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(Chest. 2005;128:3519-3525.)
© 2005 American College of Chest Physicians

Risk Stratification for Lung Cancer Surgery*

Impact of Induction Therapy and Extended Resection

Yoko Matsubara, MD; Shin-ichi Takeda, MD, FCCP and Takashi Mashimo, MD, PhD

* From the Departments of Anesthesiology (Dr. Matsubara) and General Thoracic Surgery (Dr. Takeda), Toneyama National Hospital, Toyonaka City, Osaka, Japan; and the Department of Acute Critical Medicine (Anesthesiology) [Dr. Mashimo], Osaka University Graduate School of Medicine, Suita City, Osaka, Japan.

Correspondence to: Shin-ichi Takeda, MD, FCCP, Toneyama National Hospital, Toneyama 5–1-1, Toyonaka 560-8552, Japan; e mail: stakeda{at}toneyama.hosp.go.jp


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: Current surgical strategies for lung cancer are directed toward the following two distinct targets: the increased prevalence of early-stage lung cancer; and locally advanced lung cancer treated with induction therapy (IT). To establish the risk stratification for operative morbidity from this viewpoint, we evaluated the impact of IT and/or an extended surgical procedure on operative results.

Design: Retrospective study.

Setting: A 674-bed teaching hospital.

Patients and methods: The morbidity and mortality of 758 consecutive patients who underwent surgery for the treatment of non-small cell lung cancer were analyzed. There were 666 patients who underwent surgery alone (S group; 560 standard lobectomies and 106 extended resections) and 92 patients who received IT (IT group; 35 standard lobectomies and 57 extended resections). Comparisons between the groups were performed using unpaired t tests or {chi}2 tests. Univariate and multivariate logistic regression analyses were used to determine the risk factors for operative morbidity and mortality.

Results: IT and extended surgery were strong independent factors for predicting postoperative morbidity (p < 0.0001). Significant differences were observed for pathologic stage (p < 0.0001), preoperative hemoglobin and DLCO levels (p < 0.001), the ratio of extended resection (p < 0.0001), and operation time and intraoperative bleeding (p < 0.001) between the S and IT groups. The overall morbidity and mortality rates were 16.8% and 0.9%, respectively, in the S group, and 55.4% and 5.4%, respectively, in the IT group (p < 0.01). The overall morbidity and mortality rates were 63.2% and 7.0%, respectively, for extended resection after IT, and 12.8% and 0.3%, respectively, for those who underwent a standard resection without IT.

Conclusions: The morbidity and mortality of lung resection are both significantly increased after IT, and the patients with the greatest risk are those who have undergone IT and extended resection. The impact of IT on risk stratification should be emphasized in perioperative care.

Key Words: extended surgery • induction therapy • lung cancer • pulmonary resection • risk stratification


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The overall operative mortality rate for lung cancer patients who undergo a thoracotomy in Japan is satisfactorily low,1 with a 30-day death rate of 1.3%. The prevalence of early-stage lung cancer treated with a standard or lesser resection has increased because of the institution of a nationwide mass screening system.23 On the other hand, induction therapy (IT) has become a standard treatment for patients with locally advanced stage non-small cell lung cancer (NSCLC)45 because it is able to downstage and render the advanced cases completely resectable. However, despite refinements in operative techniques and advances in perioperative care, an extended resection and/or resection following IT results in higher rates of mortality and morbidity compared to those following a standard resection.67

We considered that the risk of surgery for patients undergoing extensive surgery and/or IT should to be assessed with reference to a standard procedure. Namely, the operative risk for lung cancer surgery should be determined for two distinct targets, early-stage lung cancer and locally advanced lung cancer treated with IT, to establish the standardized clinical care pathways. However, general anesthesiologists, pulmonary physicians, and thoracic surgeons, who evaluate patient comorbidity and pulmonary function reserve, have few reports available regarding the impact of IT and extended surgery. The objective of the present study was to determine whether IT and/or extended resection have an effect on morbidity and mortality in order to provide risk stratification for surgical patients with lung cancer.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Between January 1994 and December 2003, pulmonary resections were performed on 758 consecutive patients with NSCLC, (576 men and 182 women; average age, 62.5 years) at Toneyama National Hospital in Japan. Of those patients, 666 patients (502 men and 164 women; average age, 62.9 years) underwent surgical resection without receiving IT (S group), and 92 patients (74 men and 18 women; average age, 59.6 years) underwent surgery following IT (IT group). Eighty-two patients underwent chemoradiotherapy, and 10 patients received chemotherapy alone. Induction chemoradiotherapy consisted of two cycles of cisplatin/vindesine/mitomycin C therapy for 48 patients, cisplatin/vindesine therapy for 28 patients, and cisplatin/vinorelbine therapy for 6 patients, with conventional radiation ranging from 30 to 60 Gy (average, 42.5 Gy). Induction chemotherapy consisted of two cycles of cisplatin/docetaxel therapy for four patients and carboplatin/docetaxel for six patients.

Pathologic nodal status classification was determined from a pathologic examination of the resected lymph nodes. The evaluation of stage M1 disease included results from examinations by abdominal CT scan, bone scan, brain CT scan, or MRI, as well as by laboratory tests. All patients were evaluated for predicted postoperative function, as we previously have reported,89 and met the criteria for lung resection. A complete mediastinal lymphadenectomy was performed for all lesions mainly through an axillary thoracotomy approach. For 15 patients, video-assisted thoracic surgery lobectomy was employed. A tracheobronchoplasty was performed in 29 patients in the S group and in 19 patients in the IT group, using a telescoping technique and followed by wrapping with the pericardial fat pad.10

All operations were supervised by attending surgeons (S.T., M.O., and H.M.) and anesthesia was conducted by a chief anesthesiologist (Y.M.), who followed the same management philosophy for each patient. Patients received preoperative epidural anesthesia for pain management, which usually remained in place for 3 to 5 days or until the chest drainage tubes could be removed, after which they were switched to oral analgesia. Other postoperative management included early ambulation, bronchial toilet including bronchoscopy, and low-flow nasal oxygen supplementation, as necessary.

The term extended resection in the present study was defined as a procedure that included a complex lobectomy with bronchoplasty, pulmonary angioplasty, combined resection of adjacent organs, and pneumonectomy. Postoperative complications were divided into the following categories: minor complications (eg, pneumonia with chest radiographic finding requiring antibiotics, hypoxemia, atelectasis, persistent air leak for > 7 days, chyle leak, and cardiac arrhythmia); and major complications (eg, respiratory failure requiring mechanical ventilation, and bronchopleural fistula, empyema, and severe chylothorax requiring reoperation).

The hospital mortality rate included the 30-day mortality rate and the operation-related death rate during the same hospitalization to 6 months after the operation. Data are reported as the mean ± SD or as a proportion. Comparisons of two groups were made using an unpaired t test, and {chi}2 testing was utilized for categoric values. Stratified logistic regression analyses were used to explore the risk factors for operative morbidity and mortality. Variables significantly related to the morbidity and mortality in univariate analyses were considered in a multivariate analysis. Probability values of < 0.05 were considered to be significant (StatView, version 5.0; Abacus Concepts; Berkeley, CA).


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Clinical and pathologic staging of the S and IT groups are detailed in Table 1 . Both clinical and pathologic stages were significantly lower in the S group than in the IT group (Table 1). Detailed operative procedures of the S and IT groups are listed in the Table 1. In the S group, 69 segmentectomies, 530 lobectomies, 40 pneumonectomies, 53 combined resections, and 29 tracheobronchoplasties (24 sleeve lobectomies and 5 carinoplasties) were performed.


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  		Table 1.. Demographic Information for 758 Patients*

 
In the IT group, 1 segmentectomy, 57 lobectomies, 18 pneumonectomies, 37 combined resections, and 19 tracheobronchoplasty (15 sleeve lobectomies and 4 carinoplasties) were performed. An extended surgical resection, including pneumonectomy, combined resection, and tracheobronchoplasty procedures, was more common in the IT group than in the S group (p < 0.0001) [Table 1]. Further patients in the IT group showed significantly lower levels of hemoglobin (Hb) and diffusing capacity of the lung for carbon monoxide (DLCO), longer operating times, and larger amounts of blood loss. No differences were found in gender, age, histologic type, and vital capacity between the two groups.

Univariate and multivariate analyses (Tables 3, 4 ) revealed that IT and extended surgery were strong independent factors for predicting postoperative morbidity, followed by gender. In addition, extended surgery and advanced disease stage were independent factors for predicting mortality, as shown by multivariate logistic analysis (Table 4). We further subdivided the 666 patients who underwent surgery alone and the 92 patients who underwent IT into four groups according to the extent of surgery, as follows: standard lobectomy or lesser resection (group 1; n = 560); extended resection (group 2; n = 106); standard lobectomy after IT (group 3; n = 35); and extended resection with IT (group 4; n = 57). There were statistical differences among each of the four groups except for the comparison between groups 2 and 3 (Table 5 ). With respect to the postoperative morbidity, including life-threatening major complications, the risk of lobectomy after IT was similar to that of an extended operation without IT.


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  		Table 3.. Univariate Analysis of Factors Influencing the Morbidity and Mortality in Lung Cancer Patients (Stepwise Logistic Regression Analysis)*

 

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  		Table 4.. Multivariate Analysis of Factors for Prediction of Morbidity and Mortality in Lung Cancer Patients (Stepwise Logistic Regression Analysis)*

 

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  		Table 5.. Morbidity and Mortality in the Four Groups

 

   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We have demonstrated the impact of extended resection and/or IT on morbidity and mortality with reference to the standard resection performed in patients with controlled comorbidities and fair pulmonary function. In previous reports from North America,11121314 Europe,1516 and Japan,117 which are listed in Table 6 , the overall mortality rate ranged from 0.6 to 6.6%, and the morbidity rate ranged from 17 to 41% for all surgical procedures for lung cancer. The rate of performance of pneumonectomy ranged from 4 to 14%.111121315 Controversies exist as whether IT affects the operative mortality rate.4567181920 In the initial report by Fowler and colleagues,6 the operative mortality rate following IT was 23%, with an operative morbidity rate of 62% due to the higher requirement for extended resections. Martin et al18 reported a 23% operative mortality rate in patients who underwent a right pneumonectomy after IT. In the series by Roberts et al,7 major or life-threatening complications increased by threefold to fourfold in patients who received preoperative chemotherapy, and the results were consistent with those of the current study. On the other hand, Siegenthaler and colleagues19 from the M.D. Anderson Cancer Center reported that preoperative chemotherapy did not increase operative morbidity and mortality; however, they did not include the trimodalities with radiation therapy. Collectively, in reports from five medical centers, mortality rates ranging from 4.3 to 9.0% that were associated with IT were considered to be acceptable.4571920 However, additional risks following IT and extended operation have not been clarified to date, despite the fact that both IT and extended surgery were independent factors for predicting morbidity.


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  		Table 6.. Studies of Overall Operative Morbidity and Mortality*

 
Although operative risks have been considered from the viewpoint of patient comorbidity and pulmonary functional reserve,14151621 there were few analyses based on the surgical procedure-related factors and IT. We think that anesthesiologists should consider the impact of IT and its association with extended resection in perioperative care, including recognition of the decrease in Hb and DLCO, to prevent complications.

It has been well documented that pneumonectomy and complex lobectomy with bronchoplasty and/or combined resection of the adjacent organs would increase operative morbidity and mortality.222324 The operative mortality rate associated with a bronchoplastic procedure was 7.5% in the collective series reported Tedder et al,22 and it ranged from 6 to 10% for patients undergoing chest wall resection.2324 Later, Izbicki et al25 called all of those procedures extended resection, for which the mortality rate ranged from 7 to 10%, and the morbidity rate ranged from 50 to 70%. Our results on multivariate analyses (Table 4) revealed that both IT and extended surgery were strong independent factors for predicting postoperative morbidity. Taken together, operative indications for advanced NSCLC that require IT and/or an extended resection should be considered based on these risks. For this purpose, we categorized the related procedures into the following four groups to reflect postoperative morbidity and mortality: standard lobectomy with lymphadenectomy (group I); extended resection without IT (group II); standard lobectomy after IT (group III); and extended resection with IT (group IV). IT caused a threefold increase in morbidity and a sevenfold increase in mortality in the present patients who received a standard lobectomy. As for extended operations, IT increased both morbidity and mortality twofold (Table 5). From our results, we stratified the operative morbidity and mortality associated with IT and/or an extended operation. Our institutional experience had a strong impact on the results, as the current analysis was performed in a single medical center in which 530 consecutive standard lobectomies had been performed without death within 30 days (in-hospital mortality rate, 0.4%).

To improve operative results, we critically assessed the pulmonary functional reserve according to our criteria89 and estimated the risk as well as meticulous postoperative care with reference to respiratory muscle function.26 The contention by Siegenthaler and colleagues19 that chemotherapy does not increase operative mortality was based on analysis with a small percentage of extended operation as well as the exclusion of patients who had undergone chemoradiotherapy. In contrast, the current series encompassed a large percentage of patients who had undergone extended resections or pneumonectomies in the IT group as well as control patients.

As a preoperative evaluation of the risk factors, it should be considered in particular that chemoradiotherapy induced a decrease in DLCO, a marker of gas exchange, by 20 to 30%.27 In the current series, life-threatening pulmonary complications occurred more commonly in the IT group, and two patients died of ARDS in the early postoperative period. One explanation is that complications were associated with a decrease in DLCO as well as a limited pulmonary vascular and lymphatic system reserve, which may be due to potential radiation and/or chemotherapy-induced pneumonitis.28 Intensive care should be directed to these patients, including the early use of catecholamine agents, pulmonary vasodilators, as well as strict fluid replacement to prevent cardiopulmonary complications. Thus, in patients who have received IT who have borderline vital capacity and DLCO percentage of predicted values after undergoing pulmonary resection, extended resections should not be preferred. In addition, the restaging of patients after they have received IT to select those who will potentially obtain a survival benefit is an important issue.

Both the morbidity and mortality of lung resection are significantly increased after IT, and the patients who are at greatest risk are those who have undergone IT and extended resection. It is concluded that the impact of IT, with or without extended resection, on morbidity and mortality should be emphasized in risk assessment and perioperative care.


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  		Table 2.. Detailed Description and Classification of Complications*

 

   Acknowledgements
 
The authors thank Dr. Hajime Maeda, Dr. Noriyoshi Sawabata, and Dr. Mitsunori Ohta, attending thoracic surgeons, for contribution to this project and for critical review of the manuscript.


   Footnotes
 
Abbreviations: DLCO = diffusing capacity of the lung for carbon monoxide; Hb = hemoglobin; IT = induction therapy; NSCLC = non-small cell lung cancer

Received for publication March 6, 2005. Accepted for publication June 16, 2005.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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