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Ann Thorac Surg 2000;70:1168-1171
© 2000 The Society of Thoracic Surgeons

Original articles: general thoracic

Prognostic factors in patients with surgically resected stages I and II non-small cell lung cancer

Abdul R. Jazieh, MDa, Mohammad Hussain, MDa, John A. Howington, MDb, H.J. Spencer, MSa, Muhammad Husain, MDc, Jerome T. Grismer, MDd, Raymond C. Read, MDd

a Divisions of Hematology, University of Arkansas of Medical Sciences, Little Rock, Arkansas, USA
b Oncology and Thoracic Surgery, University of arkansas for Medical Sciences, Little Rock, Arkansas, USA
c Department of Pathology, University of Arkansas for Medical Sciences, Central Arkansas Veterans Health Care System, Little Rock, Arkansas, USA
d Division of Thoracic Surgery, Central Arkansas Veterans Health Care System, Little Rock, Arkansas, USA

Address reprint requests to Dr Jazieh, Division of Hematology and Oncology, University of Arkansas for Medical Sciences, 4301 West Markham, Slot 508, Little Rock, AR 72205
e-mail: jaziehabdulr{at}exchange.uams.edu


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Background. About one-third to one-half of patients with early stages of non-small cell lung cancer (NSCLC) succumb to their disease. In this study, we attempted to identify prognostic factors that predict outcome in patients with stages I and II NSCLC.

Methods. A retrospective evaluation of 454 patients with surgically resected stages I and II NSCLC was performed to determine the impact of various clinical, laboratory, and pathological factors on patient outcome such as overall survival (OS) and event-free survival (EFS).

Results. Patients older than 65 years had shorter EFS and OS than younger patients (p = 0.002). Patients with preoperative hemoglobin less than or equal to 10 g% had shorter EFS and OS compared to patients with a hemoglobin greater than 10 g% (p = 0.001). Expectedly, OS and EFS were shorter in patients with stage II as compared to stage I patients (p < 0.001). In a multivariate analysis, age, hemoglobin level, and stage remain significant predictors for EFS and OS.

Conclusions. Older age, anemia, and higher stage are important prognostic factors in patients with surgically resected stage I and II NSCLC.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
More than 171,000 Americans will be diagnosed with lung cancer in 1999 and over 158,000 persons will succumb to that disease in the same year [1]. A low 5-year survival of less than 15% combined with high incidence make lung cancer the leading cause of cancer deaths in the United States. Different therapeutic modalities are used in the management of lung cancer depending on the tumor stage and the clinical status of the patients.

Surgical resection remains the mainstay therapeutic modality for early stages of non-small cell lung cancer, especially stages I and II. However, one-third to one-half of these patients die within 5 years of diagnosis [2–5]. In order to improve the outcome of patients with early stages of the disease, patients with high risk for relapse should be identified in order to consider adjuvant treatment following surgery. Multiple factors were reported to bear prognostic implications [6, 7]. These prognostic factors can be categorized into clinical factors, tumor-related factors, and treatment-related factors. Clinical factors include, for example, the presenting signs and symptoms such as weight loss and performance status [8–11]. Tumor-related factors encompass numerous features that reflect the behavior and biology of the tumor. These include histologic subtype and degree of differentiation, stage (which involves the tumor size and lymph node status), blood vessel invasions, tumor margins, angiogenesis, and the expression of certain tumor suppressor genes and oncogenes [6, 12]. Treatment-related factors include the type of surgery performed and the experience of the surgeon [13].

In spite of many reports about prognostic factors in lung cancer, a great deal of inconsistency in the findings of these studies makes it difficult for practitioners to adopt factors to help guide management of non-small cell lung cancer. This article reports the value of various prognostic factors in predicting the outcome of patients with stages I and II non-small cell lung cancer treated with surgical resection alone without additional therapy.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
Patient selection
This study included all patients with stages I and II non-small cell lung cancer who underwent surgical resection between 1991 to 1998. Patients who received adjuvant chemotherapy or radiotherapy were excluded from the review. A total of 454 patients were included in this analysis. These patients were treated at both the University Hospital as well as the Veterans Administration Hospital.

Study design
Data was collected by a retrospective review of the medical records, tumor registry records, pathology reports and slides, and radiology reports. The data collected included patient characteristics, such as age, race, and sex; date of diagnosis; tumor site; date and type of surgery; date of relapse or recurrence; type of relapse; and date and cause of death. Other data collected related to the tumor include histologic subtype and grade, tumor margins, tumor size, number of lymph nodes sampled, number of positive lymph nodes, and pathologic TNM staging. Laboratory data such as hemoglobin and albumin as well as a forced expired volume in the first second (FEV1) were also included.

Statistical analysis
Patient demographics and medical characteristics were summarized using descriptive statistics, ie, percentages, medians, and ranges. Event-free (EFS) and overall survival (OS) estimates for each factor were obtained using Kaplan-Meier (product-limit) methodology, and survival distributions were compared using log-rank tests. Factors found to be significantly associated with outcome were included in a Cox proportional hazards model. For all analyses, p values less than or equal to 0.05 were considered to be statistically meaningful. All analyses were performed using SAS/STAT software, Version 7 (SAS Institute Inc, Cary, NC).


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
Four hundred and fifty-four patients were included in this study. The median age of these patients was 67 years (39 to 83), 90% were males (which was a result of the larger proportion of the Veterans Administration patients), and 89% of them were white. Median follow-up was 28 months (1 to 109). Patients’ characteristics are listed in Table 1.


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  		Table 1. Patient Characteristics

 
Patients older than 65 years had shorter EFS compared to younger patients (34 versus 55 months, p = 0.002). Overall survival was also shorter in patients older than 65 years as compared to the younger group (39 versus 58 months, respectively, p = 0.002) (Fig 1).



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  		Fig 1. Kaplan-Meier survival curves for patients > 65 years versus <= 65 years.

 
Preoperative hemoglobin of 10 g% or less also predicted worse outcome with EFS of 18 versus 45 months for those who had a hemoglobin more than 10 g% (p < 0.001) and OS of 25 versus 52 months, respectively (p < 0.001) (Fig 2). As expected, the stage of the disease did predict for outcome (Fig 3). The median EFS for stages I and II were 53 and 27 months, respectively (p < 0.001) and the OS was 44 and 22 months, respectively (p < 0.001).



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  		Fig 2. Kaplan-Meier survival curves for patients with hemoglobin <= 10 g% versus patients with hemoglobin > 10 g%.

 


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  		Fig 3. Kaplan-Meier survival curves for patients with stage I versus stage II.

 
A multivariate analysis was performed including age, race, gender, stage, hemoglobin, histology, and type of surgical resection. Hemoglobin, age, and stage remained significant predictors for both EFS and OS (Table 2). Race and gender did not impact patients’ outcome nor did the preoperative FEV1 and albumin. Furthermore, the tumor location did not have any prognostic indicator nor was the type of surgery performed a significant factor in the outcome of this group. There was no difference in survival between those who had wedge resection, segmentectomy, lobectomy, or pneumonectomy in terms of disease-free survival or overall survival.


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  		Table 2. Results of Cox Proportional Hazards Model for Event-free and Overall Survival

 
There was no significant difference in performing wedge resection or segmentectomy in patients older than 65 years and younger patients, nor between patients with hemoglobin greater than 10 g% and those with less hemoglobin. Patients with tumor size greater than 3 cm were less likely to have wedge resection or segmentectomy than those with smaller size tumors (23% versus 52%, p < 0.01). However, the type of operation did not impact the survival of these patients.

The tumor histology evaluation did not reveal any difference in survival between the different histologic types. In addition, the histologic grades did not impact outcome.


   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
Identifying prognostic factors in non-small cell lung cancer has been the focus of many investigators in order to improve the outcome of these patients and properly understand the biology of this malignancy. Because of the heterogeneity of this disease and the variation in the surgical interventions and expertise as well as the patient’s characteristics, these prognostic factors vary from one study to another. Factors proven to be significant in predicting for outcome in one study may not be reproduced in another study. However, these prognostic factors can be classified into three categories as mentioned earlier. These categories are: (1) factors related to clinical status of the patient, (2) factors related to the tumor; and (3) factors related to the treatment.

In our study, factors related to the clinical status of the patients included age, race, gender, hemoglobin, albumin, and FEV1. Patient’s age predicted for outcome since patients older than 65 years did worse than younger patients. This finding is consistent with another study revealing a significant prognostic implication for ages older than 70 years among 272 patients with resected stage I lung cancer [14]. However, our study included stage II patients and used the age of 65 years as a cut-off point. Performance status is one of the best clinical predictors for outcome in lung cancer patients [8–10]. However, performance status was not available in this study, therefore, evaluation of other variables such as hemoglobin and albumin level was attempted in order to identify a measurable surrogate marker for the general condition of the patient. Patients with hemoglobin higher than 10 g% fare better than those with lower hemoglobin levels. Although anemia was reported to impact outcome in lung cancer patients receiving chemotherapy or radiation therapy [15, 16], its impact on the outcome of patients with early lung cancer has not been reported. Albumin level did not reveal any significant prognostic implication in this study. Albumin level of 3 g% was used as the cut-off number, since only a few patients had a serum albumin less than 2.5 g%.

Among tumor-related factors, only stage provided a significant prediction for outcome in our patients population, while the histologic type and histologic grade did not have prognostic implication. A few studies have reported significant prognostic value to histologic types [3, 17–21]. However, other studies did not find prognostic implications for histology [5, 11, 22]. In addition, tumor differentiation was found to predict survival by several investigators [11, 23, 24]. Evaluating the impact of the extent of surgery revealed similar outcome of patients who had wedge resection, segmentectomy, lobectomy, or pneumonectomy. A few authors reported worse outcome with lesser surgery [25–27]. However, our results are consistent with other reports, which found limited resection produces similar outcome to larger surgery [14, 22] especially for tumors less than 3 cm [28]. These results should not imply that surgeons should perform lesser surgery on all patients. However, these finding should encourage physicians to consider performing limited operations on patients with poor pulmonary reserve. This approach may provide curative treatment when performed on patients with pulmonary function tests that suggest that they are not candidates for resection of a larger portion of their lungs.

The duration of follow-up may be short, and longer follow-up is warranted to evaluate the impact of different factors on outcome. Finally, prospective studies are needed to better determine the importance of various prognostic factors.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
The authors are indebted to Ian Cawich and Pat Coke for their help in data collection and Dr Tamim Antakli for critical review of the manuscript.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

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Accepted for publication March 29, 2000.




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