L cancer-related deaths in Japan. The number of patients

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1 Extended Resection of the Left Atrium, Great Vessels, or Both for Lung Cancer Ryosuke Tsuchiya, MD, Hisao Asamura, MD, Haruhiko Kondo, MD, Tomoyuki Goya, MD, and Tsuguo Naruke, MD Division of Thoracic Surgery, Department of Surgery, National Cancer Center Hospital, Tokyo, Japan One hundred one patients with locally advanced lung cancer underwent combined resection of the lung and the left atrium with or without the great vessels. A single additional organ was resected in 92 patients, two organs in 8 patients, and three organs in 1 patient. The left atrium was resected in 44 patients, the superior vena cava in 32, the adventitia of the aorta in 21, the aorta in 7, and the pulmonary artery in 7. The most important factors affecting survival defined by multivariate analysis were postoperative pneumonia, complete resection, postoperative bleeding, and lymph node metastasis (p < 0.05). Thirteen patients survived 3 years or more and 10 of the 13 survived 5 years or more. The 5-year survival rate for all patients, including 8 with operative death, was 13%, and the median survival time was 9.2 months. The 5-year survival and median survival time were 19% and 13.8 months after complete resection and 0% and 6.5 months after incomplete resection (p < 0.01). The 5-year survival and median survival time for patients with pathologic stage IIIA, IIIB, and IV were 16.8% and 16.8 months; 18.3% and 9.8 months; and 0% and 5.4 months, respectively. There was a significant difference between stages IIIA plus IIIB and stage IV (p < 0.05). The 5-year survival after left atrium resection was 22%. Extended resection was worthwhile for the patients undergoing complete resection and without postoperative complications. (Ann Thorac Surg 1994;57:960-5) ung cancer causes the second highest number of L cancer-related deaths in Japan. The number of patients with lung cancer is increasing rapidly and will exceed the number of patients with gastric cancer, which is the number one cancer causing death today. Only one third of the patients with lung cancer can be identified as operative candidates. For the other two thirds operation is not indicated, because they have advanced lung cancer with distant metastases or locally advanced lung cancer invading neighboring organs. The results of resection of lung cancer depend on the TNM staging. Resection is indicated for stage I lung cancer, because it gives a 5-year survival rate of 70%, but the 5-year survival rates for stage IIIA and IIIB are 19% and 6%, respectively [l]. The results of resection of stage IIIB cancers are poor; however, there are a few 5-year survivors without any evidence of recurrence of lung cancer. The prognostic factors for patients with lung cancer resected with a part of the left atrium with or without the great vessels, were examined in this study, and the indications for these operations are discussed. Material and Methods Pa tien ts One hundred one patients underwent combined resection of the left atrium with or without the great vessels for lung Accepted for publication Aug 4, Address reprint requests to Dr Tsuchiya, Division of Thoracic Surgery, Department of Surgery, National Cancer Center Hospital, 1-1 Tsukiji 5-Chome, Chuo-ku, Tokyo 104, Japan. cancer. They constituted 3.7% of 2,700 patients with lung cancer resected from May 1962 to December 1991 in the National Cancer Center Hospital in Tokyo. Ninety patients were men and ll were women, ranging in age from 27 to 79 years. Fifty patients had a cancer in the right lung and 51 in the left. Seventy-two patients underwent pneumonectomy, 28 underwent lobectomy and 1 patient, who was 1 of 2 with recurrent cancer, underwent resection of the left residual main bronchus and descending aorta invaded by locally recurrent carcinoma. Fifty-two patients had squamous cell carcinoma, 31 had adenocarcinoma, 3 had small cell carcinoma, 13 had other cell types, and 2 had unclassified carcinomas treated preoperatively. Two of 3 patients with small cell carcinoma were treated with chemotherapy and radiation before operation, and were recommended for salvage surgery. The other patient with small cell carcinoma was diagnosed as having non-small cell lung cancer by cytology before the operation. Combined resection of the lung and a single additional organ was performed in 92 patients. Two additional organs were resected in 8 patients. Three organs, the left atrium, adventitia of the aorta and main pulmon,ary artery, were resected in 1 patient. The left atrium only was resected in 37 patients, the superior vena cava only in 30, the adventitia of the aorta only in 19, the aorta only in 4, and the pulmonary artery only in 2. Left atrium and superior vena cava were both resected in 2 patients, left atrium and pulmonary artery in 2, aorta and pulmonary artery in 2, left atrium and adventitia of aorta in 1, left atrium and aorta in 1, and left atrium with adventitia of by The Society of Thoracic Surgeons /94/$7.00

2 Ann Thorac Surg 1994; TSUCHIYA ET AL 961 aorta and pulmonary artery in 1. The 7 patients receiving resection of main pulmonary artery were operated on by cardiopulmonary bypass. Seventy-two patients underwent combined resection of the lung and only the left atrium with or without the great vessels; however, the other 29 patients underwent not only combined resection of the lung and the left atrium with or without the great vessels, but also resection of other neighboring, invaded organs. In 12 of 13 patients with tracheal carinal resection, the superior vena cava was also resected. Chest wall, parietal pleura and esophagus were resected in 9, 4, and 4 patients respectively. Patients with distant metastases were excluded from these types of operations. Computed tomography (CT), echography of the thorax and abdomen, and bone scintigram were added to physical examination to detect distant metastases. The patients with pleural effusion detected by echography or CT were excluded. The patients with cancer cell-positive effusion were also excluded. When we found positive pleural or pericardial effusion or dissemination of carcinoma, we did not perform the operation. Pulmonary angiography and CT of the thorax gave us good information for patient selection. If bulky mediastinal lymph node metastases invading the left atrium or great vessels were detected by CT, we opened the thorax to perform the operation if the preoperative evaluation suggested that complete resection would be possible technically, even with cardiopulmonary bypass. Eighty-two patients received ipsilateral mediastinal and hilar lymph node dissection, 12 only ipsilateral hilar lymph node dissection, and 7 ipsilateral mediastinal and hilar lymph node dissection with dissection of the contralateral mediastinal lymph node added. Ten patients were treated by chemotherapy before the operation and 7 after operation. Six were irradiated before the operation and 28 after the operation. Two patients with small cell lung cancer received chemotherapy and radiation before the operation. Forty-nine of the cancers were classified as stage IIIB by pathologic staging. There were sixty-four cancers of pt4, sixty-one of pn2, four of pn3 and twentysix of M1. Seventeen of the twenty-six cancers were evaluated as M1 after the operation due to intrapulmonary metastases detected by microscopic examination of surgical specimens. The other 9 patients were included in M1 due to distant metastases diagnosed before operation; in 2 patients, solitary brain metastases were resected, and in the other 7 patients, metastases were detected within 1 month after operation. We resected the left atrium in each of these 9 patients. Solitary brain metastases were resected before lung resection in 2 patients. The sites of metastases not detected before operation and diagnosed within 1 month after the operation were brain in 2 patients, bone in 2, neck lymph nodes in 1, lung in 1, and liver in 1. Statistical analyses were performed by using the SAS program with a HITAC 660-H (Hitachi) computer. Survival curves were calculated by the Kaplan-Meier method, and tests for significance were based on the generalized Wilcoxon test and log rank test. Multivariate analysis for prognostic factors was performed by the Cox proportional hazards general linear model (PHGLM) stepwise procedure on the SAS program. A significance level of 5% was set as the limit for inclusion in the model. Preoperative and postoperative characteristics were examined as prognostic factors by univariate and multivariate analyses. Characteristics examined as variables are sex, side, age, procedure (pneumonectomy, lobectomy), histology, adjuvant therapy, organs resected, pathologic stage, pathologic TNM, surgeon's judgment of completeness of resection, pathologic judgement of completeness of resection, and complications. Surgical Technique LEFT ATRIUM. Digital subtraction angiography and echocardiography give us good information on the relationship between the left atrium and lung cancer, not only on hard copies but also on video as dynamic pictures. Intraoperative echocardiography helps us to decide whether to use vascular clamps (Fig 1A). In all 44 patients receiving left atrium resection, the operation could be performed by using vascular clamps only, without cardiopulmonary bypass, and the defect of the left atrium could be sutured directly. In 1 patient, with lung cancer growing into the left atrium as a polypoid tumor, the polyp was grasped with the vascular clamp along with the wall of the left atrium. After part of the posterior wall of the left atrium was cut, the vascular clamp was opened, and the head of the long, hard polyp was pulled out using forceps and the operator's index finger, similar to the technique for closed commisurotomy (Fig lb, C). SUPERIOR VENA CAVA. Twenty-one of the 32 patients underwent partial resection of the superior vena cava with a side clamp and direct suture of the defect. In 7 patients, the vena cava was replaced with a Gore-Tex (W. L. Gore & Assoc, Naperville, IL) bypass graft between the left brachiocephalic vein, or the confluence of both brachiocephalic veins, and the right atrium (Fig 2). In 4 patients,, partial resection of the vena cava was performed, and the defect was covered with pericardium under a side clamp or cross-clamp of the vena cava. ADVENTITIA OF THE AORTA. It is difficult to peel the adventitia of the aorta precisely. Therefore, 12 of the 21 patients in this category underwent incomplete resection of the lung cancer invading the aorta, and a massive tumor was left in the aortic wall. The defect of the adventitia was wrapped in a woven Dacron artificial vessel. AORTA. The aorta was invaded near Bottalo's ligament by lung cancer or metastatic subaortic lymph nodes in 6 patients. The aorta of the other patients was invaded at the root of the left subclavian artery. Five of the 7 patients received total replacement of the aorta with an artificial vessel. The other 2 received a patch graft for repair of the

3 962 TSUCHIYA ET AL Ann Thorac Surg 1994;5796C-5 A B C Fig 1. (A) Echocardiogram showing a long polyp (T) beaten by the mitral valve (MV). (B) Operative procedure. First the long, hard polyp was grasped by a vascular clamp with the wall of the left atrium. (0 After part of the posterior wall of the left atrium was cut, the polyp was pulbd out using forceps and the operator's index finger. (LA = left atrium; LV = left ventricle; PVI = inferior pulmonary vein; PVS = superior pulmonary vein.) defect. Five patients received a temporary bypass between the subclavian artery and the thoracic descending aorta. A central vascular clamp was placed obliquely to the aortic arch to maintain blood flow to the left subclavian artery (Fig 3). The other 2 were operated on without a bypass technique. PULMONARY ARTERY. In 7 patients, the bifurcation of the pulmonary artery was resected with a cardiopulmonary bypass to open the main pulmonary artery. In 5 of these 7, the defect of the pulmonary artery was repaired with a Gore-Tex sheet, and in the other 2, the defect was sutui:ed directly (Fig 4). Fig 2. The superior vena cava (SVC) was stapled after a bypass was made between the confluence of both brachiocephalic veins and the auride of the right atrium (RA). The defect of the partial resection of the vena cava was covered with pericardium. (A0 = aorta; PA = pulmonay artery; PVS = superior pulmonary vein.) ' I Fig 3. The aorta was cross-clamped obliquely by a long-arm vascular clamp to maintain blood flow to the left subclavian artery. (A0 = aorta; PA = pulmonary artery; SCA = subclavian artery; T = tumor.)

4 Ann Thorac Surg 1994;5796C-5 TSUCHIYA ET AL 963 Table 2. Results of Univariate Analysis for Prognostic Factors Variable p Value Postoperative pneumonia < Complete resection Pathologic M-factor Pathologic stage Pathologic curativity Pyothorax Local residual tumor Postoperative bleeding Fig 4. In 7 patients, the pulmonary artery was opened for complete resection with cardiopulmona y bypass. Lung cancer (T) had invaded the bifurcation of the main pulmonary artery. (A0 = aorta; CPB = cardiopulmona ry bypass; IVC = inferior vena cava; PA = pulmona y artery; PVI = inferior pulmonary vein; PVS = superior pulmonary vein; RA = right atrium; RV = right ventricle; SVC = superior vena cava.) Results Thirty-four operations were judged by surgeons as cases of incomplete resection because of locally residual cancer in the thorax, intrapulmonary metastases, or distant metastases diagnosed before operation or within 1 month after the operation. The other sixty-seven operations were judged as cases of complete resection because the lung cancers were resected completely and there was no metastasis. However, thirty-six of these sixty-seven were judged as cases of noncurative operation (incomplete resection) by pathologists after their pathologic examination, because the tumors were found at the surface of surgical specimens or microscopic intrapulmonary metastases were found. Thirty-one of the sixty-seven cases were finally judged as of curative operations. Forty-two patients had postoperative complications Table 1. Postoperative Complications Complication No. of Patients No. of Operative Deaths Without complications 59 1 With complications 42 Arrhythmia 13 0 Recurrent nerve palsy 9 0 Dysphagia 7 0 Pneumonia 6 2 Bronchopleural fistula 6 1 Bleeding 5 1 Adult respiratory distress syndrome 4 1 Pyothorax 1 0 Mediastinitis 1 1 Mallory-Weiss syndrome 1 1 Others 8 0 (Table 1). Eight patients died within 30 days after operation and 5 died in the hospital more than 30 days after operation. The operative mortality was 8%, and the hospital death rate was 13%. There were 8 patients with stage IIIB tumors, 3 with stage IV, 5 with incomplete resection, and 4 with noncurative operation. Therefore, for 9 of the 13 patients who died, operation was not indicated, retrospectively. The most frequent causes of death were infection and bleeding. Eight variables (postoperative pneumonia, surgeon s judgement of completeness of resection, pathologic M-factor, pathologic stage, pathologic curativity of operation, pyothorax, local residual tumor, and postoperative bleeding) were statistically significant by univariate analysis ( p < 0.05). Four variables (postoperative pneumonia, surgeon s judgement of completeness of resection, postoperative bleeding and pathologic N-factor) were significant by multivariate analyses (p < 0.05). The results of the analyses are summarized in Tables 2 and 3. Thirteen patients survived 3 years or more. Seven of them underwent resection of the left atrium, 2 underwent resection of the superior vena cava and tracheal canna, 3 underwent resection of the adventitia of the aorta, and 1 underwent resection of the aorta. Seven patients had stage IIIB lung cancer and the other 6 had stage IIIA. Mediastinal lymph node metastases were found in 5 patients, hilar lymph node metastases in 4, and no lymph node metastasis in 4. Eight patients had squamous cell carcinoma, 2 had adenocarcinoma, and the other 3 had large cell carcinoma, bronchial gland carcinoma, and unclassified carcinoma respectively. All operations were judged as complete resection by the surgeon; however, four of them were judged as noncurative operation by the pathologists because the cancers were found at the sur- Table 3. Results of Multivariate Analysis for Prognostic Factors Standard P Variable Beta Error Value Postoperative pneumonia < Complete resection < Postoperative bleeding Pathologic N-factor

5 964 TSUCHIYA ET AL Ann Thorac!Surg 1994;5796&5 Table 4. Long-Term Survivors Patient Age Completeness No. (y) Sex Resected Organ p Stage ptnm Histology of Resection Outcome 1 65 M Left atrium IIIB T4 N2 MO Squamous Noncurative 13 y 7 mo Died of unknclwn cause 2 57 M Left atrium IIIA T3 NO MO Squamous Complete 12 y 5 mo Alive 3 49 M Adventitia of aorta IIIA T3 NO MO Adenocarcinoma Complete 10 y 9 mo Alive 4 54 M Left atrium IIIB T4 N1 MO Squamous Complete 10 y 5 mo Alive 5 46 M Left atrium IIIB T4 N1 MO Adenocarcinoma Noncurative 9 y 5 mo Died of liver cirrhosis 6 54 M Aorta IIIB T4 N2 MO Adenocarcinoma Complete 9 y 1 mo Alive 7 55 M Left atrium IIIB T4 N1 MO Squamous Noncurative 6y 8 mo Alive 8 60 M Left atrium IIIA T3 N2 MO Squamous Complete 6 y 1 mo Alive 9 61 M SVC + tracheal canna IIIB T4 N2 MO Squamous Complete 6 y 0 mo Alive M SVC + tracheal canna IIIB T4 N2 MO Large Noncurative 5y 1 mo Alive M Left atrium IIIA T3 N1 MO Squamous Complete 4 y 4 mo Alive M Adventitia of aorta IIIA T3 NO MO Unclassified Complete 3 y 6 mo Died of unknalwn cause F Adventitia of aorta IIIA T3 NO MO Squamous Complete 3 y 1 mo Died of cancer a Bronchial gland adenocarcinoma. F = female; M = male; SVC = superior vena cava. face of the surgical specimen. Ten patients survived 5 years or more and 8 of them are still alive. Two patients died more than 5 years after their operations (Table 4). The 5-year survival rate for all 101 patients including 8 operative deaths was 13%, and the median survival time was 9.2 months. The 5-year survival and median survival time were 19% and 13.8 months after complete resection and 0% and 6.5% after incomplete resection. There was a significant difference between these subgroups (p < 0.01) (Fig 5). There was no difference, however, between curative operations and noncurative operations as judged by pathologic examination. The 5-year survival and median survival time for the patients with pathologic stage IIIA, IIIB, and IV cancers were 16.8% and 16.8 months; 18.3% and 9.8 months; and 0% and 5.4 months, respectively. There was a significant difference between stages IIIA and IIIB and stage IV (p < 0.05) (Fig 6). The 5-year survival rate after left atrium resection was 22%. Comment Lung cancer invading the left atrium with or without the great vessels is classified as pt4 belonging to stage IIIB of the TNM classification, and stage IIIB is recognized as inoperable [2]. Naruke and colleagues [l] reported that the 5-year survival rate for patients with stage IIIB lung cancer treated surgically was 6%. Burt and colleagues [3] reported that there were no 5-year survivors among 19 patients with involvement of the aorta, 18 patients with superior vena cava invasion, and 3 patients with invasion of the atrium. Inoue and colleagues [4] reported some 5-year survival after resection of the superior vena cava. Therefore, it is acceptable that the 5-year survival rate among the patients who received complete resection was 19% and the overall operative mortality was 8% in this study. Development of computed tomography, echography, and magnetic resonance imaging improved preoperative evaluation of intrathoracic spread of lung cancer, and encouraged us to apply the techniques of cardiovascular surgery to lung cancer surgery. Computed tomography 1.oi, 0.9- W 0.8- I- < 0.7- CX A A a 0.5 N=101 include 8 operative deaths MST=9.2 months 13% O-ll, I I I I I I I I I MONTHS 0.6j \>L\ CURATIVE(N=?.L MST=16.3M).-! COMPLETE RESECTION CURATIVE OPERATION NONCURATIVE OPERAT~ON~~=~S~.,, <0.01 INCOMPLETE RESECTION. I MONTHS B Fig 5. (A) Overall survival curve, including 8 operative deaths. (B) Survival curves for complete versus incomplete resections. (M = months; MST = median survival time; NS = not significant.)

6 Ann Thorac Surg 1994: TSUCHIYA ET AL 965 W l- a nnb u.u ~~ L , 16.8% 1 0 do MONTHS Fig 6. Survival curves for pathologic stage llla versus lllb versus IV. There is a significant difference between stages llla and lllb and stage IV (p < 0.05). (M = months; MST = median survival time; NS = not significant.) was introduced in 1975 in our hospital for routine diagnosis of lung cancer. Eighty-nine patients in this study were operated on from 1975 until now, and only 12 patients underwent this type of operation through In addition to development of these diagnostic tools, introduction of the techniques of cardiovascular surgery into lung cancer surgery has made possible en bloc resection of the lung with part of the involved left atrium, aorta, superior vena cava, and pulmonary artery [5,6]. In 67 of our 101 patients, the primary tumor and the invaded part of the left atrium or great vessels was resected completely by using the techniques of cardiovascular surgery. Thirty-six of the sixty-seven resections were judged as noncurative operation by pathologists after microscopic examination due to tumor location on the surface of the surgical specimen or to microscopic intrapulmonary metastases. More exact diagnosis of the relationship between lung cancer and invaded neighboring organs and diagnosis of intrapulmonary metastases is needed to improve the success of these operations. Eleven of the 21 patients in whom the adventitia of the aorta was involved underwent incomplete resection and the other 10 received complete resection. However, four of these ten operations were evaluated as noncurative, and the remaining six cases were evaluated as curative, but the tumor did not invade the adventitia. According to these results, the procedure of peeling the adventitia of the aorta is inadequate for lung cancer invading the aorta. Cardiopulmonary bypass has been used for ventilatory support during resection of the trachea or tracheal canna with airway reconstruction, or during operations for patients with compromised pulmonary function [7]. Seven patients underwent resection of the bifurcation of the main pulmonary artery using cardiopulmonary bypass in our study. Six of the 7 patients were discharged from the hospital without any postoperative fatal complication, but all died within 2 years and 6 months after their operations. The other patient, who had small cell lung cancer treated preoperatively with four courses of intensive chemotherapy and radiation of 70 Gy, died of mediastinitis caused by wound infection after median sternotomy. Lung cancer invading the bifurcation of the pulmonary artery seemed to be resectable technically by using cardiopulmonary bypass but to be inoperable biologically for cure without any effective combined treatment. We should continue to try these extended resections of the left atrium with or without the great vessels invaded by lung cancer, with careful and exact evaluation of the extent of primary lung cancer and invaded organs using information provided by new diagnostic equipment. We gratefully acknowledge the operative assistance of Kouzou Kawada, MD, the editorial assistance of Mary L Robbins, PhD, and statistical analysis by Kinuko Tajima, MS. References 1. Naruke T, Goya T, Tsuchiya R, Suemasu K. Prognosis and survival in resected lung carcinoma based on the new international staging system. J Thorac Cardiovasc Surg 1988;96: Mountain CF. A new international staging system for lung cancer. Chest 1986;89: Burt ME, Pomerantz AH, Bains MS. Results of surgical treatment of stage I11 lung cancer invading the mediastinum. Surg Clin North Am 1987; Inoue H, Shoutsu A, Koide S, et al. Resection of superior vena cava for primary lung cancer: 5 years survival. Ann Thorac Surg 1990;50: Nakahara K, Ohno K, Mastumura A, et al. Extended operation for lung cancer invading the aortic arch and superior vena cava. J Thorac Cardiovasc Surg 1989; Yoshimura H, Kazama S, Asari H, et al. Lung cancer involving the superior vena cava: pneumonectomy with concomitant partial resection of superior vena cava. J Thorac Cardiovasc Surg 1983; Neville WE, Langston HT, Correll N, Maben H. Cardiopulmonary bypass during pulmonary surgery. J Thorac Cardiovasc Surg 1965;50: