Comparison of Morbidity, 30-Day Mortality, and Long-Term Survival After Pneumonectomy and Sleeve Lobectomy for Non Small Cell Lung Carcinoma

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1 Comparison of Morbidity, 30-Day Mortality, and Long-Term Survival After and Sleeve Lobectomy for Non Small Cell Lung Carcinoma Corinna Ludwig, MD, Erich Stoelben, MD, Manfred Olschewski, PhD, and Joachim Hasse, MD Departments of Thoracic Surgery and Medical Biometrics and Statistics, University of Freiburg, Freiburg, Germany Background. The advantage of sleeve lobectomy as an alternative to pneumonectomy for preserving lung function is obvious and among other arguments allows operating on patients with lung cancer who would not tolerate pneumonectomy. The purpose of this retrospective, nonrandomized study is to compare the early (30-day mortality) and late (5-year survival) outcomes of both procedures. Methods. The charts of 310 patients who underwent either pneumonectomy or sleeve lobectomy for lung cancer stages I to IIIA from 1987 to 1997 were reviewed. One hundred ninety-four patients underwent pneumonectomy, and 116 patients underwent sleeve lobectomy. Specific operative complications, i.e., anastomotic leakage versus stump dehiscence, perioperative complications, 30-day or in-hospital mortality, and 5-year survival were registered for comparison of the immediate risk of the respective procedures. Results. In the bronchial sleeve lobectomy group, the incidence of anastomotic leakage was 6.9% (8 of 116 patients) and the operative mortality was 4.3%. The incidence of bronchial stump fistulas after pneumonectomy was 3.6% (7 of 194 patients), and early mortality was 4.6%. All but 6 patients (98%) had a complete resection. Overall 5-year survival after sleeve lobectomy was 39% and after pneumonectomy, 27%. The distribution of 5-year survival stage by stage in either group is presented. Sleeve lobectomy, age younger than 65 years, pn0, and stage I are positive prognostic factors for long-term survival. In the multivariate analysis, pneumonectomy is a negative prognostic factor. Conclusions. The indication for pneumonectomy versus sleeve lobectomy depends on the localization of the primary tumor on the one hand, and on cardiorespiratory function, which might be more often distinctly impaired in the sleeve group, on the other hand. This could explain why the mortality in the sleeve lobectomy group was identical with that in the pneumonectomy group. However, both techniques are appropriate treatment modalities of advanced lung cancer or patients with critical functional reserve. Therefore, whenever possible, sleeve lobectomy should be performed. (Ann Thorac Surg 2005;79:968 73) 2005 by The Society of Thoracic Surgeons Patients with non small cell lung cancer (NSCLC) stage I to IIIA may benefit from a lung tissue preserving resection. Sleeve lobectomy is an alternative to pneumonectomy [1 4] in patients with a central tumor either extending into the lobar orifice or mucosa of the main bronchus or with peribronchial lymph node metastases despite severely restricted cardiopulmonary function [5]. In such cases, a standard lobectomy would be insufficient to achieve radical tumor resection, the predominant goal. There are certainly situations in which pneumonectomy is inevitable. However, in cases of vascular involvement, appropriate angioplastic procedures in selected conditions may allow the choice of a sleeve lobectomy. The purpose of this paper is to determine whether there is a significant difference in the overall Accepted for publication Aug 10, Address reprint requests to Dr Ludwig, Department of Thoracic Surgery, University Hospital Freiburg, Hugstetterstr 55, Freiburg, Germany; ludwig@ch11.ukl.uni-freiburg.de. morbidity, 30-day mortality, and long-term survival between pneumonectomy and sleeve lobectomy in patients with NSCLC. No randomized trials, only retrospective analysis of the data, are available to compare these two procedures because the final decision to perform pneumonectomy or sleeve lobectomy has to be taken during the operative procedure. Patients and Methods Between 1987 and 1997, 1,293 patients underwent pulmonary resection with curative intent for bronchial carcinoma. The objective of this retrospective study was to determine the 5-year survival after pneumonectomy or sleeve lobectomy in 310 patients with NSCLC stage I to IIIA. The data were collected retrospectively and analyzed from the patient records, including the electronic registry and documentation. Patients with a small cell lung cancer were excluded. Patients operated on after 2005 by The Society of Thoracic Surgeons /05/$30.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg LUDWIG ET AL 2005;79: SURVIVAL AFTER SLEEVE LOBECTOMY AND PNEUMONECTOMY 969 Table 1. Location of Tumor and Type of Resection Resection Right UL ML LL Left UL LL Total Sleeve lobectomy a a a Central location. LL lower lobe; ML middle lobe; UL upper lobe. December 1997 were not included to obtain a 5-year follow-up; closure date was December Preoperative staging included a chest roentgenogram, computed tomography of the chest and upper abdomen, lung function test, arterial blood gases, and perfusion scintigraphy of the lung when forced expiratory volume in 1 second was less than 2.0 L. Patients at high risk for coronary heart disease were screened by echocardiography, stress testing, or coronary arteriography if appropriate. Bronchoscopy was performed for endobronchial staging and selection of the potential candidates for sleeve lobectomy. Mediastinoscopy was performed to exclude pn3 nodal status. All patients underwent double-lumen endotracheal intubation. The routine approach was a posterolateral thoracotomy in the bed of the fifth or sixth rib. After complete exposure of the pulmonary artery, bronchus, and vein, the final decision was taken as to whether sleeve lobectomy was feasible oncologically and technically. Care was taken to manipulate the tumor as little as possible and to preserve the bronchial blood supply. Resection of the main bronchus was performed proximal and distal to the lobar orifice for sleeve resection. Intraoperative frozen section of the resection margins was performed to confirm oncologic completeness. Angioplastic procedures were performed when necessary either by oblique resection or concomitant vascular sleeve resection. A tension-free bronchial anastomosis was performed with a continuous suture using absorbable 4-0 material (Maxon, B. Braun-Dexon, GmbH, Spangenberg, Germany) over two thirds of the circumference, completed by single stitches. At the end of the procedure, the anastomosis was routinely inspected bronchoscopically. A pericardial flap, pleural flap, or mediastinal fat was usually placed between the anastomosis and the pulmonary artery. In the case of a pneumonectomy, the main bronchus was closed with absorbable 3-0 material (Maxon, B. Braun-Dexon, GmbH) until 1995, thereafter with double-row polypropylene 2-0 (Prolene, Ethicon, Johnson & Johnson Intl, Norderstedt, Germany). The first row was a to-and-fro continuous suture, the second an over-and-over running suture. The stump was routinely covered for protection on the right side as described above. In either case, suture lines were checked for air leaks with an airway pressure of 30 mm Hg or higher. Systematic lymphadenectomy was performed for lymph node staging. Two chest tubes were placed, one anterolateral and the second posterobasal, in the case of sleeve resection and a single chest tube for 12 to 24 hours after pneumonectomy. Routine postoperative bronchoscopy was performed in all patients before discharge between day 10 and 12 as a quality control and to achieve early recognition of stump insufficiency or anastomotic leakage. Adjuvant radiotherapy was indicated in all patients with pn2 nodal status, whereas induction therapy was only given in selected patients with bulky cn2 nodal status by computed tomography. Histologic classification according to the TNM classification (1997) [6] was used to determine the stage of the disease. Follow-up was complete for all patients except 7 up to April 2002 (94%). Determination of the exact location of recurrence (local versus regional versus distant) was not complete as diagnosis was often made outside of our institution without systematic bronchoscopy or computed tomography. Statistical analysis was obtained by introducing the data into SPSS (SPSS for Windows, release 10.0; SPSS Inc, Chicago, IL). Survival probabilities were estimated by the method of Kaplan-Meier. We performed univariate and multivariate analysis of survival times using the log rank test and the Cox model. Statistical significance was found for any value of p less than Results are presented as estimated relative risk with corresponding 95% confidence intervals. Table 2. Distribution of Histology in Both Groups Histologic Diagnosis Sleeve Lobectomy Squamous cell carcinoma 76 (68%) 117 (60%) Adenocarcinoma Bronchioalveolar 1 4 Large cell carcinoma Adenosquamous carcinoma 0 1 Undifferentiated carcinoma 1 3 Table 3. Distribution of Stages TNM Sleeve Lobectomy Total IA IB IIA IIB IIIA

3 970 LUDWIG ET AL Ann Thorac Surg SURVIVAL AFTER SLEEVE LOBECTOMY AND PNEUMONECTOMY 2005;79: Table 4. Subdivision According to the Tumor and Nodal Status Variable pt1 pt2 pt3 Sleeve lobectomy pn pn pn pn pn pn Table 6. Cause of Death of 14 Patients Cause of Death Sleeve Lobectomy Cardiac 3 1 ARDS 4 Bronchial stump 1 Anastomotic leakage 2 Pulmonary embolism 1 Lung necrosis 1 Gastrointestinal 1 ARDS adult respiratory distress syndrome. Results Of the 310 eligible patients, there were 274 (88%) men and 36 women. The overall median age was 60 years (range, 29 to 84 years). In 194 patients pneumonectomy was performed; here the median age was 59 years. In 116 patients, a sleeve lobectomy was performed, and the median age was 62 years. The location of the tumor is shown in Table 1. In 140 (65 were sleeve lobectomy) patients, the operation was on the right side; in 170 (51 were sleeve lobectomy), on the left side. Angioplastic procedures were performed in 30 patients (26%). The distribution of the histologic types is shown in Table 2. TMN classification and staging are shown in Tables 3 and 4. In 6 patients (1.9%), the final histologic examination showed positive resection margins, despite negative perioperative fresh-frozen sections. There were 2 after sleeve lobectomy and 4 after pneumonectomy. In 2 patients secondary pneumonectomy was performed. The rest received adjuvant radiotherapy. One patient was alive without disease at 5 years, 1 was alive with recurrent disease, and the rest had died (3 with recurrent disease, 2 without). Seventy-two patients had 94 postoperative complications (23%). Bronchial anastomotic insufficiency occurred in 6.9% of the patients after sleeve lobectomy. Bronchial stump insufficiency was seen in 3.6% after pneumonectomy. The details of the complications in both groups are listed in Table 5. Secondary pneumonectomy after sleeve lobectomy was necessary in 7 patients (6%). Thirty-day mortality was 4.5%, corresponding to 14 patients of whom 5 (4.3%) had a sleeve lobectomy and 9 (4.6%) had a pneumonectomy. In this group of patients, Table 5. Postoperative Complications for Both Procedures Complication (n 50) Sleeve Lobectomy (n 44) Cardiac 7 4 ARDS 6 Pneumonia 3 1 Pleural effusion 2 4 Air leakage 7 days 12 Bronchial stump 7 Anastomotic leakage 8 Bronchial stenosis 1 Secretion 1 6 Empyema 2 2 Pulmonary embolism 1 Postoperative bleeding 3 2 Lung necrosis 1 Kidney 4 Gastrointestinal 4 Laryngeal nerve palsy 4 1 Neurologic 6 1 Wound infection 1 ARDS adult respiratory distress syndrome. Fig 1. Overall survival after sleeve lobectomy or pneumonectomy.

4 Ann Thorac Surg LUDWIG ET AL 2005;79: SURVIVAL AFTER SLEEVE LOBECTOMY AND PNEUMONECTOMY 971 Table 7. Five-Year Survival After Sleeve Lobectomy or Depending on Nodal Status and TMN Stage Resection Sleeve lobectomy 5-Year Survival (%) Standard Error 5-Year Survival (%) Standard Error pn I pn II pn IIIA pn I pn II pn IIIA there were 13 men and 1 woman; the average age was slightly higher, 62.4 years (range, 55 to 75 years). Table 6 lists the cause of death. The overall 5-year survival after sleeve lobectomy was 39% and 27% after pneumonectomy (Fig 1). The difference is statistically significant (p ). The 5-year survival according to the nodal status and TNM stage is listed in Table 7. At closure date of follow-up, December 2003, 217 patients were dead; of these, 178 died with recurrent disease (local or distant). Ninety-three patients were alive, 83 with complete remission and 10 living with recurrent disease. Exact information on local or distant recurrent disease cannot be given as often the diagnosis was made outside our institution without bronchoscopy or computed tomography. Univariate statistical analysis of the data with a Cox model showed a significant result in favor of sleeve lobectomy, nodal status (N0), and stage I. Tumors that were T3 had a negative prognostic influence on longterm survival (Table 8). The age, histologic type, and sex were not significant for the 5-year survival. A multivariate analysis showed that a statistically significant positive effect on long-term survival was achieved in patients with the nodal status N0, the sleeve lobectomy, tumor that was less than T3, and age younger than 65 years (Table 9). Table 9. Multivariate Analysis of Prognostic Factors for Long-Term Survival Factor Relative Risk 95% Confidence Interval p Value T3 vs T1 T N0 vs N Age 65 vs Radicality is mandatory for local control [11] and was obtained in 98% of patients. The incidence of procedurespecific complications such as an anastomotic dehiscence, which is the most common major complication after sleeve lobectomy, is approximately 3.5% [4]. Most authors recommend coverage of the anastomosis either by interposition of the azygos vein or a pleural, pericardial, or pedicled muscle flap such as we do to avoid this complication [12 14]. Leakage of the bronchial anastomosis and stump insufficiency occurred in 4.8%. Of these, 3.6% occurred in the pneumonectomy group and 6.9% in the sleeve lobectomy group. Postoperative bronchoscopy before discharge between day 10 and 12 may have led to early recognition of stump insufficiency or leakage of the bronchial anastomosis without clinical relevance. Comment Bronchoplastic procedures are accepted as an alternative to pneumonectomy to preserve lung function [7 10]. Table 8. Univariate Analysis of Prognostic Factors for Long- Term Survival Factor Relative Risk 95% Confidence Interval p Value T3 vs T1 T N0 vs N Age 65 vs Stage II vs I Stage III vs I Fig 2. Survival after sleeve lobectomy or pneumonectomy with N0 nodal status.

5 972 LUDWIG ET AL Ann Thorac Surg SURVIVAL AFTER SLEEVE LOBECTOMY AND PNEUMONECTOMY 2005;79: Fig 3. Survival after sleeve lobectomy or pneumonectomy with N1 nodal status. Interestingly, in these 310 patients the predominant histologic type was squamous cell carcinoma (62%); adenocarcinoma represented 15%. Comparing histologic distribution of the 1,293 patients operated on during the same period, squamous cell carcinoma represented 41% and adenocarcinoma 27%. The high proportion of squamous cell carcinoma may be related to the central position of the tumor, which seems to be more frequent in this histologic subtype. Overall mortality after pneumonectomy ranges from 6% to 10% [15]. After sleeve lobectomy, depending on the study, mortality is considerably lower today as it lies between 2% [16] and 5% [4]. In our series, 30-day mortality was 4.9%, corresponding to 14 patients of whom 5 (4.3%) had a lung tissue sparing resection and 9 (4.6%) a pneumonectomy. In this group of patients, the average age was higher (63 years); there were 13 men and 1 woman. Retrospective analysis of the patient records showed that only in 4 patients (3 after sleeve lobectomy and 1 after pneumonectomy) could death be related directly to technical problems. For example, in 1 patient after pneumonectomy in whom the bronchial stump was closed with single stitches, bronchial stump leakage occurred at 7 days. This being contrary to our approach, we conclude that this method of closure was insufficient. The remaining 10 patients had an increased preoperative Fig 4. Survival after sleeve lobectomy or pneumonectomy with N2 nodal status. risk owing to decreased respiratory or cardiac function. The most important risk factors influencing perioperative morbidity and mortality are age, restrictive pulmonary reserve, cardiovascular disease, perioperative myocardial infarction, respiratory infection, arrhythmia, renal failure, and diabetes [17 20]. The 1-year survival argues in favor of a lung tissue preserving resection as it is 73% after sleeve lobectomy and 64% after pneumonectomy [21]. In our series, the overall 5-year survival after sleeve resection was 39% and after pneumonectomy, 27%, which is similar to that given in the literature [22]. There are definitely more patients with a T3 tumor stage who received pneumonectomy, probably as a result of the position and size of the tumor, which may also explain these results. Multivariate analysis of the data demonstrated that survival was influenced by lymph node involvement, the procedure, age younger than 65 years, and stage of the disease (Table 8). Patients with pn2 disease (Table 4) had a statistically significantly lower survival than those with pn0 and pn1 disease (Figs 1 4). This corresponds to the existing literature, in which nodal involvement is a negative prognostic factor for long-term survival [3, 16, 23 26]. Overall prognosis of these patients is mainly influ-

6 Ann Thorac Surg LUDWIG ET AL 2005;79: SURVIVAL AFTER SLEEVE LOBECTOMY AND PNEUMONECTOMY 973 enced by distant metastases, especially in patients with pn2 status. In contrast, local radicality is more important in patients without lymph node involvement. It is also significant for the tumor stage (T3) and the operation as the 5-year survival is better in the sleeve lobectomy group. is a negative prognostic factor for long-term survival independent of stage and nodal status. For short-term survival, sleeve lobectomy is of no advantage. In conclusion, sleeve lobectomy should be the method of choice when possible. Overall 5-year survival after sleeve lobectomy is superior to 5-year survival after pneumonectomy, indicating that lung-preserving surgery is not radicality-sparing surgery. References 1. Vogt-Moykopf I, Fritz T, Meyer G, Bulzerbruck H, Daskos G. Bronchoplastic and angioplastic operation in bronchial carcinoma: long- term results of a retrospective analysis from 1973 to Int Surg 1986;71: Muller C, Schinkel C, Hoffmann H, Dienemann H, Schildberg FW. Bronchoplastic resection for non-small-cell lung cancer. Thorac Cardiovasc Surg 1996;44: Tronc F, Grégoire J, Rouleau J, Deslauriers J. Long-term results of sleeve lobectomy for lung cancer. Eur J Cardiothorac Surg 2000;17: Tedder M, Anstadt MP, Tedder SD, Lowe JE. Current morbidity, mortality, and survival after bronchoplastic procedures for malignancy. Ann Thorac Surg 1992;54: Mezzetti M, Panigalli T, Giuliani L, Raveglia F, Lo Giudice F, Meda S. Personal experience in lung cancer sleeve lobectomy and sleeve pneumonectomy. Ann Thorac Surg 2002;73: Mountain CF, Dresler CM. Regional lymph node classification for lung cancer staging. Chest 1997;111: Gaissert HA, Mathisen DJ, Moncure AC, Hilgenberg AD, Grillo HC, Wain JC. Survival and function after sleeve lobectomy for lung cancer. J Thorac Cardiovasc Surg 1996; 111: Deslauriers J, Gaulin P, Beaulieu M, Piraux M, Bernier R, Cormier Y. Long-term clinical and functional results of sleeve lobectomy for primary lung cancer. J Thorac Cardiovasc Surg 1986;92: Lausberg HF, Graeter TP, Wendler O, Demertzis S, Ukena D, Schafers HJ. Bronchial and bronchovascular sleeve resection for treatment of central lung tumors. Ann Thorac Surg 2000;70: Massard G, Kessler R, Gasser B, et al. Local control of disease and survival following bronchoplastic lobectomy for non-small cell lung cancer. Eur J Cardiothorac Surg 1999; 16: Massard G, Doddoli C, Gasser B, et al. Prognostic implications of a positive bronchial resection margin. Eur J Cardiothorac Surg 2000;17: Kruger M, Uschinsky K, Hassler K, Engelmann C. Postoperative complications after bronchoplastic procedures in the treatment of bronchial malignancies. Eur J Cardiothorac Surg 1998;14: Faber LP. Sleeve resections for lung cancer. Semin Thorac Cardiovasc Surg 1993;5: Faber LP. Sleeve lobectomy. Chest Surg Clin N Am 1995;5: Ginsberg RJ, Hill LD, Eagan RT, et al. Modern thirty-day operative mortality for surgical resections in lung cancer. J Thorac Cardiovasc Surg 1983;86: Mehran RJ, Deslauriers J, Piraux M, Beaulieu M, Guimont C, Brisson J. Survival related to nodal status after sleeve resection for lung cancer. J Thorac Cardiovasc Surg 1994;107: Patel RL, Townsend ER, Fountain SW. Elective pneumonectomy: factors associated with morbidity and operative mortality. Ann Thorac Surg 1992;54: Wada H, Nakamura T, Nakamoto K, Maeda M, Watanabe Y. Thirty-day operative mortality for thoracotomy in lung cancer. J Thorac Cardiovasc Surg 1998;115: Nagasaki F, Flehinger BJ, Martini N. Complications of surgery in the treatment of carcinoma of the lung. Chest 1982;82: Duque JL, Ramos G, Castrodeza J, et al. Early complications in surgical treatment of lung cancer: a prospective, multicenter study. Grupo Cooperativo de Carcinoma Broncogenico de la Sociedad Espanola de Neumologia y Cirugia Toracica. Ann Thorac Surg 1997;63: Martin-Ucar AE, Chaudhuri N, Edwards JG, Waller DA. Can pneumonectomy for non-small cell lung cancer be avoided? An audit of parenchymal sparing lung surgery. Eur J Cardiothorac Surg 2002;21: Okada M, Yamagishi H, Satake S, et al. Survival related to lymph node involvement in lung cancer after sleeve lobectomy compared with pneumonectomy. J Thorac Cardiovasc Surg 2000;119: Van Schil PE, Brutel de la Riviere A, Knaepen PJ, et al. Long-term survival after bronchial sleeve resection: univariate and multivariate analyses. Ann Thorac Surg 1996;61: Van Schil PE. Long-term results after bronchial sleeve resection. Verh K Acad Geneeskd Belg 2000;62: Wilkins EW Jr, Scannell JG, Craver JG. Four decades of experience with resections for bronchogenic carcinoma at the Massachusetts General Hospital. J Thorac Cardiovasc Surg 1978;76: Fadel E, Yildizeli B, Chapelier AR, Dicenta I, Mussot S, Dartevelle PG. Sleeve lobectomy for bronchogenic cancers: factors affecting survival. Ann Thorac Surg 2002;74:851 8.