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Ann Thorac Surg 2008;86:376-382. doi:10.1016/j.athoracsur.2008.04.013
© 2008 The Society of Thoracic Surgeons
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Right arrow Lung - cancer

Original Articles: General Thoracic

Early Surgical Results After Pneumonectomy for Non-Small Cell Lung Cancer are not Affected by Preoperative Radiotherapy and Chemotherapy

Tomas Gudbjartsson, MD, PhD*, Erik Gyllstedt, Andreas Pikwer, MD, Per Jönsson, MD, PhD

Department of Cardiothoracic Surgery, Lund University Hospital, Lund, Sweden

Accepted for publication April 2, 2008.

* Address correspondence to Dr Gudbjartsson, Department of Cardiothoracic Surgery, Landspitali University Hospital, Reykjavik, IS 101, Iceland (Email: tomasgudbjartsson{at}hotmail.com).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background: Higher operative risks after pneumonectomy for non-small cell lung cancer (NSCLC) have been reported after neoadjuvant chemotherapy or radiotherapy, or both. Patients who underwent pneumonectomy for NSCLC were evaluated for effect of neoadjuvant treatment on mortality and morbidity, especially bronchopleural fistula.

Methods: Between 1996 and 2003, 130 consecutive patients underwent pneumonectomy: 35 received preoperative radiotherapy and chemotherapy (the neoadjuvant group), and 95 patients did not (the first-surgery group). Operative mortality and postoperative complications were compared between the groups.

Results: Minor postoperative complications were comparable in both groups (p > 0.10). Five patients in the neoadjuvant group and 10 in the first-surgery group had serious complications (p = 0.55). Eight had bronchopleural fistulas (7 right and 1 left, p < 0.01); 3 were in the neoadjuvant group (p = 0.49). Three fistulas required reoperation. One patient in the first-surgery group died within 30 days postoperatively. Duration of symptoms (hazard ratio, 6.6; p = 0.01) and right-sided pneumonectomy (hazard ratio, 2.4; p = 0.05) were associated with an increased risk of bronchopleural fistula. Induction treatment, postoperative radiotherapy, or coverage of the bronchial stump did not increase the risk of bronchopleural fistulation. Survival at 1 and 5 years was comparable for the neoadjuvant and first-surgery groups: 74% and 46% vs 72% and 34%, respectively (p > 0.2).

Conclusions: Pneumonectomy is a safe procedure with low operative mortality. Postoperative morbidity is significant, especially bronchopleural fistulas after right-sided pneumonectomy (11%). However, neither operative mortality nor morbidity appears to be directly associated with preoperative radiotherapy or chemotherapy.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Most patients with non-small cell lung cancer (NSCLC) have disseminated disease at the time of diagnosis, with poor long-term survival. Since the 1990s, induction therapy with chemotherapy and radiotherapy has been increasingly used for locally advanced NSCLC, with the aim of improving resectability (downstaging) and survival by treating micrometastatic disease [1–3]. In selected patient groups, several studies have reported benefit from this neoadjuvant approach [1–4] for survival; however, the risks of intraoperative and postoperative complications after such therapy are still being debated [5, 6].

Earlier series have reported increased morbidity and mortality, ranging from 20% to 60% and 0% to 20%, respectively [2, 6–8]. For patients who undergo pneumonectomy, these figures have been shown to be even higher [9, 10], with one study reporting operative mortality of 23.9% after right-sided pneumonectomy [6]. Authors of more recent series have, however, questioned these high morbidity and mortality figures [3, 11–16].

In Lund University Hospital, a tertiary referral hospital in southern Sweden, a combination of preoperative chemotherapy and radiotherapy has been used for more than a decade to treat patients with locally advanced NSCLC. Here we report our experience with neoadjuvant therapy in patients who underwent pneumonectomy. The main purpose of the study was to compare postoperative morbidity and mortality in patients who received neoadjuvant treatment with corresponding data for patients who were operated on directly, without induction treatment.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
This study was approved by the Bioethics Committee of Lund University Hospital, and because individual patients were not identified, consent for the study was waived.

This was a nonrandomized retrospective study including 130 consecutive NSCLC patients who underwent pneumonectomy between January 1, 1996, and December 31, 2003. Excluded were 30 patients who underwent pneumonectomy at our institution during the same period for other indications, including other malignancies and infections.

Of the 130 patients, 35 (27%) underwent preoperative chemotherapy, the latter group including 27 patients who also received preoperative radiotherapy. These 35 patients formed the neoadjuvant group, and they were compared with 95 patients who were operated on directly without any induction treatment (the first-surgery group). The indications for neoadjuvant treatment were consistent during the entire study period and involved patients at clinical (preoperative) stage IIIA, with "minimal N2 disease" (with a maximum of two positive mediastinal lymph node stations and no extranodal growth) and T4 N0 M0 disease.

In every case, the decision to use neoadjuvant treatment was made by the individual surgeon together with a pulmonologist and an oncologist. Chemotherapy consisted of three cycles of mitomycin, vinblastine, and cisplatin; or carboplatin and paclitaxel. Radiation therapy was administered in doses of 2 Gy, usually up to a total dose of 44 Gy. The median time between the end of chemotherapy or radiotherapy and operation was 54 days.

Clinical information was obtained from medical and pathology reports. The data recorded included demographic information (age, sex), medical comorbidities (eg, pulmonary and coronary artery disease, arrhythmia), and patient and tumor characteristics (laterality, stage, smoking history). The preoperative American Society of Anesthesiologists (ASA) score was compared in the two groups. Details of the neoadjuvant treatment and the surgical procedure were recorded. The tumors were classified and staged according to the 1997 International System for Staging of Lung Cancer [17].

Table 1 reports the patient demographics. Patients in the neoadjuvant group were significantly younger (p < 0.001), and the male/female ratio was lower than in the first-surgery group (1.5 vs 3.8; p = 0.03). The most common symptoms were cough (74%), chest pain (26%), hemoptysis (25%), and dyspnea (25%). The diagnosis in 21 patients (15%) was incidental, most often by chest computed tomography (CT) imaging performed for other diseases or symptoms.


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  		Table 1 Patient and Tumor Characteristics for Both Groups
 
There were no significant differences in preoperative lung-function tests, including predicted forced expiratory volume in 1 second percentage (FEV1%) and forced vital capacity percentage (FVC%), incidence of coronary artery disease, chronic obstructive disease, and history of smoking. The preoperative ASA scores were almost identical in the neoadjuvant and first-surgery groups, most of the patients being in class II or III (p = 0.36).

Tumors were evenly distributed in the right and left lung, and tumor size and histology were comparable in both groups; altogether, 74 patients had squamous cell carcinoma (57%), 42 had adenocarcinoma (32%), and 14 had large cell carcinoma (11%).

Pretreatment clinical stage classification, which would be equally applicable to both groups, was not available. The postresection stage is complicated by the fact that it also reflects the effect of chemotherapy in the neoadjuvant group. Despite this potential downstaging in the neoadjuvant group, this group had higher postresection stages than patients in the first-surgery group, most of them being at stages IIIA and IIIB (Table 1). No patients in the neoadjuvant group were diagnosed at stages I or II compared with 34 patients diagnosed at these stages in the first-surgery group. One patient in each group was diagnosed at stage IV because of distant metastases that had not been discovered preoperatively.

Pulmonary ventilation-perfusion scintigraphy was performed in most patients and also skeletal scintigraphy. All patients underwent lung-function tests and a treadmill test to evaluate cardiovascular performance.

Preoperative staging involved a chest roentgenogram and a thoracoabdominal CT scan. Mediastinoscopy was performed in all but 2 patients, with biopsies from at least three different mediastinal lymph node stations. During the study period, positron emission tomography (PET) scan was not available in our institution; however, it is currently used for staging purposes in selected patients.

The pneumonectomies were performed by a team of 4 general thoracic surgeons using a similar technique, including thoracic epidural anesthesia and double-lumen intubation. An anterolateral thoracotomy under the fourth or fifth rib was performed in all cases, and staplers were used for dividing the pulmonary arteries, pulmonary veins, and the main bronchus. With few exceptions, patients were extubated directly after the operation. One chest tube (with either no suction or –5 cm H2O) was placed in the chest and removed within 12 hours if no significant bleeding occurred. Patients were kept in the intensive care unit for 16 to 24 hours postoperatively, with strict perioperative fluid restriction and monitoring with a central venous and arterial catheters. All patients received digoxin intraoperatively, and this treatment was continued orally for 1 month postoperatively.

The bronchial stump was covered intraoperatively in 73 patients (56%), of whom 25 (71.4%) were in the neoadjuvant group and 48 (50.5%) were in the first-surgery group (p = 0.04). The most common stump coverage was the usage of a flap, usually from the parietal pleura (n = 30), the pericardial or mediastinal fat (n = 17), or the azygos vein (n = 14). Muscle flaps were used in 7 patients, most commonly from an intercostal muscle or the diaphragm. In 5 patients, tissue glue (Bioglue [CryoLife, Kennesaw, GA] or Advaseal [Ethicon Inc, Somerville, NJ]) was used.

Postoperative radiotherapy was given to 8 patients in the neoadjuvant group; most of these patients had not received radiotherapy preoperatively. In the first-surgery group, 35 patients (36.8%) received postoperative radiotherapy for inadequate microscopic resection-margins or unsuspected pN2-disease. Four of these patients were also treated with postoperative chemotherapy shortly after the pneumonectomy.

Operative mortality was defined as death that occurred within 30 days of operation, and hospital mortality was defined as patient death before leaving the hospital. Morbidity data were recorded from medical charts and either classified as major or minor. Major complications included bronchopleural fistula (BPF), myocardial infarction, pneumonia, respiratory failure requiring ventilator treatment for more than 48 hours, empyema, sepsis, and cardiac failure.

The Student t test and Mann-Whitney U test were used to compare groups, and values of p < 0.05 were considered statistically significant. Overall survival was evaluated using the Kaplan-Meier method, and the log-rank test was used to compare unadjusted survival curves. Survival in all the patients was followed up by using data from the Swedish National Population Registry and an updated population register. In this way, patients could be assigned a date and a cause of death (as registered on death certificates or in medical records) or were identified as living on July 31, 2006. Mean follow-up time was 39 months, and no patients were lost to follow-up.

Logistic regression was used to evaluate the effects of neoadjuvant treatment on morbidity and mortality, including the risk of BPF, and also other major and minor complications (Table 2). Continuous variables were tested in their original continuous form, in a logarithmic form, and with a set of dummy variables. The hazards ratio (reported here with 95% confidence intervals) was used to determine the effect of different clinical and pathologic variables on the risk of morbidity.


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  		Table 2 Comparison of Early Major and Minor Postoperative Complications a
 

   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
Table 2 reports major and minor complications in the two groups. Serious major complications (p = 0.55) occurred in 5 patients in the neoadjuvant group (14.3%) and 10 in the first-surgery group (10.5%). These included BPF, major intraoperative bleeding, myocardial infarction, and respiratory insufficiency with adult respiratory distress syndrome (ARDS). A BPF was diagnosed in 8 patients, 7 on the right side and 1 on the left (p = 0.001). Three of these fistulas were in the neoadjuvant group and five in the first-surgery group (p = 0.49). In 6 of 8 BPF cases, the bronchial stump was covered at the primary operation. Of the 5 patients with BPF in the first-surgery group, 3 had received postoperative radiotherapy. Only 3 patients with BPF required a reoperation, 1 with direct suture and 2 with latissimus dorsi muscle flap. The other 5 were treated with Tisseel injection (Baxter, Deerfield, IL) by bronchoscopy, one treatment being sufficient in all cases (except for 1 patient who required two injections). Two patients in the first-surgery group needed urgent reoperation for a herniation of the left ventricle through a defect in the pericardium. These defects had been covered with a Gore-Tex patch (W. L. Gore and Associates, Flagstaff, AZ) after a partial resection of the pericardium, and the sutures slipped several hours later in the intensive care unit. Both patients underwent immediate reoperation in their beds and made an uneventful recovery.

The difference in minor complications between the two groups, 14 in the neoadjuvant group (40%) and in 31 the first-surgery group (32.6%), was not significant (p > 0.1). Atrial fibrillation and congestive heart failure were the most common complications. Only 3 patients had superficial wound infections (Table 2), and 2 patients in each group required a reoperation for postoperative bleeding. Three patients were diagnosed with empyema that responded to treatment with chest tube and intravenous antibiotics.

One patient in the first-surgery group died within 30 days of operation due to pneumonia and respiratory failure after aspiration shortly after extubation. All patients in the neoadjuvant group survived the operation and were discharged from hospital. Length of stay was comparable in both groups (median, 9 days).

A logistic regression analysis showed that duration of symptoms (HR, 6.6) and right-sided pneumonectomy (HR, 2.4) were significantly associated with increased risk of BPF (p = 0.01 and p = 0.05, respectively). However, neoadjuvant treatment, postoperative radiotherapy, or coverage of the bronchial stump had no effect on the risk of BPF. Logistic regression analysis on other major and minor complications listed in Table 2 did not reveal any significant risk factors.

Figure 1 shows overall survival for both groups. Median overall survival for the entire group was 28 months. There was no significant difference in survival of the two groups, with respective 1- and 5-year survivals of 74% and 46% in the neoadjuvant group and 72% and 34% in the first-surgery group (p > 0.21).


Figure 1
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  		Fig 1. Kaplan-Meier curve shows overall survival of 130 patients who underwent pneumonectomy for non-small cell lung cancer. This included 35 patients who received preoperative neoadjuvant (dashed line) treatment and 95 patients who were treated only with surgical intervention (solid line; Surg 1st group). No statistically significant difference was noted in survival at 1 and 5 years postoperatively.

 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
This study shows that mortality after pneumonectomy is low (0.8%), lower than reported in many previous studies, where the mortality rate has usually been 4% to 10% [18–20]. This is also true for the subgroup of patients who received neoadjuvant therapy preoperatively (no deaths). Table 3 compares the mortality rate of pneumonectomy after neoadjuvant therapy in selected studies of more than 10 patients with the present study [3, 5–8, 13, 16, 21–25].


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  		Table 3 Selected Reports of Pneumonectomies After Neoadjuvant Treatment for Non-Small Cell Lung Cancer a
 
Several studies have reported survival benefit from neoadjuvant therapy in NSCLC, especially for patients at stage IIIA [26, 27]. However, only a few of these studies have been randomized, and the number of patients was small [13]. In the randomized study by Depierre and colleagues [28], increased survival in the chemotherapy arm was shown to be mainly due to reduced metastatic relapse. For advanced N2 disease, both chemotherapy and preoperative radiotherapy have been used [1, 29]. These studies indicate that tumor and nodal downstaging is associated with improved survival. However, the risks of intraoperative and postoperative complications after such therapy have been debated, especially in patients undergoing pneumonectomy [3, 5–7, 10, 13–16, 22–24, 30]. In a famous study, Martini and colleagues [6] reported a 90-day mortality rate of 23.9% after right pneumonectomy. The operative deaths were often associated with the development of BPF, resulting in chronic sepsis and debilitation.

In more recent series, however, these high mortality figures have been questioned. Perrot and colleagues [13] reported only 1 death in 27 patients undergoing pneumonectomy after induction therapy, and Siegenthaler and colleagues [15] reported no mortality in 8 patients. In a much larger series by Mansour and colleagues [23], induction chemotherapy in 60 of the patients did not significantly jeopardize postoperative outcome, with a 30-day mortality of 6.7% compared with 5.5% in 238 patients undergoing surgical treatment alone.

In the present study, no postoperative deaths occurred within 30 days in the neoadjuvant group, and only 1 patient died in the other group. The same figures apply to 90-day mortality in this study. Other authors have reported that 90-day mortality can be up to twice as high as the 30-day mortality [5, 6, 23].

Postoperative mortality in the present study was very low, especially when considering that a quarter of our 130 patients were treated preoperatively with both chemotherapy and radiotherapy. All the operations were performed by 4 experienced general thoracic surgeons, and postoperative control was tight. All patients stayed overnight in the cardiothoracic intensive care unit with strict perioperative fluid restriction and close monitoring. Our series was consecutive but only included NSCLC patients, excluding 30 patients who underwent pneumonectomy for other malignant conditions (eg, sarcoma) or diseases (eg, tuberculosis), 2 of whom did not survive the procedure.

We could not identify any significant differences between the groups, either for minor or major postoperative complications, or for hospital stay (median 9 days in both groups). This is in line with the results of several recent studies reporting on morbidity after pneumonectomy, with or without induction treatment [3, 13–16, 23]. Atrial fibrillation, congestive heart failure, and pneumonia were the most common complications in both groups, and although there was a trend toward a higher complication rate in the neoadjuvant group (14.5% vs 10.5%), the difference was not statistically significant. The same was true for major complications, including major intraoperative bleeding, myocardial infarction, and respiratory insufficiency.

We looked specifically at BPF, which is one of the most dangerous complications of pneumonectomy, and there were no significant differences for the patients in each group. All the BPFs except one were on the right side. This finding is in line with many other studies [5, 7–10, 24], but not all [23]. This is probably related to the right bronchial stump remaining in the pleural space after the procedure, whereas the left stump retracts into the mediastinum. Other authors have reported higher operative risks after right pneumonectomies [5, 19, 31], often related to the development of BPF. However in two recent studies, as in the present study, the side of pneumonectomy did not affect mortality [32, 33]. Interestingly, only 3 of the 8 patients with BPF needed to undergo reoperation. The other 5 patients were treated with chest tube and tissue glue (Tisseel) administered by bronchoscopy.

The rate of BPF was not affected by neoadjuvant therapy in the logistic regression analysis. The same was true of bronchial stump coverage. With so few BPF cases, however, our data must be interpreted with caution; they do not prove that the bronchial stump should not be covered at the primary operation. Different techniques of stump coverage were used in our series. We most often used pleural or pericardial/mediastinal fat flaps. Some authors advocate the use of muscular (eg, intercostal muscle) flaps, especially in high-risk patients such as those with diabetes mellitus [34].

Rather than survival, the main end point in this study was early surgical results and operative mortality. Thus, potential risk factors for late mortality were not looked at specifically. This has, however, been done in many other studies [29, 35].

A limitation of the present study was that it was not randomized. The patients who received the neoadjuvant treatment therefore represented a selected subgroup, as they were an average of 8 years younger than the patients who were treated solely with a surgical intervention. Thus, the survival figures as presented in Fig. 1, with no significant differences in survival detected at either 1 or 5 years postoperatively, must be interpreted with caution. However, it must also be kept in mind that patients in the neoadjuvant group were diagnosed at significantly higher stages than patients in the first-surgery group (88.6% vs 47.4% at stage IIIA or IIIB, respectively; p < 0.001). Ideally, staging should have included both preoperative clinical staging and pathologic stating after the resection. However, accurate information on preoperative staging was not always available, and postresectional staging was therefore used.

Our reported 5-year survival rate for the neoadjuvant group of 46% must be considered favorable, and our survival rates are somewhat higher than in other studies that have included patients with regionally advanced disease (the 5-year survival usually being in the 30% to 40% range) [13, 22, 30]. Still, our results show that survival for the whole group is poor. Every second patient in both groups did not survive for 2 years postoperatively, and most of these patients died from metastatic relapse. The fact that most long-term failures after lung resection, including pneumonectomy, are systematic has been well documented previously [36]. This is a matter for concern and underscores the need for effective systemic therapy administered in conjunction with surgical intervention.

Our data do not prove that pneumonectomy is the best oncologic treatment for all of these patients. This is especially true for patients with N2 disease, where the role of pneumonectomy has recently been debated [37]. Since systematic therapy is probably better tolerated in patients operated on with lung-preservation therapy, procedures such as extensive sleeve resections should be used where possible [38].

Altogether, our results suggest that the potential risks after induction chemotherapy and radiotherapy on postoperative morbidity and mortality for patients undergoing pneumonectomy may have been overestimated. This includes the risk of BPF.

In conclusion, pneumonectomy is a safe procedure with low operative mortality of less than 2%, even in patients treated with preoperative radiotherapy or chemotherapy, or both. Postoperative morbidity is significant, especially BPFs after right-sided pneumonectomy (11%). However, neither operative mortality nor morbidity seems directly associated with neoadjuvant treatment. Hence, pneumonectomy may be justified in selected groups of patients, even those with regionally advanced disease who are treated preoperatively with induction therapy.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
We are grateful to Helgi Sigvaldason for help with statistics and to Birgitta Sjögren and Lena Martensson for secretarial assistance.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

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