Early Complications in Surgical Treatment of Lung Cancer: A Prospective, Multicenter Study

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1 Early Complications in Surgical Treatment of Lung Cancer: A Prospective, Multicenter Study José L. Duque, MD, Guillermo Ramos, MD, Javier Castrodeza, MD, Jorge Cerezal, MD, Manuel Castanedo, MD, Mariano G. Yuste, MD, Felix Heras, MD, and the Grupo Cooperativo de Carcinoma Broncogénico de la Sociedad Española de Neumología y Cirugía Torácica* Thoracic Surgery Service and Preventive Medicine Service, Hospital Universitario, Valladolid, Spain Background. We prospectively analyzed the postoperative morbidity, mortality rate, and risk factors in 605 patients who underwent thoracotomy for bronchogenic carcinoma. Methods. Patients were categorized by postsurgical tumor stage: I, 287 patients (47.4%); II, 49 patients (8.1%); IIIA, 154 patients (25.5%); IIIB, 80 patients (13.2%); IV, 16 patients (2.7%); unavailable, 19 patients (3.1%). Two hundred ninety-four patients (48.6%) underwent lobectomy, 172 (28.4%) pneumonectomy, 20 (3.3%) bilobectomy, 29 (4.8%) segmentectomy, 27 (4.5%) wedge resection, and 63 (10.4%) exploratory thoracotomy. The importance of the factors that influence the morbidity and mortality rates was calculated from their relative risks. Univariate and multivariate methods for a logistic regression model were used for this analysis. Results. Postoperative complications developed in 196 patients (32.4%); there were 165 (27.3%) cases of operation-related complications and 152 (25.1%) cases of respiratory and cardiovascular complications. The morbidity rate was highest in patients with preexisting vascular disease (50.9%; odds ratio [OR], 2.20) or insulindependent diabetes mellitus (52.4%; OR, 2.77) and in patients who underwent pneumonectomy (40.1%; OR, 1.82). Forty patients (6.6%) died postoperatively, most commonly of respiratory failure (67.5%). The mortality rate was highest in patients with postoperative morbidity (OR, 31.9) or vascular disease (15.8%; OR, 2.83) and in patients who underwent pneumonectomy (13.4%; OR, 4.9). Conclusions. Postoperative complications are more likely to develop in patients with peripheral vascular disease or insulin-dependent diabetes mellitus, or both. Postoperative mortality was found to be significantly higher in patients with vascular disease and those who underwent pneumonectomy. (Ann Thorac Surg 1997;63:944 50) 1997 by The Society of Thoracic Surgeons Accepted for publication Nov 4, *The coordinators and the members of the Grupo Cooperativo de Carcinoma Broncogénico de Sociedad Española de Neumología y Cirugía Torácica are listed in Appendix 1. Address reprint requests to Dr Duque, Servicio de Cirugía Torácica, Hospital Universitario, c/ Ramón y Cajal s/n, Valladolid, Spain. Surgical resection is the best therapeutic option for patients with bronchogenic carcinoma. However, the results depend on the precise determination of the anatomic extent of the tumor and perioperative management, which includes careful patient selection and appropriate postoperative care. The surgical treatment for bronchogenic carcinoma is not free of complications [1 3], however. Some are directly related to the treatment; others arise as the result of preexisting conditions. Such postoperative complications may significantly darken the prognosis in patients with this disease. A thorough analysis of all possible postoperative complications, including their etiology and incidence, is therefore mandatory during the planning of treatment in patients with disease that has been diagnosed early. We report here the postoperative morbidity and mortality and the risk factors identified in 605 prospectively studied patients who underwent surgical treatment for bronchogenic carcinoma in Spain. Patients and Methods From October 1, 1993, to September 30, 1994, 605 consecutive patients underwent thoracotomy for the management of bronchogenic carcinoma in 16 hospitals in Spain. Data from all patients were prospectively entered on standard data collection forms, and the information gathered included demographic, clinical, biologic staging, therapeutic, pathologic, and follow-up information [4]. These forms were registered by the Grupo Cooperativo de Carcinoma Broncogénico de la Sociedad Española de Neumología y Cirugía Torácica. All known prognostic variables were included, and the methods of analysis were described for each to ensure reproducibility. The TNM system published in 1986 by the American Joint Committee on Cancer International Classification, and partially modified in 1992 [5, 6], was used for classification and staging. The Eastern Cooperative Oncology Group [6] scale was used to categorize clinical status. Comorbidity was defined as the occurrence of bronchogenic carcinoma in association with other diseases. The extent of the surgical procedure was classified according 1997 by The Society of Thoracic Surgeons /97/$17.00 Published by Elsevier Science Inc PII S (97)

2 Ann Thorac Surg DUQUE ET AL 1997;63: COMPLICATIONS IN LUNG CANCER 945 Table 1. Patient Characteristics Variable No. of Patients Percentage Age (y) Sex Male Female Smoking history Yes Present Past No Previous disease Yes No Respiratory disease Cardiac disease Hypertension Previous neoplasia Vascular disease Diabetes mellitus Performance status Unavailable Asymptomatic ECOG ECOG ECOG Clinical findings Cough, or change of cough Hemoptysis Thoracic pain Fever Weight loss 10% Bone pain Histology Squamous cell Adenocarcinoma Small cell Large cell Mixed carcinoma Undetermined ECOG Eastern Cooperative Oncology Group. to the slightly modified recommendations of the Sociedad Española de Neumología y Cirugía Torácica [7]. A standard procedure consists of lung resection and mediastinal lymph node dissection. An extended procedure consists of the resection of neighboring anatomic structures invaded by the tumor in addition to the lung resection and mediastinal lymph node dissection. The patient characteristics are summarized in Table 1. The forced vital capacity, forced expiratory volume in 1 second predicted postoperatively, arterial oxygen pressure, and arterial carbon dioxide pressure were analyzed in every patient. A forced vital capacity of more than 50% was found in 583 patients. The forced expiratory volume in 1 second was above 2,500 ml in 166 patients, between 2,500 and 2,000 ml in 201 patients, between 2,000 and 1,500 ml in 158 patients, and between 1,500 and 1,000 ml in 67 patients; data were not available for the remaining 13 patients. Two hundred ninety-four patients (48.6%) underwent lobectomy, 172 (28.4%) pneumonectomy (72 right sided, 100 left sided), 20 (3.3%) bilobectomy, 29 (4.8%) segmentectomy, and 27 (4.5%) wedge resections. Operation was complete in 484 (80%) patients (complete operationcomplete node dissection; apparently complete operation-sampling) and incomplete in 58 (9.6%). Sixty-three (10.4%) exploratory thoracotomies were performed. A descriptive quantitative and qualitative evaluation of morbidity and mortality was done during the first 30 days postoperatively. Postoperative complications were divided into the following four groups: (1) complications directly related to operation (air leak, residual pleural space, empyema, bronchopleural fistula, hemothorax, and wound infection); (2) respiratory complications (pneumonia, respiratory failure, atelectasis, and mechanical ventilation for longer than 72 hours); (3) cardiovascular complications (arrhythmia, pulmonary thromboembolism, acute myocardial infarction, and acute cerebrovascular accident); and (4) complications affecting other organs (gastrointestinal tract bleeding, renal failure). The possible contribution of other factors to morbidity and mortality, such as age, sex, smoking history, previous diseases, respiratory function, type of surgical procedure, and adjuvant therapy, was also analyzed. In the univariate analysis, the significance of each factor registered for the dependent variables, morbidity and mortality, was evaluated using 2 analysis for categoric data. Factors with a univariate significance level of p 0.25 were initially included as independent variables in the analysis. Forward and backward, stepwise logistic regression analysis was used to determine the effect of risk factors on morbidity and mortality. The final model included factors that remained significant with a p value of less than This analysis was completed in 495 patients with complete information on all factors considered in this model. Results The morbidity rate was 32.4% (196 patients). A total of 361 complications were identified, the most common being those directly related to operation and those that were respiratory and cardiac in origin. The most common complications were cardiac arrhythmia and air leaks (Table 2). The morbidity rate in patients who had preexisting cardiac and vascular disease or who had insulindependent diabetes mellitus was significantly higher than that in patients without these problems. Patients over 70 years of age and those who were smokers had a higher, but not statistically significant, morbidity rate. The morbidity rate was lower, but not significantly so, in female patients. rates in those patients with a predicted postoperative forced expiratory volume in 1 second of approximately 800 ml, a 30% theoretical value,

3 946 DUQUE ET AL Ann Thorac Surg COMPLICATIONS IN LUNG CANCER 1997;63: Table 2. Complication No. of Patients Percentage of MB Percentage of Total Patients Operation related (27.3%) Air leaks Residual pleural space Empyema Bronchopleural fistula Hemothorax Infection Pneumothorax Total 165 Respiratory (17.4%) Pneumonia Respiratory insufficiency Atelectasis Mechanical ventilation h Total 105 Cardiovascular (7.8%) Arrhythmias Pulmonary embolism Myocardial infarction Cerebrovascular accident Total 47 Extrathoracic complications (7.3%) or both, and in those with an arterial oxygen pressure of less than 60 mm Hg were higher, but the differences did not reach statistical significance. Regarding the variables related to therapy, pneumonectomy was associated with high morbidity rates (Tables 3 to 5). The mortality rate in this series was 6.6% (40 patients). Two patients died in the perioperative period and 38 within the first month postoperatively. Thirty-seven of these had had postoperative complications. Respiratory failure (67.5%) was the most common complication in this group of patients, followed by complications arising from other organs or systems (62.5%), those directly related to operation (32.5%), and those of cardiac origin (32.5%). rates were higher in patients over 70 years of age and in those with a history of heart or respiratory disease, but the differences were not statistically significant. However, the mortality rates were significantly higher in patients with a history of vascular disease and in those who had undergone pneumonectomy (see Tables 3 to 5). In the logistic regression model (Table 6), the risk of morbidity was increased in patients with concomitant peripheral vascular disease (odds ratio [OR], 2.20), those with insulin-dependent diabetes mellitus (OR, 2.77), those who had undergone pneumonectomy (OR, 1.82), and those who had respiratory disease (OR, 1.49). When mortality was analyzed as a dependent variable, morbidity was found to contribute greatly to the increase in the mortality risk (OR, 31.92). In this model, patients undergoing pneumonectomy had a poorer prognosis (OR, 4.99). If the effect of morbidity had not been considered in the statistical model, similar variables would have appeared to contribute to mortality. An especially poor prognosis can be anticipated in patients with peripheral vascular disease (OR, 2.83) and in those undergoing pneumonectomy (OR, 6.10) (Table 7). Comment The morbidity rate of 32.4% found in this series is higher than some reported rates [1, 8] but similar to other published figures [9]. This higher rate may have resulted from several factors: the high prevalence of previous and concomitant diseases in the patients and the prospective nature of the study. The incidence of cardiovascular disorders was generally found to be less than that in other series, with cardiac rhythm abnormalities the most common such complication (6.8%) in this series. This is in the lower limit of the range of reported values of 3.8% to 37% [10]. Cardiac arrhythmias have been reported to occur in from 9% to 24% of patients undergoing pneumonectomy (15.7% in this series) [10, 11] and are common in patients over 70 years of age (10.7% in this series) and in those with an arterial oxygen pressure of less than 60 mm Hg (17.6% in this series). Their causes have been analyzed [10, 11]. In general, arrhythmias do not represent a serious threat unless the resulting changes in cardiac output modify the hemodynamic balance, which leads to a cycle of hypoxemia and arrhythmia. Atrial flutter and atrial fibrillation have been reported to increase mortality risk; however, these arrhythmias can usually be controlled with digitalis [10]. Indeed, in our series, they were not found to influence the global mortality when they occurred in isolation. Surgically related complications were the most common complications (27.3%) in this series, with air leaks (6.8%) and residual pleural spaces (4.6%) the most frequent ones. Empyema and bronchopleural fistula (both 4.4%) occurred less frequently but were more clinically relevant. Their incidence is in the upper limit of other reported values [3, 12]. As reported previously [1, 9, 13], these complications are of great clinical relevance and occur more frequently after pneumonectomy (in 21 of 28 patients [75%] in our series). The right side is especially prone to this complication, as pointed up by the fact that 16 of the 21 patients (76%) in this series who suffered such complications had undergone a right-sided pneumonectomy. Bronchopleural fistula is the most series postoperative complication and is usually associated with a poor quality of life and high mortality rate (13.3% in this series). Respiratory complications constitute a highly interrelated group, in that pain, inefficient cough, and hypoventilation may lead to atelectasis, pneumonia, and respiratory failure. The frequencies noted in this series (3.6%, 5.3%, and 5.1%, respectively) are similar to those noted in previous studies [3, 13]. The average postoperative mortality rate is approxi-

4 Ann Thorac Surg DUQUE ET AL 1997;63: COMPLICATIONS IN LUNG CANCER 947 Table 3. Univariate Analysis of General Risk Factors Variable Frequency (No. of patients) % % Age (y) Sex Male Female Smoker Yes No Previous disease Yes No Diabetes mellitus Yes No Non insulin-dependent diabetes mellitus Yes No Insulin-dependent diabetes mellitus Yes No Cardiac disease Yes No 525 Respiratory disease Yes No Vascular disease Yes No Hypertension Yes No Previous cancer Yes No mately 3.5% (range, 1% to 7.1%) [1, 3, 8, 9, 13, 14], with the 6.6% (40 patients) noted in this series in the upper range. The many pneumonectomies (28.4%) and the high comorbidity rate (83.3%) may have contributed to the relatively high mortality rate in our series. It has been reported that the mortality rate associated with pneumonectomies increases from 8.6% to 19% in patients with concomitant diseases [12]. Postoperative morbidity and death have also been linked to other factors, such as age [2, 14], cardiovascular disorders [2], compromised pulmonary reserve [1, 9, 12], and to some therapeutic procedures [1, 15]. All these have therefore been considered as risk factors. Age greater than 70 years has been considered a risk factor for both morbidity and death. However, controversy exists regarding this point [2, 14 17]. The difference in results noted for various series may originate from the fact that different criteria were used to select patients undergoing lung resection or from the fact that the extent of surgical resection varied in different series. A mortality rate of 7% was found in a multicenter study [2] that included 453 patients over 70 years of age who had undergone operation for bronchogenic carcinoma. We also found a relative increase in the morbidity and mortality rates in the patients in this age group in our series, but the differences did not reach statistical significance. A history of diseases or the existence of concomitant diseases clearly increases the morbidity risk and to a minor degree the mortality risk. Cardiac or vascular

5 948 DUQUE ET AL Ann Thorac Surg COMPLICATIONS IN LUNG CANCER 1997;63: Table 4. Univariate Analysis of Pulmonary Function Risk Factors Variable Frequency (No. of patients) % % FVC (%) 50% % FEV 1 (ml) 1, , FEV 1 pp (ml) 800 to 1, , FEV 1 pp (theoretical value) 35% % PaO 2 (mm Hg) PaCO 2 (mm Hg) FEV 1 forced expiratory volume in 1 second; FEV 1 pp predicted postoperative FEV 1 ; FVC forced vital capacity; PaCO 2 arterial carbon dioxide pressure; PaO 2 arterial oxygen pressure. diseases and, to a lesser extent, diabetes mellitus and respiratory disease are the preexisting disorders that predispose the most to postoperative morbidity and death. Cardiac disorders are commonly accepted [1] as important risk factors, and our morbidity rate of 43.7% and mortality rate of 11.2% in patients with such disorders agree with this. However, in the multivariate analysis, Table 5. Univariate Analysis of Risk Factors Associated With Therapy Variable Frequency (No. of patients) % % Thoracotomy without resection Yes No Standard operation Yes No Extended operation Yes No Segmentectomy Yes Undetermined No Lobectomy Yes No Pneumonectomy Yes No Neoadjuvant therapy Yes No

6 Ann Thorac Surg DUQUE ET AL 1997;63: COMPLICATIONS IN LUNG CANCER 949 Table 6. Logistic Regression Analysis of Factors Associated With Independent Factors Influencing Coefficient p Value Constant 1.24 Peripheral vascular disease Insulin-dependent diabetes mellitus Pneumonectomy Respiratory disease Table 7. Logistic Regression Analysis of Factors Associated With Independent Factors Influencing Coefficient p Value Constant 3.68 Peripheral vascular disease Pneumonectomy cardiac disorders appear as risk factors only if the model included the factors significance as p However, peripheral vascular disease is not usually analyzed as an isolated risk factor but conjointly with cardiovascular diseases. We believe that it should be analyzed separately, partly because it is responsible for a significant increase in the morbidity and mortality rates and also because surgeons may have to decide whether the vascular or pulmonary disorder should be treated first. Because of the relevance of peripheral vascular disease as a risk factor, it may be necessary to also evaluate the severity of the disease and its anatomic location to arrive at a correct preoperative assessment in these patients. Diabetes mellitus is an underestimated risk factor, although it is well known to increase the risk of pulmonary infection [18]. This stems from the fact that diabetic microangiopathy alters the diffusion capacity and thus impairs pulmonary function. Respiratory dynamics may also be affected by muscular disorders [19]. A morbidity OR of 1.9 has been previously reported for patients with such disorders [15]. In our series the morbidity (41.3%) and mortality (10.8%) rates were higher in patients with diabetes than in those without diabetes, but these differences were not statistically significant. However, differences in the morbidity rates were significant only when patients with insulin-dependent diabetes mellitus were considered in the analysis. Preoperative pulmonary function has been considered a predictive variable of postoperative morbidity and death [1, 9, 12, 20]. However, in our series, there was a moderate, nonsignificant increase in the morbidity and mortality rates in patients with a postoperative by predicted forced expiratory volume in 1 second of approximately 800 ml (morbidity rates, 36.5%; mortality rate, 6.3%); in patients with a postoperatively predicted forced expiratory volume in 1 second that was 30% of the theoretical value (morbidity rate, 41.4%, mortality rate, 4.9%); and in patients with arterial oxygen pressures of less than 60 mm Hg (morbidity rate, 47.1%; mortality rate, 5.9%). Arterial oxygen pressures of less than 60 mm Hg appear as risk factors only in less strict regression models (p 0.15). This discrepancy may result from the fact that only the 30-day mortality rate was considered in the present study. The mortality rate in these patients may increase later on. The contribution of neoadjuvant therapy to postoperative morbidity and death should also be analyzed. Unfortunately, this has seldom been done. In a series of 13 patients who received neoadjuvant therapy, high morbidity (62%) and mortality (23%) rates were noted [21]. They were greatly influenced by pneumonectomy. A lower incidence of complications was reported for another series [22]. In the present series, we detected a nonsignificant increase in the morbidity rate (39%) and an even lesser increase in the mortality rate (7.3%) in patients who had received neoadjuvant therapy preoperatively (see Table 5). The incidence of postoperative complications and the mortality rates in patients who had undergone lesser lung resections (wedge resections and segmentectomies) and lobectomies are clearly less than the rates associated with pneumonectomies (morbidity rate, 40.1%; mortality rate, 13.3%). Pneumonectomy is recognized, with some exceptions [3], as one of the primary risk factors [1, 13, 15]. The average mortality rate associated with pneumonectomy is approximately 8%, with reported values ranging between 4.6% and 20% [1, 9, 12, 15, 20]. In the present series the mortality rate associated with pneumonectomies was in the upper limit of the range (p 0.001). Right-sided pneumonectomy is associated with a higher, but not statistically significant, mortality rate (15.28% versus 12%). Extended procedures are also associated with a distinctly greater risk (morbidity rate, 36.6%; mortality rate, 9.9%) than standard procedures. Finally, the mortality rate is highest in patients with postoperative complications, which clearly indicates that postoperative morbidity indicates a poor prognosis. In conclusion, our analysis of a large series of patients who underwent operation for bronchogenic carcinoma in Spain revealed high postoperative morbidity and mortality rates. On the basis of our findings we concluded that patients with a history of peripheral vascular disease or with concurrent insulin-dependent diabetes mellitus and respiratory disease are more likely to suffer postoperative complications and therefore require a thorough preoperative assessment. Those patients with vascular disease, those who undergo pneumonectomy, and those with a postoperative complication, especially respiratory failure, need to be closely monitored because their postoperative mortality risk is significantly increased.

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