Patients with T4, N0-1 non-small cell lung cancer

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1 Endothoracic Sonography Improves the Estimation of Operability in Locally Advanced Lung Cancer Thomas G. Lesser, MD Department of Thoracic and Vascular Surgery, SRH Wald-Klinikum Gera, Teaching Hospital of Friedrich-Schiller-University of Jena, Gera, Germany Background. Patients with T4 non-small cell lung cancers with limited involvement of mediastinal structures can undergo resection, with acceptable long-term survival. Computed tomography has not proven to be reliable in determining the operability of locally advanced lung carcinoma. This study evaluated the ability of video-assisted thoracoscopy alone and with endothoracic sonography to determine operability. Methods. Computed tomography showed a close contact of the tumor with mediastinal structures (T4) in 155 patients. Staging was expanded with video-assisted thoracoscopy, followed by thoracoscopic ultrasound. Lateral thoracotomy with hilar and mediastinal dissection was considered the gold standard in determining operability. Results. Thoracoscopic ultrasound, compared with thoracoscopy alone and computed tomography, had the highest sensitivity (94.1% vs 75.2% vs 43.6%, p < 0.001) and specificity (98.1% vs 57.4% vs 37.0%, p < 0.001) for determining operability. Computed tomography, thoracoscopy, and thoracoscopic ultrasound were falsely negative in 57 (36.8%), 25 (16.1%), and 6 (3.9%) patients and falsely positive in 34 (21.9%), 23 (14.8%), and 1 (0.6%). False-negative results for operability by thoracoscopic ultrasound were found only in tumors involving the left atrium (3.9%). Conclusions. Estimation of operability in locally advanced lung cancer can be improved with video-assisted thoracoscopy and ultrasound. More than one-third of patients classified as inoperable by computed tomography were able to undergo complete resection. (Ann Thorac Surg 2010;90:217 22) 2010 by The Society of Thoracic Surgeons Patients with T4, N0-1 non-small cell lung cancer (NSCLC) with limited involvement of mediastinal structures can undergo resection with acceptable longterm survival [1 3]. The results of computed tomography have not proven to be reliable in determining the involvement of mediastinal organs and great vessels. Computed tomography (CT) correctly staged less than 60% of patients with T4 tumors, and most were overstaged [4 6]. Videothoracoscopy as the initial step of an operation has proved useful in obtaining a decisive evaluation of lung cancer resectability [7]. But this method is limited by the lack of manual palpation of hilar and mediastinal structures to assess the local extension, especially the invasion of mediastinal structures. Endothoracic sonography allows the delimitation of tumor margins and the relationship of contiguity or continuity with deep vascular structures [8]. Endothoracic sonography seems to be reliable in determining whether T4 structures are truly invaded by a tumor. This study compared the ability of CT, thoracoscopic examination by itself, and thoracoscopy with endothoracic sonography to determine operability in patients with locally advanced tumors. Accepted for publication March 26, Address correspondence to Prof Dr Lesser, Department of Thoracic and Vascular Surgery, SRH Wald-Klinikum Gera, Straße des Friedens 122, D Gera, Germany; thomas.lesser@wkg.srh.de Material and Methods The study was approved by ethic committee of the medical association of Thuringia. Written consent was obtained from patients for participation in this study. Patients Between 2000 and 2008, 176 patients with clinical T4, N0-1 NSCLC were staged with video-assisted thoracoscopy (VAT) and endothoracic sonography (also referred to as ultrasound). The reference method was mediastinal dissection after thoracotomy. Preoperative evaluation included chest roentgenogram, fiberoptic bronchoscopy, CT of the chest and upper abdomen, brain magnetic resonance imaging, and bone scintigraphy. Since 2005, each patient underwent fluorodeoxyglucose positron emission tomography. All suspicious N2 lymph nodes by chest CT or by positron emission tomography were biopsied. Involvement of the esophageal muscularis was ruled out by preoperative transesophageal sonography. In all patients, CT demonstrated close contact of the tumor with mediastinal structures (pulmonary artery, left or right atrium, superior vena cava, thoracic aorta) with questionable resectability. Together with a roentgenologist, CT scans were criticized regarding operability. A tumor was considered resectable in the presence of one or more of these imaging findings: less then 90 of contact with the aorta, at least a 2-cm tumor-free part of pulmonary artery, and a plane between the mass and medias by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 218 LESSER Ann Thorac Surg ULTRASOUND FOR LUNG CANCER OPERABILITY 2010;90: tinal structures [9]. Despite a determination of inoperability by CT, patients underwent the operative staging procedure. Intraoperative Algorithm VAT was performed to explore the entire pleural space. Suspected pleural lesions were biopsied and specimens were evaluated microscopically by frozen section. When pleural lesions were absent, pleural biopsies were taken systematically to rule out microscopic pleural metastases. Histopathologic determination of pleural metastases resulted in stopping the procedure, but patients with malignant pleural effusion were treated with talc pleurodesis. In some cases, VAT was impossible due to severe pleural adhesions, and a conversion to thoracotomy was necessary. In cases where pleural involvement was excluded, VAT exploration and instrumental palpation of ventral and dorsal hilar and mediastinal structures was performed to assess resectability. The following criteria were defined in determination of operability: the tumor-seized lung can be retracted and dissected from the superior vena cava, aortic arch, and descending aorta; ventral and dorsal hilum can be explored, and instrumental palpation gives no evidence for intrapericardial tumor masses. The exploration was followed by the use of endothoracic sonography positioned over hilar and mediastinal structures under VAT control (Fig 1), and resectability was assessed again. Criteria were also defined in determination of operability: infiltration of superior vena cava less than one-third of circumference without invading right atrium, no infiltration of aortic wall, at least 1 cm tumor-free part of intrapericardial pulmonary artery, and left atrial invasion less than 1 cm in proximity to the origin of pulmonary veins. Finally, lateral thoracotomy with hilar and mediastinal dissection was considered the gold standard in determining operability (Fig. 2). Operability after open mediastinal and intrapericardial dissection is defined as follows: the tumor must be resectable by the use of vascular clamps and without the need of total cardiopulmonary Fig 1. Video-assisted thoracoscopy with endothoracic sonography. Video image (inset) shows the ultrasound probe over the mediastinal structures. Fig. 2. Schematic shows the study design and outcome. (CT computed tomography; ETS endothoracic sonography; NSCLC nonsmall cell lung cancer; VAT video-assisted thoracoscopy.) *Exclusive of 21 patients with pleural metastasis who could not be resected or explored by VAT. bypass. The same surgeon performed the CT scan evaluation and the operative staging procedure. Thoracoscopic Techniques VAT was carried out under general anesthesia, by double-lumen tube intubation for 1-lung ventilation, with the patient lying laterally as for lateral thoracotomy. Two or 3 incisions are placed in variable positions (2 on the incision line of possible thoracotomy and 1 for pleural drainage), using flexible thoracoports with diameters of 7 and 10 mm. Pleural exploration required 2 ports, a 10-mm port for the endocamera and a 7-mm port for the biopsy forceps. A third 10-mm port was necessary for the sonographic probe. The video system consisted of a 30 Hopkins optic, videocamera, light source, and monitor (Karl Storz, Tuttlingen, Germany). The sonographic system was equipped with multifrequency convex probe (5.0, 6.0, and 7.5 MHz) with mechanical flexibility in 2 planes and color Doppler availability (probe type 8666; 2002 Panther Device, B&K, Herlev, Denmark). Statistical Analysis The diagnostic value of CT, thoracoscopy alone, and with ultrasound was compared with the results of thoracotomy by calculating sensitivity and specificity. The -Quadrat test to Pearson was used to compare the sensitivity and specificity between CT and thoracoscopy,

3 Ann Thorac Surg LESSER 2010;90: ULTRASOUND FOR LUNG CANCER OPERABILITY 219 Table 1. Estimation of Operability in 155 Patients with T4, N0-1 Non-Small Cell Lung Cancer by Thoracotomy, Computed Tomography, Video-Assisted Thoracoscopy, and Video-Assisted Thoracoscopy and Ultrasound Method TP ( operable) Patients Sensitivity (%) TN ( inoperable) Patients Specificity (%) Patients (%) Patients (%) CT VAT a VAT and US b,c b,c Thoracotomy a Significant difference to computed tomography (p 0.001). b Significant difference to video-assisted thoracoscopy (p 0.001). c Significant difference to computed tomography (p 0.001). CT computed tomography; false negative; false positive; TN true negative; TP true positive; VAT video-assisted thoracoscopy; US ultrasound. CT and thoracoscopy with ultrasound, and thoracoscopy alone and with ultrasound. A 2-sided value of p 0.05 or less was considered as a statistically significant difference between the groups unlikely to be due to chance. The statistical analysis was performed using SPSS 18 software (SPSS Inc, Chicago, IL). Results A total of 176 patients (145 men, 31 women) who were a median age of 64 years (range, 45 to 82 years) with T4, N0-1 NSCLC underwent thoracoscopy to determine the operability. Adenocarcinoma was present in 97 patients (55.1%), squamous cell carcinoma in 53 (30.1%), and large cell carcinoma in 26 (14.8%). The study excluded 21 patients because the staging procedure could not be completed. In 16 (91%) of these patients, VAT pleural exploration demonstrated malignant pleural involvement based on histologic evaluation by frozen section of biopsy specimens, and in 5 (2.8%) VAT exploration of hilar and mediastinal structures was impossible due to widespread sticky pleural adhesions. Resectability was assessed by CT, VAT, VAT and ultrasound, and thoracotomy (Fig 2) in 155 patients, of whom 101 (65.2%) were considered operable. The surgical procedures in those 101 patients included pneumonectomy in 69, sleeve lobectomy in 18, bilobectomy in 5, lobectomy in 4, sleeve pneumonectomy in 3, and sleeve bilobectomy in 2. The results of this study are summarized in Table 1. Sensitivity for operability was only 43.6% by CT. The cancer was overstaged in 57 patients (36.8%) and misclassified as inoperable (false-negative). Sensitivity increased significant to 75.2% with VAT (p 0.001) and 94.1% with VAT and ultrasound (p 0.001). False-negative results occurred in 25 (16.1%) with VAT and in 6 (3.9%) with VAT and ultrasound. Specificity was 37.0% by CT, 57.4% with VAT, and 98.1% with VAT and ultrasound. The difference between VAT and CT was not significant (p 0.053). However, VAT and ultrasound has a significantly higher specificity than CT and VAT (p 0.001). False-positive results occurred in 34 patients (21.9%) with CT, 23 (14.8%) with VAT, and in only 1 patient (0.6%) with VAT and ultrasound. Results of intraoperative staging of resectability regarding involved mediastinal structures are reported in Table 2. The pulmonary artery and left atrium were the most frequent structures with tumor involvement. The highest false-positive results for resectability by VAT alone were found where tumors involved the pulmonary artery (12 cases) or left atrium (10 cases). In all but 1 patient (involving the descending aorta), tumor involvement of the superior vena cava, descending aorta, or right atrium was not overstaged by VAT alone. With VAT and ultrasound, no false-positive results occurred. In only 1 Table 2. Results of Intraoperative Staging of Resectability in 155 Patients with T4, N0-1 Non-Small Cell Lung Cancer Regarding Involved Mediastinal Structures Patients Clinically Suspected Involvement Staging by VAT Staging by VAT and US Resectability by Thoracotomy 65 Pulmonary artery (49.2) 18 Superior vena cava (88.9) 46 Left atrium (67.4) 21 Descending aorta (81.0) 5 Right atrium (100) (16.1) 23 (14.8) 6 (3.9) 1 (0.6) a 101 (65.2) a The operability was false in 1 patient because of diffuse intrapericardiac cancer cell infiltration. false negative; false positive; VAT video-assisted thoracoscopy; US ultrasound.

4 220 LESSER Ann Thorac Surg ULTRASOUND FOR LUNG CANCER OPERABILITY 2010;90: patient (0.6 %) was operability by VAT and ultrasound incorrect because of diffuse intrapericardiac cancer cell infiltration. However, false-negative results occurred with VAT and ultrasound in 6 patients (3.9%) who had tumor involvement of the left atrium. All 6 were resectable at thoracotomy. This misjudgment regarding resectability occurred only with involvement of the left atrium. Comment Resectability of T4 NSCLC depends on the degree of tumor involvement of the mediastinal structures. CT is poor in distinguishing between tumors abutting the mediastinum and tumors invading mediastinal structures. The cancer in 36.8% of these patients was overstaged and misclassified as inoperable. VAT has been used for operative staging of lung cancer [10, 11], and is of great value in clinical N2 stages, especially when lymph nodes are located in areas inaccessible through mediastinoscopy [8, 12, 13]. In the case of ipsilateral pleural effusion in patients with lung cancer, thoracoscopy should be used to stage those patients before proceeding to thoracotomy [14]. VAT has proved useful in determining whether tumor has infiltrated into the descending aorta, superior vena cava, or right atrium, because mediastinal dissection can be performed by thoracoscopy. However, false-negative and false-positive results regarding the pulmonary artery and left atrium were too high (16.1% and 14.8%). Surgical removal of the tumor and mediastinal dissection to determine operability is limited by VAT. However, impossibility of tumor removal from the aorta does not mean inoperability. Despite opening the pericardium thoracoscopically, examination of intrapericardial tumor spreading is very difficult due to the absence of manual palpation. The dorsal pericardium cannot be opened without a high risk for the patient. In the study of Roviaro and coworkers [10], 6.1% of patients with stage II or IIIA disease underwent exploratory thoracotomy after VAT operative staging. Although sensitivity and specificity for resectability were increased by the results of VAT alone, these levels are still unsatisfactory. With VAT and ultrasound, the Fig 4. Videothoracoscopy with endothoracic sonography of the patient in Figure 3 shows the absence of tumor invading the left main pulmonary artery. The ( ) marks the tumor-free part in proximity to the margin of tumor infiltration. Findings at thoracotomy demonstrated resectability. (LMB left main bronchus; LMPA left main pulmonary artery; PT pulmonary trunk; TU tumor.) staging of resectability was improved, with sensitivity of 94.1% and specificity of 98.1%. In particular, resectability regarding tumor infiltration of the pulmonary artery can be staged with high degree of confidence (Fig 3 and Fig 4), as previously reported by Menconi and colleagues [8]. This is important because T4 NSCLC patients with pulmonary great vessel involvement who are resectable had better survival rates than other T4 subgroups [2]. Inoperability was adequately assessed. In only 1 patient was intrapericardial carcinosis not detectable by sonography. To determine tumor infiltration in the left atrium, the Fig 3. Computed tomography scan shows a patient with central non-small cell lung cancer involving the left main pulmonary artery. Fig 5. Computed tomography scan of a patient with central nonsmall cell lung cancer adjacent to the lower right pulmonary vein (1) and left atrium (11).

5 Ann Thorac Surg LESSER 2010;90: ULTRASOUND FOR LUNG CANCER OPERABILITY 221 In conclusion, staging of resectability of T4, N0-1 NSCLC can be improved by means of VAT and ultrasound with high sensitivity and specificity, compared with thoracotomy. Use of this method may reduce the number of diagnostic thoracotomies and the danger associated with open mediastinal dissection. Patients who until now would be classified as inoperable by CT can have complete resection performed. Fig. 6. Videothoracoscopy with endothoracic sonography of the patient in Figure 5 shows the margin of tumor invading the left atrium (1). Findings at thoracotomy demonstrated resectability. ultrasound probe must be positioned exactly on the lung hilum from the dorsal aspect in various planes. Figures 5 and 6 show a patient with a large tumor in contact with the left atrium. By ultrasound, it was possible to determine the exact margin of tumor infiltration in the left atrium. The tumor was judged resectable, which proved correct by thoracotomy. Because of immobility of the infiltrated lung caused by retention pneumonia, it was difficult to position the ultrasound probe on the left atrium. However, this is necessary to determine the area of infiltration exactly. Therefore, 6 patients (3.9%) were misclassified as inoperable by ultrasound, because of overstaging of intrapericardiac infiltration of the left atrium. Pericardiotomy and intrapericardial placement of the sonographic probe could be helpful. Furthermore, ultrasound on a higher frequency could be advantageous. Takahashi and coworkers [15] reported that breath-hold gadolinium-enhanced 3-dimensional magnetic resonance imaging angiography has been proposed as a useful tool to improve preoperative evaluation of the extent of atrial involvement. Patients with a suspicion of esophageal tumor infiltration were excluded because transesophageal endosonography has high sensitivity for detecting such infiltration. Endobronchial sonography could be reliable in determining resectability regarding involvement of the pulmonary artery. This method, however, has anatomic limitations and blind spots, and its sensitivity and specificity should be determined in future studies. It is unclear whether intraoperative staging by VAT and ultrasound will result in success after induction therapy. The discrimination between tumor necrosis and viable tumor tissue could be problematic. Dr Thomas Lehmann from the Institute of Medical Statistics, Computer Sciences and Documentation of the University Hospital of Jena, provided assistance in data calculation. References 1. Detterbeck FC, Jones DR, Kernstine KH, et al. Lung cancer. Special treatment issues. Chest 2003;123:244 58S. 2. Yang HX, Hou X, Lin P, Rong TH, Yang H, Fu JH. 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