Usefulness of Lung Perfusion Scintigraphy Before Lung Cancer Resection in Patients with Ventilatory Obstruction

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1 Usefulness of Lung Perfusion Scintigraphy Before Lung Cancer Resection in Patients with Ventilatory Obstruction Tommaso C. Mineo, MD, Orazio Schillaci, MD, Eugenio Pompeo, MD, Davide Mineo, MD, and Giovanni Simonetti, MD Thoracic Surgery Division and Department of Radiology, Emphysema Center, Policlinico Tor Vergata University, Rome, Italy Background. The study was conducted to evaluate the efficacy of preoperative lung perfusion scintigraphy performed by planar acquisition and single-photon emission computed tomography (SPECT) in predicting postoperative pulmonary function of patients with resectable lung cancer and obstructive ventilatory defect. Methods. The study enrolled 39 patients (mean age, years). All patients underwent preoperative and postoperative pulmonary function tests. Cut-off values for postoperative forced expiratory volume in 1 second (FEV 1 ) were 65% of the predicted value for pneumonectomy and 45% for lobectomy. A semiquantitative analysis of planar and SPECT lung perfusion scintigraphy images was performed preoperatively to estimate postoperative predicted FEV 1 (FEV 1 ppo). Relationships between FEV 1 ppo and measured postoperative FEV 1 were tested by the Pearson correlation and Bland Altman agreement tests. Results. Twenty-eight lobectomies and 11 pneumonectomies were performed. The FEV 1 ppo estimated by mean planar lung scintigraphy was L, with a Pearson correlation coefficient to the measured FEV 1 of (p < 0.001). The mean FEV 1 ppo estimated by SPECT was L, with a Pearson coefficient to the measured FEV 1 of (p < 0.001). Both values showed a more significant correlation with postoperative measured FEV 1 after lobectomy (p < 0.001) than after pneumonectomy (p 0.045). The Bland Altman test confirmed satisfactory agreement of FEV 1 ppo estimated by both planar lung scintigraphy and SPECT with FEV 1 measured by spirometry. Conclusions. Both planar lung scintigraphy and SPECT can accurately predict postoperative FEV 1 and can therefore be considered reliable tools in establishing operability of patients with lung cancer and ventilatory obstruction. (Ann Thorac Surg 2006;82: ) 2006 by The Society of Thoracic Surgeons Among cancer deaths, lung cancer still ranks first in mortality statistics. Although surgical resection of lung cancer remains the best therapeutic option, only 1 in 4 patients presents with a resectable disease. In many other patients, surgical treatment is forgone because of the coexistence of severe smoking-related chronic obstructive pulmonary disease (COPD) resulting in significant ventilatory defect [1]. These patients therefore constitute a high-risk group for both perioperative and long-term postoperative complications after anatomic lung resection, and careful preoperative functional evaluation is mandated [2, 3]. A forced expiratory volume in 1 second (FEV 1 ) 2Lor 60% of the predicted value usually accounts for a feasible pneumonectomy, with the values lowered to 1.5 L or 40% of the predicted value for a lobectomy [4, 5], thus excluding a considerable number of subjects who have a resectable disease but whose pulmonary function Accepted for publication May 15, Presented at the Poster Session of the Forty-second Annual Meeting of The Society of Thoracic Surgeons, Chicago, IL, Jan 30 Feb 1, Address correspondence to Prof T. Mineo, Cattedra di Chirurgia Toracica, Policlinico Tor Vergata, Viale Oxford 81, I Rome, Italy; mineo@med.uniroma2.it. appears too compromised for them to successfully undergo lung resection. Spirometry-based pulmonary function tests have become the gold standard of preoperative functional assessment of lung function, but the constant need for more accurate evaluation tools led to the use of perfusion or ventilation lung scintigraphy, or both, to provide a regional assessment of lung function and thus offer the possibility of estimating postoperative pulmonary function by means of the predicted postoperative FEV 1 (FEV 1 ppo). In particular, a FEV 1 ppo of 0.8 to 1.0 L or exceeding 40% of the predicted value is currently accepted as the cutoff for pneumonectomy [6, 7], although reliability and usefulness of these are still under scrutiny [8 10]. The aim of this study was to compare the role and usefulness of preoperative planar acquisition lung perfusion scintigraphy (PALPS) versus single-photon emission computed tomography (SPECT) in patients with ventilatory obstruction undergoing surgery for lung cancer. Patients and Methods A prospective study was conducted on 39 patients (31 men, 8 women) with a mean age of who had 2006 by The Society of Thoracic Surgeons /06/$32.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg MINEO ET AL 2006;82: LUNG SCINTIGRAPHY AND CANCER RESECTION 1829 Fig 1. See next page for legend.

3 1830 MINEO ET AL Ann Thorac Surg LUNG SCINTIGRAPHY AND CANCER RESECTION 2006;82: anatomic resection for lung cancer between January 2004 and January The ethics committee of the Tor Vergata University approved the study, and written informed consent was obtained from all recruited patients. Preoperative and postoperative (60 22 days) pulmonary function tests were performed according to the American Thoracic Society guidelines [4]. The preoperative evaluation included a total body CT scan, fiberoptic bronchoscopy, and videomediastinoscopy when appropriate. For the purpose of this study, PALPS and SPECT were also performed with semiquantitative analyses of planar and CT images. Cutoff values of 65% of the predicted FEV 1 % for pneumonectomy and 45% for lobectomy were established for inclusion in the surgical protocol. Since an increase of 5% in both these values has been assumed to be a safety threshold on postoperative outcome [2, 3, 11, 12], we maintained the same criteria. Twenty-eight lobectomies and 11 pneumonectomies were performed. Lung Perfusion Scintigraphy A dual-head, variable-angle gamma camera (Millenium VG; General Electric Medical Systems, Milwaukee, WI) with high-resolution low-energy collimators was used to perform lung perfusion scintigraphy. Five minutes after intravenous administration of technetium Tc 99m macroaggregated albumin (about 185 MBq), planar images of the lungs were acquired in the anterior, posterior, lateral, and oblique posterior projections (1 million counts each). Once PALPS was completed (Fig 1A), a SPECT acquisition over 36 nm (matrix , 0.3 nm angle steps, 25 seconds/frame) was performed (Fig 1B). PALPS and SPECT images both underwent semiquantitative evaluation. In PALPS, only anterior and posterior planar scans projections were considered. Regions of interest were marked in each lung with the perfusion percentage calculated by the geometric mean. The following formula was used for postoperative FEV 1 estimation in pneumectomy: FEV 1. ppo FEV 1 (FEV 1 % perfusion of affected lung/100). The same parameter for lobectomy was calculated with the formula proposed by Bolliger and colleagues [13]: FEV 1.ppo FEV 1 (1 functional contribution of perfusion of the parenchyma to be resected). For SPECT imaging, we used the method proposed by Piai and colleagues [14] for the estimation of postoperative FEV 1 in both pneumonectomy and lobectomy: FEV 1 (FEV 1 % perfusion of resected lobes), where % perfusion of resected lobes is the percentage of perfusion of lobes to be resected with regard to total radiation of both lungs. Statistical Analysis FEV 1 ppo values were compared with the postoperative FEV 1 values. The Pearson correlation test was used to investigate the relationship between postoperative predicted and measured FEV 1 values. The Bland Altman test [15] was used to test agreement between scintigraphyestimated and spirometry-measured data. Results Of 39 operated patients, 28 subjects underwent lobectomy and 11 had pneumonectomy. Histologic diagnosis was squamous cell carcinoma in 22 patients, adenocarcinoma in 11, and large cell carcinoma in 6. Preoperative and postoperative data of each patient are summarized in Table 1. The overall mean preoperative FEV 1 % was 59.41% 5.44%, with a mean of 61.54% 3.2% in patients undergoing a pneumonectomy and 58.57% 6.6% in those undergoing a lobectomy. Correlations are listed in Table 2. The mean PALPS estimated FEV 1 ppo was L, with a Pearson linear correlation coefficient to measured postoperative FEV 1 of (p 0.001). Mean FEV 1 ppo, as estimated by SPECT, was L, with a Pearson linear correlation coefficient to the measured postoperative FEV 1 of (p 0.001). Correlation was still significant when the values were expressed as a percentage of the predicted value. When the type of surgical procedure was considered, FEV 1 ppo values estimated by PALPS and SPECT both showed a stronger correlation with measured postoperative FEV 1 after lobectomy than after pneumonectomy, even though SPECT seemed to be more accurately predictive in the latter (Table 2). When agreement between PALPS estimated FEV 1 values and those measured by pulmonary function tests were examined, the Bland Altman test showed a difference of the means of L, with 97.4% of the values within the mean 2SD for absolute FEV 1 values and of 3.304% with 92.3% of values within the mean 2SD for the percent predicted values. In a similar manner, SPECT showed a satisfactory agreement with spirometry-measured FEV 1 in absolute values (difference between the means, L with 92.3% of values within the mean 2SD) and in percent predicted (difference between the means, 1.177% with 92.3% of values within the mean 2SD) (Figs 2 and 3). Comment Prediction of postsurgical pulmonary function is crucial in limiting morbidity and mortality after lung resection in patients with ventilatory obstruction, making accurate preoperative evaluation the key to successful outcome [2 4, 6, 7, 10, 11]. Measurement of ventilatory indexes, including FEV 1, diffusing capacity of the lungs for carbon monoxide, and maximal oxygen uptake, usually represents the first step of this evaluation process, although 4 Fig 1. Planar acquisition lung perfusion scintigraphy (a) versus single-photon emission computed tomography (SPECT) (b). Planned surgery: left lower lobectomy. SPECT is better defining hypoperfused segments. The following formulas were used for predicted postoperative (ppo) forced expiratory volume in 1 second (FEV 1 ) estimation in lobectomy: Planar lung scintigraphy FEV 1 ppo FEV 1 (1 functional contribution of perfusion of the parenchyma to be resected); SPECT FEV 1 (FEV 1 % perfusion of resected lobes).

4 Ann Thorac Surg MINEO ET AL 2006;82: LUNG SCINTIGRAPHY AND CANCER RESECTION 1831 Table 1. Preoperative and Postoperative Pulmonary Function Values in the Study Cohort Preoperative Postoperative No. Age Surgical Procedure Measured FEV1 Estimated by Planar Scintigraphy FEV 1 ppo Estimated by SPECT FEV 1 ppo Measured FEV 1 (L) % (L) % (L) % (L) % 1 65 Pneumonectomy Pneumonectomy Pneumonectomy Pneumonectomy Pneumonectomy Pneumonectomy Pneumonectomy Pneumonectomy Pneumonectomy Pneumonectomy Pneumonectomy Lobectomy Lobectomy Lobectomy Lobectomy Lobectomy Lobectomy Lobectomy Lobectomy Lobectomy Lobectomy Lobectomy Lobectomy Lobectomy Lobectomy Lobectomy Lobectomy Lobectomy Lobectomy Lobectomy Lobectomy Lobectomy Lobectomy Lobectomy Lobectomy Lobectomy Lobectomy Lobectomy Lobectomy FEV 1 forced expiratory volume in 1 second; PA planar acquisition lung perfusion scan; SPECT single photon emission computed tomography. the usefulness of each of these indexes remains a matter for discussion. Safety threshold values for FEV 1 are currently set at 2 L for a pneumonectomy and 1.5 L for a lobectomy. The percent predicted FEV 1 appears a more useful index because it accounts for gender and size variability of patients being evaluated for lung resection. A predicted FEV 1 80% therefore makes a patient suitable for pneumonectomy without need for further evaluation [3, 16, 17]. Several studies have confirmed the value of the FEV 1 ppo in predicting postoperative morbidity and mortality after lung resection [2, 4, 6, 10, 12, 18]. Even this index has, nonetheless, never been universally accepted,

5 1832 MINEO ET AL Ann Thorac Surg LUNG SCINTIGRAPHY AND CANCER RESECTION 2006;82: Table 2. Pearsons Linear Correlation Coefficients Type of Resection Variables Coefficient p Value All FEV 1 ppo PALPS and measured FEV1 (L) All FEV 1 ppo PALPS and measured FEV1 (%) All FEV 1 ppo SPECT and measured FEV1 (L) All FEV 1 ppo SPECT and measured FEV1 (%) Pneumonectomy FEV 1 ppo PALPS and measured FEV1 (L) Pneumonectomy FEV 1 ppo PALPS and measured FEV1 (%) NS Pneumonectomy FEV 1 ppo SPECT and measured FEV1 (L) Pneumonectomy FEV 1 ppo SPECT and measured FEV1 (%) NS Lobectomy FEV 1 ppo PALPS and measured FEV1 (L) Lobectomy FEV 1 ppo PALPS and measured FEV1 (%) Lobectomy FEV 1 ppo SPECT and measured FEV1 (L) Lobectomy FEV 1 ppo SPECT and measured FEV1 (%) All FEV 1 ppo PALPS and FEV1.ppo SPECT (L) All FEV 1 ppo PALPS and FEV1.ppo SPECT (%) PALPS planar acquisition lung perfusion scintigraphy; SPECT single photon emission computed tomography; FEV 1 forced expiratory volume in 1 second; ppo predicted postoperative. gradually shifting clinicians interest to methods able to effectively estimate postoperative residual lung function. This because postsurgical functional loss varies with the amount of resected lung, the relative function of the removed tissue being compared with the remaining one, and the baseline functional impairment. Split function studies such as quantitative lung perfusion scintigraphy have made it possible to calculate the function of the excised tissue in relation to overall pulmonary function, therefore predicting postoperative residual function [7]. Lung perfusion scintigraphy with Tc-labeled macroaggregates of albumin is the currently recommended protocol to estimate the FEV 1 ppo. Alternative, cheaper techniques such as segment counting have been proposed by Zeiher and colleagues [19]. The major drawback of this technique is that it assumes that each segment of both lungs contributes equally to lung function, an assumption that does not fit most patients with COPD. In addition, gross underestimation of postoperative FEV 1 may be determined by centrally located cancer masses causing uneven lung perfusion [9, 20]. Therefore, even though the American College of Chest physicians and the British Thoracic Society do not currently recommend using scintigraphy for preoperative assessment of lung cancer patients undergoing lobectomy, this technique has become a standard test in the preoperative evaluation of patients scheduled for pneumonectomy. PALPS is a simple technique that proved effective in predicting postoperative outcome of patients with severe COPD [21]. We hypothesize that surgical candidates with preoperative FEV 1 60% should always undergo lung perfusion scintigraphy to achieve accurate postoperative outcome prediction with an estimated FEV 1 ppo 40% indicating an acceptable surgical risk. Preoperative assessment by means of perfusion SPECT imaging is still being evaluated. Postoperative FEV 1 estimation by perfusion SPECT demonstrates good correlation with spirometrically measured FEV 1. In addition, SPECT estimation of FEV 1 ppo proved more accurate than planar scintigraphy estimated values [21], leading Hirose and colleagues [22] and Wu and colleagues [23] to consider SPECT images as more useful than planar images to assess resectability [22, 23]. In our study, FEV 1 ppo, estimated by planar scintigraphy or SPECT acquisition, was similar compared with spirometrymeasured postoperative FEV 1. These results are comparable with those reported in a previous study by Piai and colleagues [14] in which no significant difference was observed between the two techniques, although in this latter study, integration of SPECT images with CT was suggested to provide more precise anatomic information. Wu and colleagues [23] also considered quantitative CT scanning to be an adequate tool because it is now routinely performed during the preoperative work-up for lung cancer surgery, it is semiautomated and can be performed by a trained technician, and it is not complicated or time-consuming. The same authors [23], however, admit that patients undergoing lobectomy with a quantitative CT-predicted FEV 1 ppo of about 40% or less should also receive a perfusion scintigraphy. Such technique has effectively been extensively used to predict lung function after resection and is still the simplest and most reliable method, even if it can underestimate postoperative measured FEV 1 values. Conversely, CT-based methods require more postprocessing and are limited by the need for scanner calibration, the dependence of lung density on the inspiratory effort, and the x-ray beam collimation [20]. In our opinion, FEV 1 ppo estimated by both planar lung scintigraphy and SPECT correlates well with spirometrymeasured postoperative FEV 1, and therefore appears to be a good marker of surgical feasibility in patients with ventilatory obstruction. Although results achieved by planar lung scintigraphy and SPECT were comparable in

6 Ann Thorac Surg MINEO ET AL 2006;82: LUNG SCINTIGRAPHY AND CANCER RESECTION 1833 this study, we have found that SPECT accounts better for spatial overlapping of the pulmonary lobes and differences in their size or perfusion and better estimates hypoperfused areas/segments in candidates for lobectomy or pneumonectomy with no additional cost. Our overall results seems to confirm the usefulness of combining CT-provided anatomic information with physiologic information obtained by scintigraphy-based image fusion algorithms [17, 21, 24]. In conclusion, PALPS and SPECT both helped predict postoperative pulmonary function in patients in this study with significant ventilatory defect undergoing anatomic lung resection. Eventual confirmation of our findings by larger studies will probably contribute to further increase the number of patients with resectable lung Fig 3. Bland Altman agreement test between single-photon emission computed tomography (SPECT)-estimated and spirometry pulmonary function test (PFT)-measured postoperative forced expiratory volume in 1 second (FEV 1 ) in liters (a) and in percent predicted (b). The black line is the mean and dashed lines are mean two standard deviations (SD). cancer and impaired pulmonary function who might benefit from curative lung resection with acceptable risks of mortality and morbidity. This research was supported by a grant from the Italian Health Ministry. Fig 2. The Bland Altman agreement test between planar acquisition lung perfusion scintigraphy (PALPS)-estimated and spirometry pulmonary function test (PFT)-measured postoperative forced expiratory volume in 1 second (FEV 1 ) in liters (a) and in percent predicted (b). The black line is the mean and dashed lines are mean two standard deviations (SD). References 1. Reif MS, Socinski MA, Rivera MP. Evidence-based medicine in the treatment of non-small-cell lung cancer. Clin Chest Med 2000;21: Win T, Jackson A, Sharples L, et al. Relationship between pulmonary function and lung cancer surgical outcome. Eur Respir J 2005;25: Datta D, Lahiri B. Preoperative evaluation of patients undergoing lung resection surgery. Chest 2003;123:

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