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Ann Thorac Surg 1995;60:466-472
© 1995 The Society of Thoracic Surgeons

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Current Reviews

Survival in Early-Stage Non—Small Cell Lung Cancer

Department of Thoracic and Cardiovascular Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

	Abstract

Top Footnotes Abstract Introduction Overall Survival Other Prognostic Factors Molecular and Biological Markers Summary References

 
The duration of survival in early-stage lung cancer (stages I and II) varies between reports in the literature. Several reasons account for this: patient population heterogeneity, inconsistent staging, anatomic variability, dissimilar tumor morphology, and unpredictable tumor biology. This report addresses some of the issues in early-stage non-small cell lung cancer that relate to variability between estimates of survival in end stage reporting. We review several large series since the introduction of the International Staging System in 1986 and other selected, contemporary reports that address end results in patients with pathologic stage I or stage II lung cancer. Overall survival for patients with pathologic stage I disease is 64.6% (range, 55% to 72%) and 41.2% for patients with stage II disease (range, 29% to 51%). Reducing morphologic differences by placing patients in groups based on the TNM subset and refinement in categorization by matching TNM subsets based on histology and other factors can improve considerably homogeneity and enhance prognostic predictability. The development of more accurate measures for predicting prognosis may serve to clarify the roles of primary and adjuvant treatment, particularly in those patients with early-stage disease associated with poor prognostic factors in whom the potential for long-term survival is reduced.

	Introduction

Top Footnotes Abstract Introduction Overall Survival Other Prognostic Factors Molecular and Biological Markers Summary References

 
Th is year almost 170,000 Americans will be diagnosed with lung cancer [1]. Fewer than 25% of these patients will present with early-stage disease (stage I or stage II); they have the greatest hope for cure. Within this group, the duration of survival varies, depending on the biology of the disease and its extent at the time of diagnosis. The extent of disease, or stage, is defined by the International Staging System (ISS) [2]. Developed within the guidelines of the American Joint Committee on Cancer and the International Union Against Cancer, the ISS was based on the careful analysis of several thousand patients and gained international acceptance in 1986. It recognized the existence of the heterogeneity not only among subsets of each stage but also within the subsets. It sought to reduce this heterogeneity by selecting patients with similar survival patterns based on anatomic and morphologic criteria, permitting a structured, organized method for grouping patients with analogous disease characteristics for prognostic, therapeutic, and research purposes.

In the literature, the duration of survival in stage I and stage II non-small cell lung cancer (NSCLC) varies. Several factors may account for this. The characteristics of the patient population, the relative proportion of patients in each subset within the stages, selection of patients for operation (criteria), sophistication of the staging process, and length of follow-up all have a significant bearing on the end result and in fact, may be the most important factors in the reported differences in survival. Moreover, end results may be related to the lymph node mapping procedure used and to the type of map, the American Joint Committee on Cancer/Japanese Lung Cancer Society map developed by Naruke or the American Thoracic Society map later revised by the Lung Cancer Study Group of North America (LCSG). Series of patients in whom lymph node sampling or dissection is not complete will have a demonstrably lower surgical survival rate due to errors in assigning nodal stage (ie, N0, N1). Surgeons using the American Thoracic Society/LCSG staging map will cite a level 10 node as N2, whereas those using the American Joint Committee on Cancer/Japanese Lung Cancer Society map will cite a level 10 lymph node as N1. Clearly such differences affect comparison of reported survival rates among series.

To summarize patient survival within each stage, we have reviewed several large series since the introduction of the ISS in 1986 and other selected, contemporary reports that address end results in patients with pathologic stage I or stage II lung cancer. Most of the information comprises retrospective analyses showing varied and, at times, conflicting results. Recognizing these reported differences and the heterogeneity of the patient population, we have gathered the information collectively by stage and by subsets. This review focuses on some of the issues in stage I and stage II disease that relate to variability between estimates of survival in end result reporting. Although anatomic and morphologic classification remains a fundamental method of proven validity, it is recognized that intrastage and intrasubset heterogeneity does exist. Numerous recent studies report a variety of biological and molecular markers that appear to correlate with survival. If any of these can be developed for reliable and practical clinical application, they will serve as powerful tools to identify more homogeneous subsets of the lung cancer population and could be incorporated into a more sophisticated staging system.

	Overall Survival

Top Footnotes Abstract Introduction Overall Survival Other Prognostic Factors Molecular and Biological Markers Summary References

 
The average 5-year survival rates for the reviewed series of patients with NSCLC are approximately 64.6% for 3,987 patients with stage I disease (range, 55% to 72%) (Table 1) and 41.2% for 1,384 patients with stage II disease (range, 29% to 51%) (Table 2). All patients were staged surgically.

Survival rate differences can be reduced by analyzing the factors that enhance uniformity within a group. Reducing morphologic differences by placing patients in groups based on the TNM subset and further refinement in categorization by bracketing TNM subsets based on histology and other factors can considerably improve homogeneity, albeit at the expense of small groups that may have insufficient numbers for analysis. Yet statistically comparable, homogeneous sets of patients provide the most accurate information. Recognition and identification of the various factors that affect survival in each stage of disease are important in understanding the relative differences between patient sets and between series in the literature.

Stage I
Stage I disease comprises the T1 N0 and T2 N0 subsets. When the subsets are analyzed separately, the overall 5-year survival rates range from 68.5% to 83% for patients with T1 N0 tumors and from 53.8% to 65% for patients with T2 N0 disease (Table 3) [2, 5, 6]. The median survival period for all patients with T1 N0 NSCLC is approximately 8 years [7]. The factors that affect survival at this stage include histologic type, T status, tumor size, and presence of visceral pleural invasion.

The T status alone consistently influences survival duration. Patients with T1 tumors have an overall 5-year survival advantage of 15% to 20% over those with T2 tumors [3, 15, 18, 19, 21]. Tumor size, irrespective of the other factors that determine T status, also appears to affect survival duration. Several authors have reported longer survival for patients with small tumors than for those with large tumors [17, 22–25]. Watanabe and co-workers [21] found that patients having tumors larger than 5 cm in diameter had a significantly worse prognosis than those having tumors less than 5 cm.

The T2 descriptor includes tumors of any size that involve the visceral pleura. Reviews have not addressed this issue consistently, but an interesting observation regarding visceral pleural invasion has been made by Merlier and associates [26] and by Brewer [27]. The rate of early survival was lower in patients with ``subpleural'' or visceral pleural involvement than in other groups, although the criteria used to select and identify tumor stages were not specifically defined. A more recent analysis by Inchonise and colleagues [20] of patients with stage I tumors showed that the absence or presence of exposed tumor on the pleura had prognostic significance. It is suspected that tumors extending through the pulmonary parenchymal envelope may seed the pleural cavity and use this route for systemic spread, shortening the survival period.

Naruke and co-workers [5] identified a subset of patients who had tumors that were confined to the bronchial mucosa yet resided within 2 cm of the carina and had no associated lymph node metastases. They showed that these patients had a 5-year survival rate of more than 80%. Watanabe and co-workers [28] also showed an excellent rate of survival in their cohort of patients with such early lesions. Accordingly, such lesions have been classified as T1 N0 tumors by the ISS.

Satellite lesions are separate, accessory foci of histologically identical tumor that are present in association with, but clearly separated from, the primary tumor [29]. Deslauriers and associates [29] have shown that patients with stage I tumors associated with satellite lesions have significantly lower 5-year survival rates than those without satellite lesions (32% versus 54.4%). Watanabe and co-workers [21] also identified the poor prognostic implication of satellite lesions, noting survival rates similar to those of patients with stage IIIA disease. Deslauriers and associates [29] and Mountain [30] believe that satellite tumors represent intrapulmonary metastases, suggestive of more aggressive disease. In consideration of the poor prognostic implication of satellite tumors, they have specifically recommended that the T status of these tumors be upgraded at least one level.

Stage II
Stage II NSCLC includes the T1 N1 and T2 N1 subsets. When the subsets are considered separately, the cumulative 5-year survival rates range from 40% to 63% for patients with T1 N1 tumors and from 38% to 45% for those with T2 N1 tumors (Table 4) [2, 5, 6, 31]. The Ludwig Cancer Study Group has reported median survival periods of 4.8 years and 2.3 years for patients with T1 N1 and T2 N1 disease, respectively [32]. The factors that may affect survival duration include histologic type, T status, tumor size, visceral pleural involvement, and the number of involved lymph nodes.

Several reports address the impact of T status and tumor size on survival in stage II patients. Yano [33] and Maggi [34] and their co-workers found no significant effect by these factors in their reviews. But Naruke and co-workers showed that the mean 5-year survival rate of patients with T1 tumors is approximately 15% higher than that of patients with T2 tumors (53% versus 38%) [35]. In addition, Martini and co-workers [31] showed that patients with tumors less than 3 cm in size have a mean 5-year survival rate of 47%, whereas those with tumors greater than 5 cm in size have a mean 5-year survival rate of 29%.

Satellite tumors probably represent intraparenchymal metastases, signifying less prognostically favorable disease than other stage II tumors. In Deslauriers' series [29] of patients with T1 N1 or T2 N1 tumors and associated satellite tumors, the mean 5-year survival rate was only 12.5%. Clearly this group of patients should be considered to have a more severe malignancy than others with early-stage disease; the reduced survival rate approximates that of stage III disease (9% to 15%) [35]. Although satellite lesions are not addressed in the TNM categories of the ISS, again, as stated earlier, both Mountain [30] and Deslauriers and colleagues [29] have recommended upgrading the T status at least one level for patients with these tumors.

As in stage I disease, visceral pleural invasion may have a negative impact on survival duration in patients with stage II disease. Furthermore, tumor size in association with visceral pleural involvement may be an important determinant of survival duration. One review showed a worse prognosis for patients with stage II tumors that invade the visceral pleura and are greater than 5 cm in size, with a mean 5-year survival rate of 25% [31].

Stage II indicates locally resectable metastatic disease in hilar lymph nodes or other intrapulmonary lymph nodes. Martini and co-workers [31] have shown that the overall rate of survival is affected not only by the presence of N1 disease but also by the number of involved N1 nodes. The difference in 5-year survival rates between those with a single N1 node and those with multiple N1 nodes is nearly 15% (45% versus 31%). Furthermore, the highest 5-year survival rates are found in those patients with tumors that are less than 3 cm in size and with only one lymph node affected by metastatic disease (48%).

	Other Prognostic Factors

Top Footnotes Abstract Introduction Overall Survival Other Prognostic Factors Molecular and Biological Markers Summary References

 
Other factors that may influence survival are gender, age, performance status, weight loss, tumor location, and tumor markers. A consensus report by Feld and associates [36] addresses these factors as they pertain to prognosis in NSCLC. Women may survive somewhat longer than men. Reviews by Mountain [3], Williams [18], and Shimizu [19] and their associates showed higher rates of 5-year survival in women, independent of other factors. Survival rates of young patients and elderly patients with early stage NSCLC appear to be the same, although conflicting data do exist [37, 38]; sample sizes for each stage and cell type have accounted for the difficulty in analyzing comparable age groups. Functional status and weight loss have been shown to be important prognostic factors in patients with advanced stages of disease. For early-stage disease, the prognostic role of functional status is less clear, although Pater and Loeb [39] found that performance status and weight loss significantly affected survival duration in their group of patients with early-stage NSCLC. There are no definitive data to support the impression that tumor location affects survival. Whether the tumor is located in the center or the periphery or in the upper lobe or the lower lobe, survival is not uniformly affected. Some reviews have suggested that patients with more centrally located lesions do worse than those with peripheral lesions [40, 41]; centrally located tumors may have a higher association with occult mediastinal lymph node metastases. This observation remains unproven. Serum markers and hormone levels have been evaluated quite extensively, and to date, none has been shown to influence survival in NSCLC, although lactate dehydrogenase and carcinoembryonic antigen have been used as predictors of outcome in patients with small cell lung cancer [42]. The prognostic value of molecular markers remains an area of active investigation.

	Molecular and Biological Markers

Top Footnotes Abstract Introduction Overall Survival Other Prognostic Factors Molecular and Biological Markers Summary References

 
During the past decade, research has identified specific molecular and biological markers that may serve as predictors of survival. In an extensive literature review of new prognostic factors, Mountain [43] identified 18 groups of markers that have been reported to be significant predictors of outcome in patients with lung cancer. The markers are categorized as tumor-associated antigens, aberrantly expressed genes, enzymes, hormones, and other biological markers:

• Tumor-associated antigens
  • Blood group antigens
    
  • CA 125 (ovarian adenocarcinoma antigen)
    
  • 43-9F antigen
    
  • Tissue polypeptide antigen
    
  • Squamous cell carcinoma antigen
    
  
  
• Aberrant gene expression
  • ras family
    
  • myc family
    
  • HER-2/neu (p185)
    
  • p53
    
  
  
• Enzymes and hormones
  • Neuron-specific enolase
    
  • Lactin dehydrogenase
    
  • Gastrin
    
  • Epidermal growth factors (polypeptide hormones)
    
  
  
• Biological markers
  • Tumor cell proliferation
    
  • Tumor cell line growth
    
  • Immune response
    
  • DNA content
    
  • Cytokeratin
    
  • Basement membrane deposition
    
  
  

Lung cancer oncogenes include the dominant oncogenes of the K-ras and the myc families; tumor-suppressor genes include p53, bcl-2, and the retinoblastoma gene. Activated ras oncogenes are seen commonly in human malignancies. Activation of the K-ras oncogene by point mutation in NSCLC cell lines causes expression of features of the malignant phenotype. Such activation appears to indicate a higher level of malignant potential, most commonly in association with adenocarcinoma. Several small studies have shown decreased survival for patients with early-stage lung cancers that have ras oncogene mutations [46, 47], particularly in patients with adenocarcinoma [48, 49]. More than half of the patients with NSCLC have p53 mutations or deletions. p53 is a tumor-suppressor gene that becomes inactivated through mutation or deletion. There is evidence that overexpression of the p53 protein or the presence of a p53 mutation may be an independent factor portending an unfavorable outcome. Quinlan and co-workers [50] showed a significant survival difference between patients with stage I and stage II disease based on the accumulation of mutant p53. Horio and co-workers [51] reported that p53 mutations have a negative impact on survival duration in early-stage disease. They showed that the effect on survival was independent of stage, a finding that has been observed in other studies [52].

A recently identified gene, bcl-2, has been shown to be a determinant of programmed cell death (apoptosis). A study by Pezzella and colleagues [53] determined survival duration in patients with stage I or II NSCLC based on bcl-2 expression. They showed that bcl-2 is abnormally expressed in some NSCLC. Their data isolated a group of patients aged more than 60 years with squamous cell cancer in which those whose tumors expressed bcl-2 survived significantly longer.

Lung cancer cells may secrete growth factors and may also express the specific receptor for growth factor. Self-stimulatory or autocrine growth may result. In some NSCLC cell lines, epidermal growth factor and transforming growth factor-alpha have been identified as potential autocrine growth factors and may be associated with pathologic features of more aggressive disease [54]. The erb-B2 growth factor receptor is also found frequently in NSCLC. Overexpression of the erb-B2 gene in adenocarcinoma has been associated independently with shorter survival [55]. DNA ploidy patterns, as determined by flow cytometry and tumor cell kinetics, may be useful in determining prognosis and the biological aggressiveness of early lung malignancies [20, 36, 56, 57]. Histologic markers of tumor angiogenesis and vascular invasion may help to predict degrees of malignant potential as they affect survival [20, 58, 59].

The recognition and development of molecular markers has given new insight into the biology of lung cancer. As potential predictors of outcome, molecular and biological markers may provide a more sophisticated and accurate method of forecasting survival. Prospective trials are necessary to confirm the predictive value of these markers and to assess their usefulness as staging tools.

	Summary

Top Footnotes Abstract Introduction Overall Survival Other Prognostic Factors Molecular and Biological Markers Summary References

 
There are significant differences in survival duration among patients with early-stage lung cancer. The best measure of variance in survival is in the comparison of the TNM subset end results, not the comparison of stage I and stage II disease. Operation remains the best treatment for early-stage disease. Of all patients with stage I tumors, those who survive the longest are those with T1 squamous or T1 solitary bronchoalveolar carcinoma. Patients with large nonsquamous tumors that involve the visceral pleura or have associated satellite lesions survive for the shortest periods. Of all patients with stage II disease, those with small T1 tumors in conjunction with only one N1 metastatic lymph node appear to survive the longest; patients with large nonsquamous tumors associated with intraparenchymal metastases (satellite nodules) or multiple N1 lymph node metastases have the shortest survival.

The staging of lung cancer is essentially based on cumulative survival statistics. The ISS used anatomic and morphologic criteria to determine stage groupings. With the recent recognition of other prognostic factors, including biological and molecular markers, it may be possible to better isolate the groups that share specific survival characteristics within the TNM subsets. Cumulative data on each patient, including clinical and biological information, may be used to categorize patients more accurately for staging. Further investigation is necessary to determine the usefulness of factors other than the anatomic extent of disease for predicting outcome. The development of more accurate measures for predicting prognosis should clarify the roles of primary and adjuvant treatment, particularly in those patients with early stage disease associated with poor prognostic factors in whom the potential for long-term survival is reduced.

	Footnotes

Top Footnotes Abstract Introduction Overall Survival Other Prognostic Factors Molecular and Biological Markers Summary References

 
Address reprint requests to Dr Nesbitt, Department of Thoracic and Cardiovascular Surgery, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 109, Houston, TX 77030.

	References

Top Footnotes Abstract Introduction Overall Survival Other Prognostic Factors Molecular and Biological Markers Summary References

 

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