Lung resection for cancer in patients with coronary arterial disease ...

European Journal of Cardio-thoracic Surgery 22 (2002) 35–40 www.elsevier.com/locate/ejcts

Lung resection for cancer in patients with coronary arterial disease: analysis of short-term results q Paola Ciriaco a,*, Angelo Carretta a, Giliola Calori b, Patrizio Mazzone c, Piero Zannini a a

Department of Thoracic Surgery, Scientific Institute H. San Raffaele, Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy Department of Statistics and Epidemiology, Scientific Institute H. San Raffaele, Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy c Division of Cardiology, Scientific Institute H. San Raffaele, Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy

b

Received 21 September 2001; received in revised form 13 February 2002; accepted 25 March 2002

Abstract Objective: Patients with lung cancer may present concomitant coronary arterial disease. Feasibility of lung resection is dependent on the severity of the cardiac impairment since it can increase operative morbidity and mortality. The aim of this study was to analyze the results of lung resection in patients with coronary arterial disease in terms of operative complications and hospital stay. Methods: Between January 1993 and March 2001, 50 patients with coronary arterial disease underwent lung resection for cancer at our department. Nineteen patients with a curable left-main or multiple-vessel disease first underwent surgical (six patients) or transluminal (13 patients) myocardial revascularization. Twenty-two of the 31 patients who did not require myocardial revascularization presented a medium-high cardiac risk. Univariate analysis determined the impact of coronary disease on operative complications and hospital stay. Results: Surgery consisted in 40 lobectomies, three pneumonectomies and seven wedge resections. The overall mortality and morbidity rates were 4% and 28%, respectively. Ten patients (22%) experienced postoperative cardiac complications such as arrhythmia and there was one intraoperative death, three suffered secretion retention and one patient died as a consequence of a stroke. Occurrence of postoperative complications was influenced by age (P ¼ 0:02) and the presence of medium-high cardiac risk (P ¼ 0:03). Hospital stay was longer for patients who did not have prior myocardial revascularization (11.7 ^ 4 vs. 8.1 ^ 3 days) and underwent more extensive pulmonary resection (10.6 ^ 5 vs. 7.4 ^ 2 days). Conclusions: Lung resection in patients with coronary arterial disease is justified in selected cases. Previous myocardial revascularization and limited resections can decrease operative complications and hospital stay. Careful preoperative evaluation can identify patients who might benefit from myocardial revascularization prior to surgery. q 2002 Elsevier Science B.V. All rights reserved. Keywords: Lung cancer; Coronary artery disease; Myocardial revascularization

1. Introduction The simultaneous occurrence of lung cancer and cardiovascular disease is not uncommon considering that the two diseases share several risk factors such as smoking and lifestyle. Moreover, some cardiac drugs have recently been accused of being potentially carcinogenic [1]. The possible association between cancer and coronary arterial disease in the male population has been reported to be around 6.9% [1]. Less often, patients are found to have major cardiac disease during preoperative evaluation for lung cancer [2,3]. The feasibility of lung resection for non-small cell lung cancer is dependent on the severity of q Presented at the joint 15th Annual Meeting of the European Association for Cardio-thoracic Surgery and the 9th Annual Meeting of the European Society of Thoracic Surgeons, Lisbon, Portugal, September 16–19, 2001. * Corresponding author. Tel.: 139-2-2643-7138; fax: 139-2-2643-7147. E-mail address: [email protected] (P. Ciriaco).

the cardiac impairment since it can increase operative morbidity and mortality [2]. Operative risk can be reduced if the cardiac problem is addressed properly by performing prophylactic treatment of the coronary arterial disease either by percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass grafting (CABG). Surgical treatment of lung cancer can be performed at the time of sternotomy for CABG, or after a few weeks with a staged approach [3–5]. The optimal timing of the two procedures is still controversial, however [5,6]. The aim of this study was to analyze the outcome of lung resection in patients with coronary arterial disease in terms of operative and postoperative complications and hospital stay.

2. Materials and methods From January 1993 to March 2001, 50 patients with

1010-7940/02/$ - see front matter q 2002 Elsevier Science B.V. All rights reserved. PII: S 1010-794 0(02)00209-9

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P. Ciriaco et al. / European Journal of Cardio-thoracic Surgery 22 (2002) 35–40

concomitant coronary arterial disease and lung cancer underwent lung resection at our Department of Thoracic Surgery. The majority (34 patients, 68%) were referred for their lung cancer with a known coronary arterial disease. The remaining 16 patients had ischemic heart disease discovered during their preoperative assessment. Preoperative evaluation included total body computed tomography scan, bone scan, fibrobronchoscopy, pulmonary function tests and arterial blood gas. A baseline cardiac assessment was performed on all patients including cardiac history, physical examination and a 12-lead electrocardiogram (ECG). The same cardiologist (P.M.), who prescribed additional exams when indicated, saw all patients with ECG abnormalities and/or a history of chest pain and documented coronary arterial disease. The exercise tolerance test was indicated in all patients with cardiac symptoms, ECG modifications, and in patients who had had a myocardial infarction more than 1 year before at the time of hospitalization. If the test was negative, it was followed by surgery. If it was positive, it was followed by coronary artery angiography and patients discovered to have significant coronary artery obstruction had PTCA and, when indicated, positioning of a stent or CABG. Echocardiography was performed in patients who had had a myocardial infarction more than 1 year before and whose exercise tolerance test was negative in order to study their ventricular function; they underwent pulmonary surgery when the ejection fraction was . 25%: Patients with an ECG suggestive for recent ischaemic disease underwent coronary artery angiography (Fig. 1). The criteria for clinically significant coronary artery obstruction was either a 70% or greater reduction in the internal diameter of the right coronary artery, the left anterior descending, or left circumflex coronary artery, or a 50% or greater reduction in the internal diameter of the left main coronary artery. Nineteen patients with a curable left-main or multiplevessel disease first underwent surgical or transluminal

Table 1 Coronary arterial diseases and their treatment before lung resection a CABG Two-vessel disease Three-vessel disease Four-vessel disease PTCA (including 6 stents) Single-vessel disease Two-vessel disease No myocardial revascularization

6 patients (total) 3 2 1 13 patients (total) 9 4 31 patients

a

CABG, coronary artery bypass grafting; PTCA, percutaneous transluminal coronary angioplasty.

myocardial revascularization and were discharged from hospital. They were subsequently readmitted to undergo lung resection. All procedures were performed on an elective basis. Patients were put on oral anticoagulant therapy until the time of hospital readmission for lung resection. The remaining 31 patients, who presented with nonhemodynamically significant single- or double-vessel disease, were operated on for their lung cancer with intravenous administration of nitroglycerin intraoperatively and postoperatively (Table 1). Diagnosis of lung cancer was made in all patients preoperatively and prior to treatment of the coronary arterial disease by percutaneous needle biopsy or fibronchoscopy biopsy. Neoadjuvant chemotherapy was administered to those patients who presented with N2 disease and/or suspected vascular invasion by the tumor. Mediastinal lymph nodes , 1 cm at the computed tomography (CT) scan were considered to be negative. Only one patient had paratracheal lymph nodes . 1 cm at the CT scan and diagnosis of N2 disease was made by transbronchial biopsy instead of mediastinoscopy because of the favourable anatomic location of the lymph node. Lymph node staging was not carried out at the time of cardiac surgery in any of the patients who underwent prior surgical myocardial revascularization. Staging was done postsurgi-

Fig. 1. Pathway of cardiac investigations before lung resection. ETT, exercise tolerance test; CA, coronary angiography; MI, myocardial infarction; EF, ejection fraction.


cally following the new international staging system for lung cancer [7]. Twenty-two of the 31 patients who did not undergo prior myocardial revascularization presented a medium to high cardiac risk at the time of lung resection. Stratification of cardiac risk was defined according to the guidelines for perioperative cardiovascular evaluation for non-cardiac surgery of the American College of Cardiology [8]. Medical treatment was intensified in these medium–high-risk patients and they were monitored in the intensive care unit for the first 24–48 h after lung resection. All patients were intraoperatively and postoperatively monitored in the ward by means of continuous ECG until day 3. They received heparin 15 000 IU subcutaneously per day from postoperative day 1 until discharge. Patients who had undergone prior myocardial revascularization stopped their oral anticoagulant therapy on the day of hospital admission and received heparin 15 000 IU daily subcutaneously until discharge. Analgesia consisted in epidural catheter or continuous infusion of morphine intravenously when the catheter could not be placed. Patients who had not had prior myocardial revascularization were not given thromboprophylaxis preoperatively so as to reduce the risk of epidural related morbidity. All patients had an active program of physical therapy including deep-breathing exercises and incentive spirometry during the postoperative period. Deaths which occurred within 30 days of surgery, or later but during the same hospitalization period, were considered as operative deaths. 2.1. Statistical analysis Data are presented as mean ^ standard deviation, unless otherwise indicated. Continuous data were analyzed using unpaired t-test when two sets were compared or Mann– Whitney U-test for independent variables. Wilcoxon rank sum test was used when continuous variables were not normal. Categorical variables were analyzed using chisquared or Fisher’s exact test when expected cell frequencies were less than 5. Univariate analysis determined the impact of coronary arterial disease on operative complications and hospital stay. P-values less than 0.05 where considered statistically significant. 3. Results Fifty patients whose age ranged from 57 to 78 years (mean 68 ^ 5 years) were included in the study. Eighteen patients (36%) were 70 years old or over. There were 47 men and three women. Out of the 19 patients who underwent prior myocardial revascularization, six had CABG for two-vessel (three patients), three-vessel (two patients) and four-vessel disease (one patient) while 13 patients underwent PTCA, of whom nine for a single-vessel disease and four for a two-vessel disease. In six of these patients a coronary stent was also positioned.

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Table 2 Characteristics of cardiac investigations a

Positive ETT Positive CA Cardiac symptoms Only ECG modifications

Prior MR (19 patients)

No prior MR (31 patients)

19 19 13 6

16 0 10 21

a Patients with ECG modifications at admission underwent ETT even in absence of symptoms. ETT, exercise tolerance test; CA, coronary angiography; MR, myocardial revascularization.

Forty-one patients (82%) required additional preoperative cardiac exams other than ECG. Among the 19 patients who had prior myocardial revascularization, 13 presented with cardiac symptoms and six had only ECG modifications. All of them had a positive exercise tolerance test and a positive coronary angiography. The 31 patients who underwent lung surgery alone, presented in 10 cases with cardiac symptoms and underwent an exercise tolerance test that was negative in seven patients and positive in three patients. Coronary angiography performed on these patients did not show significant coronary artery obstruction. The remaining 21 patients presented only ECG modifications, and the exercise tolerance test was negative in eight cases and positive in 13 cases whose coronary angiography was also negative (Table 2). Lung surgery was performed with a mean interval of 32 ^ 9 days (range 25–53 days). None of the patients who underwent prior myocardial revascularization had a progression of their disease at the time of lung resection. When the interval between myocardial revascularization and surgery exceeded 30 days, patients underwent restaging. Neoadjuvant chemotherapy was administered in two patients: in one because of a large primitive tumor and in the other because of paratracheal N2 disease diagnosed by means of transbronchial biopsy. The latter patient underwent PTCA and positioning of a coronary stent prior to chemotherapy. Both patients had an almost complete response to chemotherapy and underwent adjuvant therapy after surgery. Preoperative neoadjuvant chemotherapy did not influence the operative and postoperative outcome. Lung surgery consisted in 40 lobectomies including one en bloc chest wall resection, three pneumonectomies including one completion pneumonectomy, and seven wedge resections. Postsurgically 29 out of the overall 50 patients were in stage I (14 IA and 15 IB), 14 in stage II (three IIA and 11 IIB) and seven in stage IIIA (four N2). The four postsurgical N2 patients had mediastinal lymph nodes , 1 cm at CT scan. The preoperative N2 diagnosed by means of transbronchial biopsy was downstaged after neoadjuvant chemotherapy. Overall mortality and morbidity was 4% and 28%, respectively. Postoperative complications occurred in four of the 19 patients who had prior myocardial revasculariza-

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Table 3 Postoperative outcome of the two groups in terms of complications and mortality

Medium–high cardiac risk Postoperative complications Mortality

Prior MR (19 patients)

No prior MR (31 patients)

0 4 (21%) 0

22 11 (35%) 2 (6.4%)

tion (21%) all consisting in supraventricular arrhythmia, and in 11 of the 31 patients who underwent lung resection alone (35%) (P ¼ not significant). Six of these 11 patients experienced minor cardiac complications such as atrial fibrillation and three underwent minitracheostomy to treat retained secretions. There were two operative deaths among patients who did not undergo myocardial revascularization: one patient, who underwent a right completion pneumonectomy, died because of a malignant intraoperative arrhythmia and one died on postoperative day 29 as consequence of a stroke. Both patients who died were considered at medium-high cardiac risk because of a positive exercise tolerance test despite negative coronary angiography. There were no deaths among the patients who had prior myocardial revascularization. Overall occurrence of postoperative complications was influenced by age (P ¼ 0:02) and presence of medium-high cardiac risk (P ¼ 0:03). Differences between the two groups of patients are described in Table 3. Hospital stay was longer for patients who did not have prior myocardial revascularization (11.7 ^ 4 vs. 8.1 ^ 3 days; P ¼ not significant) and underwent larger pulmonary resection (10.6 ^ 5 vs. 7.4 ^ 2 days; P ¼ 0:002) (Fig. 2).

4. Discussion Surgery still offers the best treatment for patients with

Fig. 2. Length of hospital stay (HS) and incidence of postoperative complications (PC) among patients who underwent prior myocardial revascularization (MR) and among patients who did not undergo myocardial revascularization (NMR).

resectable lung carcinoma. If, however, there is a coexisting coronary arterial disease, operative mortality and morbidity increase significantly [9,10]. The finding of a pulmonary lesion in the preoperative evaluation of patients undergoing myocardial revascularization has been reported to be more frequent than the discovery of ischemic heart disease in patients who are referred for lung cancer [4,11]. This is in contrast with our series, since almost all the patients (47/50) were referred to our department for lung cancer that was not revealed by routine cardiac evaluation but was evidenced by hemoptysis, cough, pain or other symptoms not correlated with their cardiac disease. Twenty patients (40%) had either a history of myocardial infarction that had never been investigated by exercise test and/or coronary artery angiography or a known pharmacologically treated angina. Only three patients (6%) were referred to us by a cardiologist for a pulmonary nodule discovered during cardiac evaluation. The remaining 54% of the patients presented with an angina that had never been evaluated by a cardiologist or that was identified as a result of ECG modifications. Six patients who only presented ECG modifications required myocardial revascularization for significant coronary artery stenoses, a predictor of operative death and morbidity after non-cardiac surgery [9,10,12,13]. This supports the view that patients with lung cancer need to be screened for the presence of coronary artery disease before elective lung resection. Patients’ history should be detailed and care should be taken to search for cardiac symptoms that may be underestimated by the patients themselves. The ECG should be interpreted by an expert cardiologist, who may then prescribe further tests. Licker et al. evaluated patients at risk for coronary artery disease or with low functional capacity, with transthoracic echocardiography, stress test or coronary angiography [9]. Ferguson and Bollinger showed that, in addition to routine investigations, a predicted postoperative diffusing capacity to carbon monoxide (DLCO) below 60% of predicted values and a preoperative maximal oxygen uptake during exercise (VO2max) below 43% are highly predictive of postoperative cardiopulmonary complications and contraindicate resections of more than one lobe [14,15]. We found that the exercise tolerance test was effective in identifying patients at high risk for coronary problems. In one of our patients, with a history of coronary arterial disease, a positive exercise tolerance test was predictive of an intraoperative fatal arrhythmia although the coronary artery angiography was negative. Echocardiography was helpful to study ventricular function when the exercise tolerance test was negative, as in patients with previous myocardial infarction that had occurred more than 1 year before. In agreement with the guidelines of the American College of Cardiology, we believe patients with a positive exercise tolerance test, unstable angina or recent myocardial infarction should undergo coronary catheterization [8]. In cases of severe coronary artery stenoses, myocardial revascularization can be achieved by means of PTCA or CABG prior to


lung resection. Whenever surgical coronary revascularization is indicated, options include either simultaneous lung and cardiac surgery, or staged procedures. The feasibility of concomitant CABG and lung resection has been widely reported but with controversial results [3–6,11]. The combined approach is attractive because it theoretically allows fast treatment of both diseases with fewer resource expenditures. The combined procedure raises a number of concerns related to the potential hemorrhage resulting from the heparinization necessary for extracorporeal circulation and to the humoral and cellular immunosuppressive effects of cardiopulmonary bypass with respect to infections and dissemination of cancer. Ulicny and colleagues reported bleeding complications in 15.8% of their patients who underwent a combined procedure with lung resection performed during cardiopulmonary circulation or after heparin reversal. Yet statistical analysis showed no correlation between timing of resection with respect to extracorporeal circulation and the risk of subsequent complications [3]. Miller et al. found that a combined procedure resulted in a higher mortality than a staged procedure [4] and Voets et al. reported 60% of postoperative deaths related to sepsis in their series of patients who underwent combined heart–lung surgery [13]. Off-pump coronary artery surgery might decrease the incidence of complications related to extracorporeal circulation [16]. In our series heart-beating myocardial revascularization was excluded because of non amenable coronary artery anatomy and/or coexisting chronic obstructive pulmonary disease [17]. Another concern is related to the limited exposure that median sternotomy offers for left lower lobectomy and for lymphadenectomy in the posterior mediastinum. Miller et al. noticed a marked discrepancy in 5-year long-term survival between postsurgical stage I patients who had undergone a combined procedure (36.5%) and those in the same stage who had had staged procedures (100%). Moreover, the percentage of patients with N2 disease was greater in the former group [4]. These results could be accounted for by an inadequate lymphadenectomy performed during the combined procedure with consequent underestimation of the surgical stage of the disease. When a staged operation is chosen, lung resection is generally recommended 4–6 weeks after open-heart surgery and 1–2 weeks after PTCA [6,9]. We preferred to stage the two procedures 3–6 weeks apart to allow optimization of the anticoagulant therapy and recovery from the effects of the cardiopulmonary bypass on immune response and lung physiology. None of the patients experienced progression of cancer. In the patient who required PTCA and positioning of a coronary artery stent and who underwent neoadjuvant chemotherapy, the interval between the cardiac and lung procedures was extended by 2 months. Preoperative diagnosis of a pulmonary lesion by means of fibrobronchoscopy and percutaneous needle biopsy is important in all patients with coronary arterial disease with or without prior myocardial revascularization. Accurate diagnosis

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and preoperative staging allow correct planning of treatment in such delicate patients. Definition of N2 disease is important and this can be achieved by means of mediastinoscopy or in favorable conditions with transbronchial biopsy. The extent of surgery is a recognized risk factor with mortality rates ranging from 3 to 17% following pneumonectomy and from 1 to 10% after lesser resection [9]. The use of a cardiopulmonary risk index might be helpful to predict outcome after thoracic surgery [18]. However, in a prospective study of 180 patients, Melendez and Carlon found that the preoperative cardiopulmonary risk index advocated by Epstein failed to predict complications after thoracic surgery since it showed a correlation only in the patients undergoing pneumonectomy [18]. Licker and colleagues also reported an increased mortality rate after pneumonectomy (7.9%) compared to the mortality rate after lobectomy (1.2%) or lesser resection (2%) [9]. We experienced a higher mortality rate after pneumonectomy (33%) than lobectomy (2.5%). However, of the three patients who underwent pneumonectomy, one had had prior myocardial revascularization and one presented a low cardiac risk while the third, who died as a result of intraoperative arrhythmia, had a medium to high coronary risk and underwent a completion pneumonectomy. None of the patients who underwent wedge resection experienced major postoperative complications. Risk factors for the occurrence of postoperative complications and mortality after thoracic surgery also include age [9,10,12]. Older age is often correlated with a long smoking history and thus with a higher probability of impaired oxygenation and cardiac function. Patients who were over 70 years old experienced more postoperative complications than younger patients (40 vs.10%) although age did not influence postoperative hospital stay. Absence of myocardial revascularization and extent of resection influenced hospital stay positively. Surgery still remains the best treatment for non-small cell lung cancer, and careful preoperative evaluation is important to minimize the risk of postoperative complications and mortality. Patients presenting with coronary artery disease considered to be at high risk for complications after thoracic surgery require aggressive perioperative management including cardiovascular monitoring with exercise tolerance tests, coronary angiography, echocardiography, pre- and postoperative physical therapy, as well as planned postoperative admission to an intensive care unit. Myocardial revascularization is advised for severe coronary artery stenoses, prior to lung resection possibly performed in a staged sequence. Moreover, limited resection, whenever feasible, should be preferred in patients at risk. References [1] Reicher-Reiss H, Jonas M, Goldbourt U, Boyko V, Bodan M. Selectively increased risk of cancer in men with coronary heart disease. Am J Cardiol 2001;87(4):459–462.

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