesk et al Fosburg et al Waxman et al
47 25 34 70 50
0.83 0.71 0.67
Neumann et al Lunia et al
38 75
Alazraki et al
1.00
0.89 0.88 O.96t 0.66* 0.301 0.55 0.92
0.86 O.56t 0.94* 0.59§ 0.63 0.70
*From Turner D. Ga-67 scintigraphy in malignant disease. In Alderson PO, ed., Nuclear Radiology. 3rd ed. Washington, DC: American College of Radiology, 1983; 458. Used with permission. tUptake in mediastinum and/or hilum (any site). *Unilateral hilar or mediastinal uptake. IBilateral hilar uptake. IV Wor1d Conference on LungCancer
that mediastinoscopy should be undertaken for the detection of metastasis only if the scan of the mediastinum is negative. In their series, abnormal mediastinal uptake of 87Ga was associated with a 90% probability of disease in that location, while there was a 33% chance of mediastinal disease in a patient with a negative study. Neumann and associates" found 87Ga scintigraphy to be neither sensitive nor specific enough to warrant its use as a substitute for mediastinoscopy. Despite the con8icting results reported by various groups regarding mediastinal and hilar accumulation of 87Ga in patients with carcinoma of the lung, it is apparent that abnormal uptake of 87Ga in the mediastinum increases the probability that mediastinal metastases are present. DeMeester et al18•17believe that whole body 87Ga scintigraphy is helpful in the identification ofclinically occult metastasis of lung carcinoma outside the thorax. In their series, 87Ga accumulation by both the primary tumor and an extrathoracic site indicated a 90% probability that the extrathoracic site was a metastasis. Furthermore, they suggested that the scan could be used as a guide for biopsy confirmation ofoccult metastasis. They also observed that routine scintigraphy of the liver and skeleton and cr scans of the brain added little to whole body 87Ga scintigraphy in the preoperative evaluation of patients without symptoms referrable to those organs. In their series, 87Ga scintigraphy demonstrated almost all occult metastases detected by other imaging techniques, as well as additional metastases to the adrenal glands, kidneys, and the diaphragm. An additional role for 81Ga scintigraphy is in detection of opportunistic pulmonary infections in patients undergoing chemotherapy. Gallium 67 has been shown to provide earlier detection of Pneumocysti8 carinii pneumonia (PCP) than chest radiographs or other approaches, 18 and should be considered for early patient evaluation if infection is suspected. The findings, of course, are nonspecific. Widespread pulmonary accumulation of 87Ga has been seen in a variety of inflammatory, iatrogenic, and idiopathic disorders, including AIDS, radiation pneumonitis (the active stage 1-2 weeks postexposure), idiopathic pulmonary fibrosis, sarcoidosis and after certain types of chemotherapy (eg, bleomycin). Most of these disorders are associated with chest roentgenographic abnormalities, whereas opportunistic infections often cause no roentgenographic changes early in their course. Leukocytes labeled with WIn also may be able to detect these early pulmonary infections but also are attracted to the lung by many noninfectious processes. At this time, WIn leukocytes do not seem to offer a clear advantage over 87Ga in evaluation of opportunistic infections.
Other Current Applications Liver, brain, and bone scans are potentially valuable adjuncts to the detection and management of distant metastases from lung carcinoma. The radionuclide brain scan has been supplanted by brain CT in most institutions, but still is a sensitive means for detecting metastatic disease when cr is unavailable. 18 The liver scan is nearly as sensitive as abdominal CT in detecting metastases, ao and it is readily available, easily tolerated, and relatively inexpensive. Radionuclide emission tomography (SPECT) of the liver further improves the resolution of the technique and, thus, its ability to detect small or deep metastases. 11.11 However, nearby organs such as
the adrenals are not visualized by either type of liver scintigraphy. The secondary effects of pathology elsewhere can be seen occasionally, however; as illustrated by the utility of the liver scan in detecting and assessing the effects of the superior vena cava (SVC) syndrome. When lung cancer causes SVC obstruction, chest wall collaterals carry How to the umbilicus and retrograde to the portal area. When the undiluted colloid particles reach the portal region, they are taken up by the liver and create an anterior hot spot. Radionuclide angiography over the chest during the colloid injection can demonstrate the pathway of the collateral Bow. The bone scan remains the most sensitive imaging test for detecting skeletal. metastases, which are seen in approximately 40% of patients who present with small cell carcinoma of the lung but in fewer than 10% of those presenting with other histologic varieties. Bone scans also may reveal the effects of cancer-associated abnormalities such as pulmonary osteoarthropathy, wherein areas of increased periosteal activity are seen in distal portions of the extremities. The scan also can detect polymyositis, or other paraendocrine abnormalities (eg, hyperparathyroidism). The strategies for employing bone scans and other conventional scintigraphic tests in patients with lung carcinoma are controversial and varied, but most suggest that routine screening of asymptomatic patients by multiorgan imaging is not warranted. Other scintigraphic studies that may benefit patients with lung carcinoma include utilization of UhtTc-Iabeled RBCs to localize the source of recurrent hemoptysis." "Bleeding" scans are able to detect extremely slow bleeding in the abdomen, where the site is surrounded by more background activity than in the lung. Thus, these studies should be even more effective in the lung. The drawback to these scans is that active bleeding must occur at some point during the course of the study. The utilization of gated blood pool scanning to evaluate ventricular function in patients who receive doxorubicin (Adriamycin) as one of their chemotherapeutic agents also is of interest. There is clear dose-related cardiotoxicity with Adriamycin that can be evaluated effectively by obtaining a series of gated blood pool scans and evaluating serial changes in the left ventricular ejection fraction (EF).14 When the baseline EF falls more than 10 points or to a resting value of less than 50%, cardiotoxicity should be considered. If Adriamycin therapy is withdrawn early enough, the cardiotoxic changes seem reversible. Thus, baseline and serial blood pool studies should be obtained at regular intervals in lung cancer patients who receive total adriamycin doses of approximately 300 mg/m" or more. FUTURE STUDIES
1\vo types of nuclear medicine studies that have been used
to evaluate other types of tumors have potential applications in patients with lung cancer: The first, Iymphoscintigraphy, relies on the injection of labeled microcolloid particles into tissue in the lymph drainage area of the organ of interest. 15 The radionuclide then is transported through the appropriate lymphatic channels and is trapped within sinusoids or actively phagocytized within lymph nodes. This process permits visualization of draining lymph nodes over a severalhour period following injection. Normal nodes accumulate activity, but nodes involved by tumor are not visualized. CHEST / 89 / 4 / APRIL, 1988 / Supplement
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Variations in lymph node anatomy and drainage patterns make interpretation of the studies somewhat difficult. However, experienced observers seem to be providing accurate interpretations in patients with breast carcinoma." Application of this technique to lung cancer have been reported, i6 but further work is needed to determine its true potential. The second new radionuclide technique with great potential in patients with lung carcinoma is that of using radiolabeled antibodies for tumor detection and, perhaps, therapy.21.28 Early experiences with labeled antibodies for tumor detection have raised several questions. These include whether radionuclides of iodine or other agents such as WIn will be optimum for labeling, whether whole antibodies or fragments of antibodies should be labeled, whether imaging can commence soon after injection or must be delayed for several days, whether allergic reactions to monoclonal antibodies are a significant clinical problem, and whether labeled antibodies can be used for tumor therapy as well as for lesion detection. The lung is relatively free from several sources of typical background activity (eg, bowel, urinary system, liver), so high tumor-to-background activity ratios should be possible following intravenous administration of the radiolabeled antibody. Work now is progressing with other tumors such as melanoma, but should be able to be extended to lung cancel: Theoretically, this would allow more sensitive detection and staging of lung cancer than possible by any other methods. If so, methods for patient selection will be needed, since monoclonal antibody imaging studies are not likely to be used for ee screening," REFERENCES 1 Olsen G, Block A, Swenson E, etal. Pulmonary function: evaluation of lung resection candidate: a prospective study. Am Rev Respir Dis 1975; 111:379-85 2 Williams CD, Brenowitz JB. "Prohibitive" lung function and major surgical procedures. Am J Surg 1976; 132:763-69 3 Kristersson S, Lindell SE, Svesnberg L. Prediction of pulmonary function loss due to pneumonectomy using 133-Xe radiospirometry. Chest 1972; 62:694-98 4 Wernly JA, DeMeester TR, Kirchner et ale Clinical value of quantitative ventilation-perfusion lung scans in the surgical management of bronchogenic carcinoma. J Thorac Cardiovasc Surg 1980; 80:535-39 5 Block AJ, Olsen GN. Preoperative pulmonary function testing. JAMA 1976; 235:257-61 6 Ali MK, Mountain CF, Ewer MS, et ale Predicting loss of pulmonary function after pulmonary resection for bronchogenic carcinoma. Chest 1980; 77:337-41 7 Ciofetta G, Silverman M, Hughes JMB. Quantitative approach to the study of regional lung function in children using krypton 81m. Br J Radioll980; 53:950-54 8 Alderson PO, Bradley E~ Mendenhall KG, et ale Radionuclide evaluation of pulmonary function following hemithorax irradiation of normal dogs with Co-6O or fast neutrons. Radiology 1979; 130:425-33 9 Bradley E~ Alderson PO, Deye JA, et ale Effects offraetionated doses of fast neutrons and photons on the normal canine lung: RBE values obtained by radionuclide studies. Int J Radiat Oncol 1979; 5:197-207
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10 KatzRD, Alderson PO, Tockman MS, etal. Ventilation-perfusion lung scanning in patients with early lung carcinoma. Radiology 1981; 141:171-78 11 Lipscomb DJ, Pride NB. Ventilation and perfusion scans in the preoperative assessment of bronchial carcinoma. Thorax 1977; 32:720-25 12 Turner DA. Ga-67 scintigraphy in malignant disease. In: Alderson PO, ed. Nuclear radiology. 3rd ed. Washington, DC: American College of Radiology, 1983:456-59 13 Waxman AD, Julian ~ Komiako M, Brachman MB, Tamasescu DE, Wolfstein R, et ale Gallium uptake in hilar and mediastinal structures in patients with pulmonary tumors: the significance of location and cell type on sensitivity and specificity. J Nucl Med 1979; 20:645-52 14 Alazraki N~ Ramsdell JW, Taylor A, Friedman PJ, Peters RM, Tlsi G M. Reliability of gallium scan chest radiography compared to mediastinoscopy for evaluating mediastinal spread in lung cancer. Am Rev Respir Dis 1978; 117:415-20 15 Fosburg RG, Hopkins GB, Kan MK. Evaluation of the mediastinum by gallium-67 scintigraphy in lung cancer. J Thorac Cardiovasc Surg 1979; 77:76-82 16 DeMeester TR, Beckerman C, Joseph JG, Toscano MS, Golomb H, Bitran J, et al. Gallium-67 scanning for carcinoma of the lung. J Thorac Cardiovasc Surg 1976; 72:699-708 17 DeMeester TR, Golumb HM, Kirchner ~ Rezai-Zadeh K, Bitran JD, Streeter DL, et ale The role of gallium-67 scanning in the clinical staging and preoperative evaluation of patients with carcinoma of the lung. Ann Thorac Surg 1979; 28:451-64 18 Levenson SM, Warren RD, Richman SD, Johnston GS, Chabner BA. Abnormal pulmonary gallium accumulation in P carlnii pneumonia. Radiology 1976; 119:395-98 19 Alderson PO, Gado MH, Siegel BA. Computerized cranial tomography and radionuclide imaging in the detection of intracranial mass lesions. Semin Nucl Med 1977; 7:161-73 20 Alderson PO, Adams D~ McNeil BJ, et ale Computed tomography, ultrasound, and scintigraphy of the liver in patients with colon or breast carcinoma: a prospective comparison. Radiology 1983; 149:225-30 21 Keyes JW Jr, Singer D, Satterlee W, Kolff ~ Harkness BA. Liver-spleen studies with the rotating gamma camera: utility of tomography. Radiology 1984; 153:537-41 22 Brendel AJ, Leccia F, Drouillard J, et ale SPEC( planar scintigraphy and transmission computed tomography: a comparison of accuracy in diagnosing focal hepatic disease. Radiology 1984; 153:527-32 23 Winzelberg GG, Wholey MH, Jarmlowski CA, Sachs M, Weinberg JH. Patients with hemoptysis examined by Tc-99m sulfur colloid and Tc-99m labelled red blood cells. Radiology 1984; 153:523-56 24 Alexander J, Dainiak N, Berger H, Goldman L, Johnstone D, Reduto L, et ale Serial assessment of doxorubicin cardiotoxicity With quantitative radionuclide angiocardiography. N Eng} J Med 1979; 300:278-83 25 Markisz JA, McNeil BI. Lymphoscintigraphy. In: Alderson PO, ed. Nuclear radiology. 3rd ed. Washington, DC: American College of Radiology, 1983; 466-75 26 Bethune DCG, Mulder DS, Chiu RCJ. Endobronchiallymphoscintigraphy. J Thorac Cardiovasc Surg 1978; 76:446-52 27 Goldenberg DM. Tumor imaging with monoclonal antibodies. J Nucl Med 1983; 24:360-62 28 Halpern SE, Dillman RO, Witzum KF, et al, Radioimmunodetection of melanoma utilizing In-III96.5 monoclonal antibody: a preliminary report. Radiology 1985; 155:493-99
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