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Ann Thorac Surg 2005;80:423-427
© 2005 The Society of Thoracic Surgeons

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Original article: General thoracic

Preoperative Chemotherapy Does Not Increase Complications After Nonsmall Cell Lung Cancer Resection

^a Department of Thoracic Oncology and Chest Disease, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Benite, France
^b Thoracic Surgery Unit, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Benite, France
^c Department of Biostatistics, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Benite, France

Accepted for publication February 9, 2005.

^_* Address reprint requests to Dr Perrot, Department of Thoracic Oncology and Chest Disease, Hospices Civils de Lyon, Pneumologie 1A, Secteur JC, Chemin du Grand Revoyet, Centre Hospitalier Lyon Sud, Pierre Benite, 69495 Cedex France (Email: emilie.perrot{at}chu-lyon.fr).

	Abstract

Top Abstract Introduction Patients and Methods Results Comment References

 
BACKGROUND: Neoadjuvant chemotherapy before resection of nonsmall cell lung cancer seems to increase survival, mainly in the early stage. Risks of postoperative complications after chemotherapy and surgery remain controversial. Here we review our experience with patients treated in one thoracic surgery center.

METHODS: Patients undergoing resection for nonsmall cell lung cancer after induction chemotherapy between January 1993 and March 2002 were reviewed. Data collected included age, sex, preoperative forced expiratory volume in 1 second (FEV₁), hemoglobin, and arterial oxygen pressure tension (PaO₂), postoperative complications, and global survival.The main objectives were postoperative mortality and morbidity. Postoperative mortality and morbidity were defined as complications or deaths occurring within 30 days after surgery. Predictive morbidity factors were identified by univariate and multivariate analysis and overall survival by the Kaplan-Meier method.

RESULTS: In all, 114 patients were reviewed. Different induction chemotherapies were used, mainly cisplatin with vinorelbine or gemicitabine. Postoperative mortality was 2 of 114, 1 of 27 after pneumonectomy, and there were no deaths after lobectomy. Complications occurred in 29% of patients (33 of 114), usually infectious pneumonia and anemia requiring transfusion. Preoperative FEV₁, hemoglobin, and PaO₂ are not associated with morbidity in univariate or multivariate analysis.

CONCLUSIONS: Preoperative chemotherapy does not increase postoperative mortality and morbidity after nonsmall cell lung cancer surgery, performed exclusively by thoracic surgeons.

	Introduction

Top Abstract Introduction Patients and Methods Results Comment References

 
Preoperative chemotherapy seems to increase survival rates in stage IIIA nonsmall cell lung cancer (NSCLC), but there have been few randomized studies and these have had a small number of patients [1, 2]. In the randomized study by Depierre and colleagues [3], an increased survival with neoadjuvant chemotherapy was observed in the early stage patients (IB and II), mainly through reduced metastatic relapse. Preoperative chemotherapy has become the standard treatment for N2 patients. The influence of induction chemotherapy on postoperative outcomes remains controversial. Depierre and colleagues [3] and a few retrospective studies [4, 5] showed increased postoperative complications after neoadjuvant chemotherapy. Here we sought to determine the incidence of surgical morbidity and mortality after preoperative chemotherapy or chemoradiation in our thoracic surgery unit. The main objective was to analyze postoperative mortality and morbidity (complications occurring in the 30 days after surgery). A secondary objective was to identify predictive factors of morbidity by univaried and multivaried analysis and overall survival by the Kaplan-Meier method.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Comment References

 
Subjects and Data Collected
We made a retrospective study of all patients who received preoperative chemotherapy or chemoradiation before thoracotomy for resectable NSCLC from January 1993 to March 2002. All patients underwent thoracotomy exclusively by two thoracic surgeons in the thoracic surgery unit of the Lyon Sud Hospital Center. The majority of patients did not have mediastinoscopy, and the preoperative stage was determined mainly through a thoracic computer scan.

Preoperative data collected included age, sex, stage, forced expiratory volume in 1 second (FEV₁), hemoglobin, and arterial oxygen pressure tension (PaO₂), form and number of chemotherapy sessions, and whether the patient had preoperative radiotherapy. Details of the surgical procedure were recorded. Postoperative data collected included the date and form of resection, the final pathologic stage, classified according to the 1997 International System for Staging Lung Cancer [6], length of hospital stay and thoracic drainage, and postoperative chemotherapy or radiotherapy. Postoperative complications occurring within the 30 days after surgery were recorded. Pneumonia, extrarespiratory infection, bronchopleural fistulas, pleural or parietal bleeding, anemia requiring transfusion, pulmonary embolism, respiratory failure and adult respiratory distress syndrome, prolonged drainage, cardiovascular complications, other complications, and death were noted.

Statistical Methods
Univariate analysis of factors associated with postoperative mortality and morbidity was performed fitting the unconditional logistic regression models of Breslow and Day [7]. Predictive complication factors reviewed were age, stage, preoperative FEV₁, PaO₂, and hemoglobin. Factors with a p value smaller than 0.20 (likelihood ratio test) were included in the multivariate analysis. Odds ratios were presented with corresponding 95% confidence intervals.

Survival was estimated using Kaplan-Meier estimators. Survival curves were compared by log-rank tests. A multivariate analysis was performed fitting a Cox proportional hazard model [8]. Statistical tests (two-tailed) were considered as significant at the 0.05 level.

	Results

Top Abstract Introduction Patients and Methods Results Comment References

 
Demographics
We reviewed 114 patients, 100 men and 14 women, with a median age of 61 years (range, 25 to 74). Histologic tumor analysis detected 64 squamous cell carcinomas, 29 adenocarcinomas, 17 large cell carcinomas, and 4 large cell neuroendocrine carcinomas. The majority of patients had reached clinical stage III before induction therapy, and mediastinoscopy was not usually carried out.

Neoadjuvant Treatments
All patients received preoperative chemotherapy, cisplatine-vinorelbine in the case of 56 patients, cisplatine-gemcitabine for 12 patients, carboplatine-vinorelbine for 5 patients, and other regimens. Twenty patients also received preoperative radiation, usually for apical tumors, and received a dose of radiation of 40 Gy.

Surgical Resection
Forty-one lobectomies, 4 bilobectomies, 55 pneumonectomies (27 right pneumonectomies and 28 left pneumonectomies), 5 wedge resections, and 9 exploratory thoracotomies were performed. Pneumonectomy was the most common operation (48%). Complete mediastinal lymphadectomy was perfomed in all patients. The 9 patients who only had exploratory surgery had nonresectable tumors. Postoperative thoracic drainage lasted from 2 to 25 days, averaging 5 days; hospitalization lasted from 3 to 27 days, with an average of 11 days. Clinical and pathological tumor extensions are presented in Table 1.

Postoperative Morbidity
Overall morbidity was 28.9%; 33 of the 114 patients had postoperative complications. The 2 deaths were included in the 33 because they had complications before death (pneumonia and massive hemoptysis). Complications are detailed in Table 2. The most common complications were pneumonia, anemia, and hemorrhage. Cardiovascular complications were usually auricular fibrillation. No bronchopleural fistulas were included in our series. The relationship between morbidity and the type of surgical resection is shown in Table 3.

We analyzed age, stage, preoperative FEV₁, PaO₂, and hemoglobin as predictors of complications. The medians were 61 years for age, 80% for FEV₁, 11.8 kPa for PaO₂, and 11.5 for hemoglobin. The thresholds used were 60 years for age, I–II versus III–IV for stage, 80% of the theoretical value for FEV₁, 10 kPa for PaO₂, and 12 g/dL for hemoglobin. The univariate analysis demonstrated that postoperative morbidity was not higher among older (60 years) patients (odds ratio = 1.55, confidence interval 0.67 to 3.55; p = 0.301), more advanced stage patients (odds ratio = 1.35, confidence interval 0.60 to 3.06; p = 0.460), patients with lower FEV₁ (odds ratio = 1.61, confidence interval 0.68 to 3.82; p = 0.274), patients with lower PaO₂ (odds ratio = 0.978, confidence interval 0.31 to 3.04; p = 0.969), or patients with lower hemoglobin (odds ratio = 0.907, confidence interval 0.39 to 2.06; p = 0.815). None of these factors was included in multivariate analysis because all the p values were higher than 0.20.

Survival
Overall survival rates, analyzed by the Kaplan-Meier method, are shown in Figure 1. One-year and 5-year survivals were 76.5% and 35.5%, respectively. We analyzed the influence of the preceding factors on survival by univariate and multivariate analysis. The stage and preoperative PaO₂ were the two factors that influenced survival among age, stage, preoperative FEV₁, PaO₂, and hemoglobin in univariate and multivariate analysis (p = 0.003 and 0.002, respectively).

View larger version (14K): [in this window] [in a new window]   Fig 1. Overall survival by the Kaplan-Meier method.

	Comment

Top Abstract Introduction Patients and Methods Results Comment References

The results from studies analyzing postoperative mortality and morbidity outside all neoadjuvant treatment are summarized in Table 5. All these studies are retrospective. Postoperative mortality rates varied from 1.3% to 6.6% for overall mortality, from 1.6% to 13.4% for death after pneumonectomy, and from 0.6% to 4% for death after lobectomy. The most frequently reported causes of death were respiratory distress, pneumonia fistulas, and pleural empyema. Table 5 shows clearly that both postoperative mortality and morbidity are higher after pneumonectomy.

The rate of postoperative complications in our study reached 28.9% (33 of 114 patients), the most common complications being pneumonia, anemia with transfusion, and hemorrhage. The majority of patients had advanced stage cancers, as 79% were in preoperative clinical stage III.

Postoperative mortality and morbidity rates in our study (1.8% and 28.9%, respectively) are identical to, or even less than, those in the majority of retrospective studies with or without preoperative chemotherapy. These figures are also less than those observed for patients operated on in the same unit without neoadjuvant treatment: of 2,238 NSCLC ablations, there were 57 deaths, or a total mortality rate of 2.7%. In addition, our results are very close to the postoperative mortality rate of patients who had resection of a NSCLC in the same thoracic surgery unit, without preoperative chemotherapy: of 2,210 patients operated on, there were 57 deaths, or a mortality rate of 2.7%.

Several elements can perhaps explain the limited number of postoperative complications in our sample. First, all the patients in our study were operated on exclusively by thoracic surgeons. It was, in any case, noted that systematic ganglion curettage carried out by the surgeons in our study did not raise the mortality rate. The retrospective study by Silvestri and coworkers [21] carried out on 1,583 patients showed a higher postoperative mortality rate for patients operated on by general surgeons than for those operated on by specialist thoracic surgeons (5.3% against 3%, p < 0.05).

In addition, all patients in the study were operated on in a unit with a high number of thoracotomies performed (about 150 bronchial cancers operated on in a year). The study by Bach and colleagues [22], which included 2,118 patients operated on in 76 different hospitals, concluded that that there were lower complication rates in large centers (3% mortality, 20% morbidity) than in hospitals handling fewer procedures (6% mortality, 44% morbidity). One reason for the higher postoperative mortality in the study by Depierre and associates [1] is probably that it was a multicenter study, which included centers with variable inclusion levels, corresponding to teams with more or less training. In our study, thanks to the high number of surgical interventions per year, the teams of anesthetists, nurses, and physiotherapists were used to performing bronchial cancer surgery.

Moreover, patients in our study did not go into the intensive care unit in the operating theaters and benefited from intensive respiratory physiotherapy in the surgical unit. That would appear to be an important point for explaining the low incidence of complications: artificial ventilation time is shorter, the risk of postoperative nosocomial infections is probably less, and the patient’s treatment is less invasive.

The selection of patients probably also has a beneficial role: the majority of operating questions were asked during a multidisciplinary meeting of lung specialists, thoracic surgeons, radiologists, and pathologists. In addition, patients who benefited from preoperative chemotherapy were often young and generally in better health, whereas older patients or those with a performance status score of 2 or more were more likely to be operated on straightaway.

Finally, the preoperative FEV₁, PaO₂, and hemoglobin values show that most patients had good respiratory function and were not anemic before the operation.

In our study, none of the data collected preoperatively was found to be predictive of complication factors. Patients who had received preoperative radiotherapy seemed to have more postoperative complications than others (35% against 28.9%, respectively), but this difference was not statistically significant. The thresholds that we chose (80% for FEV₁, 10 kPa for PaO₂, and 12 g/dL for hemoglobin) corresponded to the lowest normal limits for each value. Our analysis of the survival of 114 patients by the Kaplan-Meier method showed overall survival rates of 76% at 1 year and 35% after 5 years, rates that correspond more or less to survival at the IIB stage of the International System for Staging Lung Cancer [6], although our study contains 23% stage II and 44% stage III patients. Factors that influenced survival in our study are the stage (p = 0.003) and preoperative PaO₂ with a limit of 10 kPa (p = 0.002). The fact that stage influences survival confirms known data. On the other hand, the results concerning PaO₂ indicate increased vigilance with patients showing preoperative hypoxia.

	References

Top Abstract Introduction Patients and Methods Results Comment References

 

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