Malignant pleural mesothelioma (MPM) is an uncommon

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1 Risk Factors for Major Complications After Extrapleural Pneumonectomy for Malignant Pleural Mesothelioma Marc de Perrot, MD, Karen McRae, MD, Masaki Anraku, MD, Keyvan Karkouti, MD, Thomas K. Waddell, MD, Andrew F. Pierre, MD, Gail Darling, MD, Shaf Keshavjee, MD, and Michael R. Johnston, MD Division of Thoracic Surgery and Department of Anesthesia, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada Background. Factors associated with increased risk of major complications were older (60 8 years versus 56 major complications after extrapleural pneumonectomy 12 years, respectively; p 0.2) and received more RBC (EPP) for malignant pleural mesothelioma are not well transfusions ( units versus units, characterized; in particular, the risks of induction chemotherapy and red blood cell (RBC) transfusion have notmore frequently after right-sided EPP than after left- respectively; p 0.02). Major complications occurred been well defined. sided EPP (54% versus 21%, p 0.007). Induction chemotherapy had no impact on the risk of major complications Methods. We reviewed our experience with 62 consecutive EPP (28 right sided) performed in our institution(p 0.5). Transfusion of more than 4 units of RBC p ( for malignant pleural mesothelioma between January 0.01) and right-sided EPP p ( 0.01) were associated with 1993 and May A total of 44 patients underwentincreased risk of major complications after EPP in multivariate analysis. induction chemotherapy with cisplatin-based therapy. Results. The majority of patients (88%) received RBC Conclusions. Right EPP and more than 4 units of RBC transfusions (median, 4 units; range, 0 to 18 units). transfusion are associated with increased risk of major Patients undergoing induction chemotherapy had lower complications. Although patients undergoing induction preoperative hemoglobin ( g/l versus chemotherapy received more RBC transfusions, induction chemotherapy did not directly impact the risk of g/l in the remaining patients, p 0.02) and received more RBC transfusions ( units versus major complications. units in the remaining patients, p 0.007). Twenty-two patients (35%) experienced major postoperative complications and 4 of them died (6.5%). Patients experiencing 2008 by The Society of Thoracic (Ann Thorac Surg 2008;85: ) Surgeons Malignant pleural mesothelioma (MPM) is an uncommon neoplasm associated with a median survival of approximately 10 months from the time of histologic diagnosis [1]. Extrapleural pneumonectomy (EPP) has been performed in selected patients with MPM, but its role has remained limited because of the morbidity and mortality associated with the procedure. Recent series have demonstrated a dramatic reduction in the operative mortality since the 1970s, with a 30-day mortality ranging between 3% and 8% [2 4]. However, despite the improvement in operative mortality, the rate of major postoperative complications remains high. In addition, induction chemotherapy has been increasingly used before EPP with the hope of improving long-term survival, but its administration before surgery may increase the risk of postoperative complications [5 7]. We, therefore, performed a retrospective analysis of patients Accepted for publication Nov 26, Address correspondence to Dr de Perrot, Division of Thoracic Surgery, Toronto General Hospital, 9N-961, 200 Elizabeth St, Toronto, Ontario, M5G 2C4, Canada; marc.deperrot@uhn.on.ca. undergoing EPP for MPM in our institution to identify factors associated with an increased risk of postoperative complications. Material and Methods A total of 62 consecutive patients with biopsy-proven MPM underwent EPP in our institution between January 1993 and May Most patients (70%, n 45) underwent surgery between January 2001 and May A retrospective chart review was performed after approval by the Institutional Review Board. The Institutional Review Board approval waived the need for patient consent to perform the study. All patients were evaluated preoperatively by chest radiograph, contrast-enhanced computed tomography (CT) scan of the chest and abdomen, spirometry and ventilation-perfusion scan. Magnetic resonance imaging (MRI) was used in selected cases. Brain CT or MRI as well as bone scan were performed if clinically indicated. Resectability was defined by tumor confined to one 2008 by The Society of Thoracic Surgeons /08/$34.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg DE PERROT ET AL 2008;85: RISK FACTORS FOR COMPLICATIONS AFTER EPP hemithorax with no evidence of mediastinal organ, spine, diffuse chest wall involvement, or transdiaphragmatic extension. Positron emission tomography scan was not available in our institution until recently and was not performed for any of these patients. Mediastinoscopy was always performed if the mediastinal lymph nodes were larger than or equal to 1.5 cm in their greatest diameter on the chest CT. If lymph nodes were smaller than 1.5 cm in their largest diameter, mediastinoscopy was performed on a case-by-case basis, mainly according to the surgeon s preference. Extrapleural pneumonectomy included en bloc resection of the lung, parietal pleura, ipsilateral diaphragm, and ipsilateral pericardium. Previous biopsy sites were removed with a limited chest wall resection. Systematic mediastinal lymph node dissection or sampling was performed in all patients to allow accurate surgical staging of the disease. Paraesophageal, peridiaphragmatic, and subcarinal nodal stations were examined for tumors located on the right and on the left side. Additionally, paratracheal nodes were examined for right-sided tumors, and aortopulmonary window and para-aortic nodes were sampled for left-sided tumors. Tumors were staged according to the staging system developed by the International Mesothelioma Interest Group and published by the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC) [8]. Postoperative deaths included all patients who died within 30 days of surgery or during the same hospitalization. Postoperative complications were defined as complications within 30 days of surgery or during the same hospital stay. Major complications were defined by complications of grade 3 or higher according to the Table 1. Patient Characteristics (n 62) Age, years 58 (21 75) 60 years old years old 38 Sex Male 51 Female 11 Induction chemotherapy Yes 44 No 18 Operated side Right 28 Left 34 Histology Epithelial 44 Biphasic 13 Sarcomatoid 3 Other 2 Pathologic stage I 2 II 10 III 44 IV 6 Table 2. Postoperative Complications a Complications Number of Patients (%) Major complications 22 (35) Cardiac complications Atrial fibrillation 13 (21) Cardiac arrest 1 (2) Cardiac herniation 1 (2) Pulmonary complications Pulmonary emboli 2 (3) Acute lung injury/pneumonia 2 (3) Bronchopleural fistula 2 (3) Empyema 1 (2) Gastrointestinal complications Abdominal herniation 2 (3) Esophageal perforation 1 (2) Miscellaneous Hemothorax 1 (2) Chylothorax 1 (2) a Some patients had more than one complication. National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 3.0 guidelines. The number of units of red blood cell (RBC) transfusion was recorded during the hospital stay. Indications for blood transfusions were hemoglobin levels of less than 80 g/l, or hemoglobin levels between 80 and 100 g/l and a history of ischemic heart disease or clinical intolerance to anemia with tachycardia and systemic hypotension. Estimated blood loss was recorded intraoperatively. Results are presented in absolute number and percentage, median and range, or mean SD. For statistical analysis, major complications were grouped as a composite endpoint because of the low incidence of each individual complication. Variables tested for their potential impact on major postoperative complications and survival were induction chemotherapy (yes versus no), age greater than 60 years old (yes versus no), sex (male versus female), transfusions of more than 4 units of red blood cells (yes versus no), stage (I and II versus III and IV), and side of surgery (right versus left). Categorical variables were compared by 2 analysis and numerical variables by Student t test. Overall survival was estimated using the method of Kaplan-Meier. Differences in survival were tested for significance by the log-rank test. Multivariate analysis was assessed by logistic regression analysis for categorical variables and by the Cox proportional hazards stepwise model for numerical variables. Statview V (Abacus Concepts, Berkeley, California) was used for all analyses. A p value less than 0.05 was considered significant. Results 1207 Most patients were males and presented with epithelial cell type (Table 1). A total of 22 patients (35%) presented with major postoperative complications and 4 (6.5%) died postoperatively (Table 2). The causes of death were GENERAL THORACIC

3 1208 DE PERROT ET AL Ann Thorac Surg RISK FACTORS FOR COMPLICATIONS AFTER EPP 2008;85: Table 3. Risk Factors for Major Complications Risk Factors Univariate Analysis p Value Multivariate Analysis p Value 95% CI Male sex Age 60 years Right-sided tumor Transfusion 4 units RBC Induction chemotherapy Disease stage I and II CI confidence interval; RBC red blood cells. Fig 1. The rate of major complications was 54% after right extrapleural pneumonectomy (EPP) and 21% after left EPP (p 0.007). bronchopleural fistula with empyema (n 1), cardiac arrhythmia (n 1), cardiac herniation (n 1), and aspiration pneumonia (n 1). All deaths occurred after right EPP. The operative mortality was therefore 14% (4 of 28) after right EPP and 0% after left EPP (p 0.02). Eight patients required reoperation for hemothorax (n 1), chylothorax (n 1), cardiac herniation due to dehiscence of the pericardial patch (n 1), abdominal herniation due to dehiscence of the diaphragmatic patch (n 2), esophageal perforation (n 1), and empyema requiring a Clagett window (n 1). One patient presenting with a small bronchopleural fistula (about 5 mm) and no empyema at 4 weeks postoperatively underwent immediate closure of the fistula with a pectoralis major muscle flap with no further complication. Six patients required reintubation or prolonged mechanical ventilation and 2 required a temporary tracheostomy during their hospital stay. The rate of major complications was significantly higher after right EPP than after left EPP (Fig 1). Patients experiencing major complications were also older (60 8 years versus years, respectively; p 0.2) than patients who experienced minor or no complications. A total of 44 patients received two or three cycles of cisplatin-based doublet induction chemotherapy. Cisplatin was combined with vinorelbine (n 20), pemetrexed (n 18), adriamycin (n 3), or gemcitabine (n 3). Two patients had pulmonary emboli during chemotherapy and required inferior vena cava filter insertion before their EPP. No recurrent pulmonary emboli were observed at the time of surgery and thereafter in these 2 patients. The mean preoperative hemoglobin was g/l, but was significantly lower in patients who underwent induction chemotherapy when compared with patients who did not ( g/l versus g/l, respectively; p 0.02). The majority of patients (88%) received RBC transfusions (median, 4 units; range, 0 to 18 units; Fig 2). Estimated intraoperative blood loss ranged between 900 and 6,500 ml with a median of 2,000 ml. Patients undergoing induction chemotherapy received more RBC transfusions than patients who did not have induction therapy ( units versus units, respectively; p 0.02). Patients experiencing major complications also received more RBC transfusions ( units versus units, respectively; p 0.02) than patients who experienced minor or no complications. Factors associated with increased risk of major postoperative complications after multivariate analysis were right-sided EPP and more than 4 units of RBC transfusion (Table 3). Patient s age, sex, stage of disease, and induction chemotherapy was not associated with an increased risk of major postoperative complication. The overall 3- and 5-year survival was 27% and 23%, respectively. There was no significant difference in sur- Fig 2. Red blood cell transfusions in patients undergoing extrapleural pneumonectomy. Fig 3. Impact of red blood cell (RBC) transfusions on long-term survival. (Solid line 4 units RBC transfusion; broken line 4 units RBC transfusion.)

4 Ann Thorac Surg DE PERROT ET AL 2008;85: RISK FACTORS FOR COMPLICATIONS AFTER EPP Table 4. Impact of Red Blood Cell (RBC) Transfusion on Survival in Cox Proportional Hazards Analysis Variables p Value 95% CI Male sex Age 60 years Right-sided tumor Transfusion 4 units RBC Induction chemotherapy Disease stage I and II CI confidence interval. vival between right and left EPP, with a 3-year survival of 23% and 30%, respectively (p 0.8). However, survival was significantly worse in patients receiving more than 4 units of RBC transfusion (3-year survival of 14% versus 36% in remaining patients, p 0.03; Fig 3). Cox proportional hazards analysis demonstrated that the impact of RBC transfusion on long-term survival remained close to statistical significance after adjusting for other variables such as stage of disease, patient s age and sex, side of surgery, and induction chemotherapy (Table 4). Comment This study confirms that EPP can be performed with a low operative mortality. However, major complications still occur in a large proportion of patients. The overall incidence of major complications was 35%, with an operative mortality of 6.5% in our experience, confirming the results from other series recently published in the literature [2 4]. The rate of major complications and postoperative deaths was significantly higher after right-sided EPP than after left-sided EPP. Major complications developed in more than 50% of patients undergoing right-sided EPP, and all 4 postoperative deaths reported in our series occurred after right-sided EPP. Stewart and coworkers [3] made similar observations in their analysis of risk factors for postoperative morbidity after EPP. They observed that right EPP was associated with an increased risk of pneumonia and higher rate of admission to the intensive care unit [3]. Opitz and colleagues [4] reported a series of 63 patients undergoing EPP after induction chemotherapy and observed an incidence of postpneumonectomy empyema of 16%. We did not observe an increased rate of postpneumonectomy empyema despite induction chemotherapy in our series. In 2 patients (4%), an empyema developed after EPP, one of them being related to bronchopleural fistula. The reason for such a difference in the incidence of postpneumonectomy empyema between both series is unclear. We do perform frequent irrigation of the pleural space with povidone-iodine intraoperatively and maintain the patients on antibiotics until removal of the chest tube. The chest tube is kept for 24 to 72 hours and is usually removed once the drainage from the postpneumonectomy space becomes serous Induction chemotherapy followed by right pneumonectomy for nonsmall-cell lung cancer can have a high mortality, as high as 24% in some series [9, 10]. The mortality seems to be related to an increased risk of acute lung injury. Interestingly, right pneumonectomy for MPM after induction chemotherapy may not carry the same risk of acute lung injury. Although Stewart and associates [3] reported a higher rate of acute lung injury after induction therapy for MPM, in our experience and in that reported by Opitz and colleagues [4], in only 1 patient in each series did acute lung injury develop postoperatively. The lower risk of acute lung injury after EPP for MPM could be related to the decreased function of the diseased lung with progressive shift of the mediastinum to the diseased side and redistribution of blood flow to the contralateral lung during the months before the pneumonectomy. Hence, patients undergoing pneumonectomy for MPM may already be partially pneumonectomized, and the surgery could cause less physiologic stress on the heart and contralateral lung. The rate of RBC transfusions for EPP has not been reported previously. We observed that only about 12% of our patients could undergo EPP without RBC transfusions and that the median number of RBC transfused was 4 units in our series. Patients undergoing induction chemotherapy had significantly lower preoperative hemoglobin and required significantly more units of RBC transfusion at the time of surgery. Transfusion of more than 4 units of RBC was a risk factor for major postoperative complications. Interestingly, a similar observation has been reported for cardiac surgery in our institution [11, 12]. Transfusion of 5 units of RBC or more was associated with an eightfold increase in the odds of death after cardiac surgery despite adjusting for multiple potential confounding variables [11, 12]. Several studies have demonstrated an association between allogeneic RBC transfusion and increased morbidity and mortality after major pulmonary resections [13, 14]. Although it remains questionable whether RBC transfusion has a direct causative impact on postoperative complications, a large volume of RBC transfusion has been demonstrated to cause marked physiologic perturbations that can result in organ dysfunction and transfusion-related acute lung injury. Stewart and coworkers [3] reported that they routinely administer aprotinin for EPP to reduce blood loss. Antifibrinolytic agents such as aprotinin or tranexamic acid should only be useful if there is excessive fibrinolysis at the time of surgery or thereafter. We prospectively assessed the degree of fibrinolysis in the last 6 patients reported in this series. Thromboelastography was performed before surgery, at the end of surgery, and at 24 hours after surgery with the hope to demonstrate the presence of fibrinolysis to support the use of antifibrinolytic therapy for EPP. Thromboelastography has been extensively used to guide therapy for coagulation disorders in cardiac surgery and is one of the most sensitive methods for detecting perioperative fibrinolysis [15, 16]. Interestingly, the thromboelastography coagulation index remained within normal range at the end of the GENERAL THORACIC

5 1210 DE PERROT ET AL Ann Thorac Surg RISK FACTORS FOR COMPLICATIONS AFTER EPP 2008;85: surgery and at 24 hours postoperatively in each of our patients (data not shown). As no significant alteration in fibrinolysis was detected at any time point, we currently do not recommend the routine administration of antifibrinolytic in patients undergoing EPP in our institution. Aprotinin could potentially increase the risk of renal dysfunction, thrombosis, and other complications without providing any advantages to reduce the risk of bleeding [17]. The use of recombinant human erythropoietin to correct preoperatively any chemotherapy-induced anemia may be another strategy to minimize the risk of RBC transfusion at the time of surgery. This option was recently questioned, however, because of the potential increased risk of thrombotic events in patients with malignancy when the hemoglobin is raised above 120 g/l [18, 19]. We therefore would not recommend using it routinely until further studies are performed to determine its efficacy and safety before EPP in patients with MPM. The potential impact of perioperative RBC transfusion on long-term outcome requires further evaluation. Numerous studies have looked at the impact of RBC transfusion on outcome after surgery for stage I nonsmall-cell lung cancer, and the results have remained conflicting. Several authors found that transfusion was a significant independent predictor of earlier recurrence and cancerrelated death, whereas others did not [13, 20]. It remains unclear, however, whether RBC transfusion could be an indirect prognostic marker, whereas the true prognostic marker is anemia, as suggested by recent studies [21, 22]. Allogeneic blood transfusion can also impair the immune system and lead to increased risk of tumor recurrence [23]. This mechanism may be particularly important in MPM, as a strong immune reaction appears to be associated with better outcome [24]. In conclusion, EPP can be performed with a relatively low operative mortality. However, the morbidity remains high. Risk factors for major postoperative complications are right-sided EPP and transfusion of more than 4 units of allogeneic RBC. Induction chemotherapy was associated with an increased rate of RBC transfusion but did not increase the risk of major postoperative complications in our experience. References 1. Robinson BWS, Lake RA. Advances in malignant mesothelioma. N Engl J Med 2005;353: Sugarbaker DJ, Jaklitsch MT, Bueno R, et al. Prevention, early detection, anad management of complications after 328 consecutive extrapleural pneumonectomies. J Thorac Cardiovasc Surg 2004;128: Stewart DJ, Martin-Ucar AE, Edwards JG, West K, Waller DA. 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