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Ann Thorac Surg 2005;80:1021-1026
© 2005 The Society of Thoracic Surgeons

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Original article: General thoracic

Proper Treatment Selection May Improve Survival in Patients With Clinical Early-Stage Nonsmall Cell Lung Cancer

^a Department of Cardiothoracic Surgery, Erasmus MC Rotterdam, Rotterdam, the Netherlands
^b Department of Pulmonology, Erasmus MC Rotterdam, Rotterdam, the Netherlands

Accepted for publication March 18, 2005.

^_* Address reprint requests to Dr Kappetein, Department of Cardiothoracic Surgery, Room BD 156, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, the Netherlands (Email: a.kappetein{at}erasmusmc.nl).

	Abstract

Top Abstract Introduction Material and Methods Results Comment References

 
BACKGROUND: In patients with early-stage nonsmall cell lung cancer treatment selection is rarely assessed. Many surgical papers report only the outcome of patients who underwent surgery although selection may influence the outcome. In this report, treatment selection and the outcome of both surgically and nonsurgically treated patients is evaluated.

METHODS: Three hundred sixty patients (269 surgically treated and 91 nonsurgically treated) with clinical stage I and II were included. Risk factors were scaled according to the Charlson comorbidity index (CCI). Hospital morbidity and long-term survival were evaluated.

RESULTS: Mean age was 64 years for the surgical and 74 for the nonsurgical patients. Mean CCI score was 1.3 and 2.4, and 5-year survival was 47% and 3%, respectively. Male sex, pneumonectomy, and CCI score of 3 or more were predictive for major postoperative complications. For the nonsurgical patients receiving radiotherapy, the 2-year survival was 40%; for the patients receiving no radiotherapy, 2-year survival was 5%. Male sex, age, treatment, and clinical stage were prognostic for survival. Patients with a CCI score of 3 or more showed a better survival after surgery than after radiotherapy. Patients with a CCI score of 3 or more who were surgically treated had a higher prevalence of forced expiratory volume in 1 second of 70% or more compared with the patients receiving radiotherapy.

CONCLUSIONS: Patients with a CCI score of 3 or more have an increased risk of major postoperative complications. Nevertheless, patients with a CCI score of 3 or more show a better survival after surgery than after radiotherapy. For patients with significant comorbidity but with sufficient pulmonary reserve, surgery offers the best outcome. For patients with a high CCI score and insufficient pulmonary reserve or for those who refuse surgery curative, radiotherapy is a good alternative.

	Introduction

Top Abstract Introduction Material and Methods Results Comment References

 
For patients with stage I and II nonsmall cell lung cancer (NSCLC), surgical resection is usually regarded as the treatment of choice. The most frequent reasons for denying surgery in these patients are associated comorbidity, patient refusal to undergo surgery, or advanced age. The presence of severe comorbidity in NSCLC patients is increasing owing to the increase of lung cancer incidence among the elderly as a consequence of increased life expectancy. Careful selection of candidates suitable for curative surgery is the key issue for optimal treatment. For patients with severe comorbidity who are inoperable, radiotherapy is frequently regarded as the treatment of choice [1]. However, owing to improvements in surgical techniques and postoperative care, patients with severe comorbid disease might nowadays do better after surgery than after radiotherapy. It is very unlikely that this question will ever be answered in a prospective randomized clinical trial.

In the surgical literature, usually only cohorts of patients who underwent surgery are presented although selection of patients may influence the outcomes. In this regard, treatment selection of patients with stage I and II disease is of utmost importance. Therefore, the purposes of the present study were as follows: (1) to retrospectively assess treatment selection in clinical stage I and II (T1-2, N0-1, M0) NSCLC patients, and (2) to evaluate whether the survival of patients with clinical stage I or II NSCLC who underwent surgery was superior to that of patients who did not undergo surgery.

	Material and Methods

Top Abstract Introduction Material and Methods Results Comment References

 
From the database of the Rotterdam Cancer Registry, a consecutive series of patients with clinical stage I and II (T1-2, N0-1, M0) NSCLC diagnosed or suspected between January 1, 1989, and December 31, 2001, was provided. All these patients were treated at the Erasmus MC Rotterdam. The medical records of surgically and nonsurgically treated patients were reviewed. Patients were followed up with regular visits to the outpatient clinic. Civil administrations provided the date of death. Follow-up was completed in all patients through July 2003. Survival time was defined as the difference between date of diagnosis and date of last follow-up or date of death.

For all cases, diagnostic workup included a complete medical history, physical examination, plain chest radiography, electrocardiography, routine laboratory tests, lung function tests (pretreatment forced expiratory volume in 1 second [FEV₁%] was unknown in 29 patients), and computed tomography of the chest and upper abdomen. Additional staging procedures, namely, bronchoscopy, mediastinoscopy, and liver, bone and brain scans, were selectively performed to aid in treatment planning according to best clinical practice at the time of presentation. Pathologic lymph node staging of the surgically treated patients was based on lymph node assessment by preoperative mediastinoscopy or surgical sampling of bronchopulmonary, hilar and mediastinal lymph nodes, or both.

Histologic typing was done according to the World Health Organization histologic typing of lung tumors [2]. The histologic or cytologic diagnosis of the nonsurgically treated patients was achieved by fiberoptic bronchoscopy or percutaneous transthoracic needle biopsies. The histologic or cytologic diagnosis was unknown in 17 nonsurgically treated patients, but in all cases the probability of NSCLC was high according to medical history and the presentation on computed tomography.

The clinical stage was determined according to the international TNM classification for lung cancer [3]. Most of the nonsurgically treated patients did not undergo mediastinoscopy and their staging was based on computed tomography findings only (negative lymph nodes if mediastinal lymph nodes were 10 mm in short-axis diameter).

For the surgically treated patients, the length of hospital stay was calculated as the difference between date of surgery and date of discharge. Complications were classified as minor (nonlife-threatening: air leak lasting more than 5 days, supraventricular arrhythmia, atelectasis, transfusion, infection, paresis of the recurrent nerve), and major (life-threatening: empyema, pneumonia, pleural effusion needing pleural drainage, bronchopleural fistula, ventilatory support for more than 72 hours, cerebrovascular accident, transient ischemic attack, renal failure, ventricular arrhythmia, pulmonary embolism, rethoracotomy, acute respiratory distress syndrome, myocardial infarction or failure). Patients with both minor and major complications were coded as having major complications only, although the nature of the minor complication was also recorded. Hospital mortality was defined as death occurring within 30 days after surgery or any death later in the same postoperative hospital stay.

Comorbidity Evaluation
Comorbidity was scored according to the Charlson comorbidity index (CCI) [4]. The CCI consists of the sum of the weighted scores based on the relative mortality risk of 19 conditions that significantly influence survival. The index can be divided into four comorbidity grades: 0, 1 to 2, 3 to 4, and 5 or more. Because cardiac disease is associated with a higher risk of operation in patients with lung cancer [5–7], we modified the CCI by scoring all forms of coronary artery disease (myocardial infarction, angina, coronary artery bypass graft, and percutaneous transluminal coronary angioplasty) with a value of 1 [8, 9]. Patients were considered to have a comorbid condition if one of the diseases mentioned in the CCI was present in the records or if the patient was treated for it.

Statistical Analysis
The ² or Fisher exact test was used to analyze the categorical data. Continuous variables were analyzed using the Student t test. Univariate and multivariate logistic regression analysis was used to discriminate independent risk factors for major complications. Survival curves were estimated by the Kaplan-Meier method. The log-rank test was used to compare survival curves. Univariate and multivariate Cox proportional hazard analysis determined risk factors for survival. Both the logistic and Cox proportional multivariate analyses were performed with a stepwise backward regression model in which each variable with a p value of less than 0.20 in the univariate analysis was entered in the model. A p value of less than 0.05 was considered significant.

	Results

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Patients
Three hundred and seventy-three patients with clinical stage I or II (T1-2, N0-1, M0) NSCLC were retrieved from the database of the Rotterdam Cancer Registry. No additional data were available in 13 patients who were excluded from further analysis. A total of 360 patients were analyzed, of whom 269 (75%) were treated surgically and 91 (25%) nonsurgically. The study group consisted of 286 male patients (79%) and 74 female patients (21%). The mean age at diagnosis was 66 years (range, 37 to 90) and the median follow-up time was 2.7 years.

Surgically Treated Patients
Of the 269 surgically treated patients, 208 (77%) were men and 61 (23%) were women. The mean age at time of diagnosis was 64 years (range, 37 to 82). The patient characteristics are described in Table 1. The CCI and the comorbid conditions are presented in Table 2, and the distribution of the CCI score in Table 3. The mean CCI score was 1.3 (range, 0 to 6). The operations performed were wedge resection (10), lobectomy (157), bilobectomy (26), pneumonectomy (67), and explorative thoracotomy (9). Ten patients received neoadjuvant chemotherapy. Surgical-pathologic upstaging was observed in 81 (30%) of the patients. Because of positive mediastinal lymph nodes or invasion of extraparenchymal tissue, adjuvant chemotherapy was administered to 3 and radiotherapy to 30 patients.

View larger version (11K): [in this window] [in a new window]   Fig 1. Survival rates for surgically and nonsurgically treated patients with clinical early-stage nonsmall cell lung cancer.

View larger version (10K): [in this window] [in a new window]   Fig 2. Survival rates for patients with a Charlson comorbidity index score of 3 or more, treated surgically or with radiotherapy.

One-, 2-, and 5-year overall survival of the nonsurgical group was 46%, 21%, and 3%, respectively (Fig 1). The 1-, 2-, and 5-year survival of patients receiving radiotherapy was 68%, 40%, and 8%; and that of the patients receiving no radiotherapy was 29%, 5%, and 0% (Fig 3). Survival of patients who received radiotherapy was significantly (p < 0.0001) higher compared with patients receiving no radiotherapy. Survival for the 18 patients with a CCI score of 3 or more who received radiotherapy was 67%, 33%, and 6% after 1, 2, and 5 years, respectively (Fig 2).

View larger version (15K): [in this window] [in a new window]   Fig 3. Survival rates for surgically treated patients, patients receiving radiotherapy, and the remaining patients with clinical early-stage nonsmall cell lung cancer.

Assessment of the prognostic factors for survival in the total population, using the univariate Cox proportional hazard analysis, revealed that male sex, age over 70 years, a pretreatment FEV₁% less than 70, nonsurgical treatment, any prior tumor within 5 years of diagnosis, chronic pulmonary disease, CCI grades 3 to 4 and 5 or more, and clinical stages IB, IIA, and IIB, were significant negative risk factors for survival (Table 4). Multivariate analysis showed that male sex (odds ratio, 1.8; 95% CI: 1.2 to 1.9), age over 70 years (odds ratio, 1.3; 95% CI: 1.0 to 1.8), nonsurgical treatment (odds ratio, 3.4; 95% CI: 2.3 to 5.0), and clinical stages IB (odds ratio, 1.4; 95% CI: 1.0 to 1.9), IIA (odds ratio, 3.2; 95% CI: 1.5 to 7.2), and IIB (odds ratio, 2.6; 95% CI: 1.4 to 4.6) were independent negative risk factors for survival (Table 4). The prognostic effects of CCI, FEV₁%, any prior tumor within 5 years of diagnosis, and chronic pulmonary disease disappeared in the multivariate analysis.

	Comment

Top Abstract Introduction Material and Methods Results Comment References

 
Currently, surgery and complete removal of the primary tumor and its involved lymph nodes is the gold standard of treatment in early stages of NSCLC. The careful selection of patients for surgery is a very important factor in all circumstances, and is particularly important among elderly patients. A subset of early-stage NSCLC patients will require a viable alternative to surgery because they are either unwilling to undergo surgery or are considered inoperable.

In this study, there was an important survival difference of 44% at 5 years between the surgically and nonsurgically treated patients in favor of the surgically treated patients. Treatment selection was obviously based on the presence of severe comorbidity and pulmonary function. In the univariate analysis surgery, CCI score of 3 or more, and FEV₁% of less than 70 were associated with poor survival. However, in the multivariate analysis, surgery proved to be significant and the prognostic effects of the CCI score of 3 or more and FEV₁% of less than 70 disappeared. This underlines that we predominantly selected patients for surgery on comorbidity score and pulmonary function and not on other factors, such as clinical stage, sex, or age.

In the high-risk patient, radiotherapy is frequently regarded as the treatment of choice. For patients with early-stage NSCLC who refuse surgery or who are considered inoperable, curative radiotherapy results in a 5-year survival rate ranging from 5% to 30% [10, 11]. This is supported by our data, which showed an 8% 5-year survival for patients who received radiotherapy.

With current surgical techniques, experience, and improved postoperative care, patients with a high comorbidity rate can be operated upon. Despite a higher rate of major postoperative complications in patients with a high comorbidity rate (CCI score of 3 or more) as shown in this study and others [8, 9], these patients have a higher 5-year survival than patients receiving radiotherapy (36% versus 6%). Patients with a high comorbidity rate who were operated on had a higher mean FEV₁% compared with patients receiving curative radiotherapy. This indicates that for patients with significant comorbidity but with a sufficient pulmonary reserve, surgical resection offers the best outcome.

The morbidity and mortality after pulmonary resection for NSCLC are significant [8, 9, 12, 13], with arrhythmia (23%) and air leak lasting more than 5 days (22%) occurring as the most frequent complications. It is well known that pneumonectomy, especially right-sided pneumonectomy, is associated with higher incidence of complications when compared with limited resections [14, 15]. In our multivariate analysis, male sex, pneumonectomy, and the CCI were the determinants associated with an increased risk of major postoperative complications.

The limitations of this study were that it is retrospective in design, the nonsurgically treated patients were less rigorously staged, and complete data on these patients were not always available. The FEV₁% was not available for 17 surgically treated patients and 12 nonsurgically treated patients. Histology was not determined for 17 nonsurgically treated patients. This reflects clinical practice, in which sometimes clinical suspicion of NSCLC is high and patients are treated accordingly. Additionally, information on posttreatment morbidity and treatment-related toxicity in the nonsurgically treated group is lacking.

The presence of significant comorbidity is an important prognostic factor in early-stage NSCLC. This study illustrates that patients with severe comorbidity are generally treated nonsurgically especially when the comorbidity include impaired pulmonary function. If patients with high comorbidity are treated surgically, they have an increased risk of major postoperative complications. Nevertheless, these patients have a better survival compared with radiotherapy. In patients with high comorbidity but with sufficient pulmonary reserve, surgical resection offers the best outcome. For patients with high comorbidity and insufficient pulmonary reserve or for those who refuse surgery, curative radiotherapy is a good alternative.

	References

Top Abstract Introduction Material and Methods Results Comment References

 

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