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(Chest. 2005;128:1545-1550.)
© 2005 American College of Chest Physicians

Postoperative Survival and the Number of Lymph Nodes Sampled During Resection of Node-Negative Non-Small Cell Lung Cancer*

Michelle S. Ludwig, MD, MPH; Michael Goodman, MD, MPH; Daniel L. Miller, MD and Peter A. S. Johnstone, MD, MA

* From the School of Medicine, Departments of Radiation Oncology (Drs. Ludwig and Johnstone) and Cardiothoracic Surgery (Dr. Miller), and Rollins School of Public Health (Dr. Goodman), Emory University, Atlanta, GA.

Correspondence to: Peter A. S. Johnstone, MD, MA, Radiation Oncology Department, Emory University, 1365 Clifton Rd NE, Atlanta, GA 30322; e-mail: Peter{at}radonc.emory.org


   Abstract
TOP
 Abstract
Introduction
 Methods and Materials
 Results
 Discussion
 References
 
Study objective: To examine the association between postoperative survival and the number of lymph nodes (LNs) examined during surgery among persons who underwent definitive resection of node-negative (stage IA or stage IB) non-small cell lung cancer (NSCLC).

Design and setting: Information on postoperative survival and the number of LNs examined during surgery for stage I NSCLC treated with definitive surgical resection was retrieved from the population-based Surveillance, Epidemiology and End Results database for the period from 1990 to 2000. The association between survival and the number of LNs was examined using multivariate Cox proportional hazard models with adjustment for age, race, sex, type of surgery performed, and tumor size, grade, and histology.

Results: A total of 16,800 patients were included in the study. The overall survival analysis for patients without radiation therapy (RT) demonstrated that in comparison to the reference group (one to four LNs), patients with five to eight LNs examined during surgery had a modest but statistically significant increase in survival, with a proportionate hazard ratio (HR) of 0.90 and a 95% confidence interval (CI) of 0.84 to 0.97. Similar results for 9 to 12 LNs and 13 to 16 LNs examined produced further increases in survival, with HRs of 0.86 (95% CI, 0.79 to 0.95) and 0.78 (95% CI, 0.68 to 0.90), respectively. There appeared to be no incremental improvement after evaluating > 16 LNs. The corresponding results for lung cancer-specific mortality and for patients receiving RT were not substantially different. The highest median survival (97 months) occurred in patients with 10 to 11 LNs evaluated.

Conclusions: Our results indicate that patient survival following resection for NSCLC is associated with the number of LNs evaluated during surgery. This is likely due to reduction of staging error: a decreased likelihood of missing positive LNs with an increasing number of LNs sampled. Although we are reluctant to recommend a definitive "optimal number," our data support the conclusion that an evaluation of nodal status should include somewhere from 11 to 16 LNs.

Key Words: lymph node • non-small cell lung cancer • surgery • Surveillance, Epidemiology, and End Results • survival


   Introduction
TOP
 Abstract
 Introduction
Methods and Materials
 Results
 Discussion
 References
 
Lung cancer accounts for > 185,000 new cases of cancer per year in the United States, with non-small cell lung cancer (NSCLC) constituting approximately 75 to 80% of those cases.1 Less than one third of NSCLC patients present in stage I or II, where surgical resection can result in a 5-year survival of 50 to 80%. In contrast, only 10 to 20% of NSCLC patients who present in stages III or IV survive > 1 year.2 In stage I patients, survival is further influenced by age, gender, tumor size, histology, and tumor grade.34 Surgical resection alone has been the standard of care for medically operable stage I NSCLC, but there appears to be some disagreement regarding the benefits of complete lymph node (LN) dissection.5

Analysis of data for cancers of the colon, breast, and bladder demonstrates that the number of LNs evaluated during staging is associated with postoperative survival. For colorectal cancer, the College of American Pathologists considers 12 to 15 nodes necessary to predict node negativity6 whereas Tepper and colleagues7 recommend that approximately 14 LNs should undergo evaluation. For bladder cancer, Herr and colleagues89 determined that nine nodes should be evaluated to assign proper LN status and determine possible benefit from adjuvant chemotherapy. Three studies101112 of breast cancer also revealed that the number of nodes removed and evaluated during surgery is positively correlated with survival. In gastric cancer, patients with N2 disease may have increased survival with extended LN dissection, but this information is rarely known prior to surgery, and extensive surgery may increase morbidity and mortality.1314

For NSCLC, several small institutional studies151617 have found an association between increased number of LN removed and survival, while others18 have suggested that increased LN dissection in stage I NSCLC adds no benefit. One such study19 found that 15% of stage I surgically resected NSCLC had noncontiguous involvement of LNs; that is, N1 nodes are negative for metastatic disease, whereas N2 nodes show metastatic involvement. This finding suggests that extensive evaluation may be needed to accurately define nodal status prior to drawing conclusions about stage.

In this article, we aim to further examine the association between the number of LNs sampled during surgery and postoperative survival by analyzing the data from the Surveillance, Epidemiology and End Results (SEER) database. All data coding used by SEER is set up by a joint task force, which includes representatives from SEER, American College of Surgeons, Centers for Disease Control and Prevention, North American Association of Central Cancer Registries, National Cancer Registrars Association, and American Joint Committee on Cancer.

In contrast to previous hospital-based studies151617, we report data from a large population-based cancer registry, which represents approximately 14% of the US population and permits more extensive multivariate analyses due to its large sample size. The goal of this analysis is to test the hypothesis that among persons who underwent definitive resection of node-negative NSCLC (stage IA or stage IB), there is a positive association between survival and the number of LNs examined during surgery.


   Methods and Materials
TOP
 Abstract
 Introduction
 Methods and Materials
Results
 Discussion
 References
 
Using the public-use file of the SEER database, we selected all eligible lung cancer cases based on the following inclusion and exclusion criteria.

Inclusion Criteria
Inclusion criteria are as follows: (1) microscopically confirmed diagnosis of NSCLC; (2) stage IA (T1N0M0) or IB (T2N0M0) disease as reported by SEER according to the International System for Staging Lung Cancer20; (3) diagnosis between the years 1990 and 2000; (4) definitive surgical resection of the tumor; and (5) documented at least one LN examined during surgery.

Exclusion Criteria
Exclusion criteria are as follows: (1) exploratory surgery only; (2) unknown surgery status; (3) no LNs examined; and (4) number of LNs examined unknown.

Methods
The post-1990 period of study was selected because the extent of LN evaluation was not uniformly available in SEER until 1988. The definition of surgical resection included any of the following procedures: wedge resection, segmental resection (including lingulectomy), lobectomy, bilobectomy, partial, complete, sleeve, standard, total, or radical pneumonectomy, or surgery not otherwise specified.

The number of regional LNs evaluated was also extracted from the SEER database. The variable "number of LNs examined" is defined as the total number of regional LNs that were removed and examined by the pathologist. This information is obtained from medical records by trained SEER data abstractors.

Histology subtypes were organized into categories of adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Tumor grade as reported by SEER was divided into four categories (grades I to IV) to reflect the degree of differentiation (well-differentiated, moderately differentiated, poorly differentiated, and undifferentiated/anaplastic) according to the International Classification of Diseases for Oncology, Third Edition (ICD-O-3).

All patients who met the inclusion criteria were categorized into five groups according to the number of LNs evaluated during surgery: 1 to 4, 5 to 8, 9 to 12, 13 to 16, and ≥ 17. The differences in survival among groups were examined using a log-rank test. Multivariate analysis was performed using Cox proportional hazards models to examine the association between the number of LNs evaluated and survival while controlling for the effects of other potentially prognostic factors. The proportional hazards assumption was evaluated by visual examination of life table curves, and all models were assessed for collinearity and interaction.

The follow-up time in the multivariate analyses was limited to 5 years to minimize the impact of non-cancer-related mortality on study results. Lung cancer-specific mortality and overall mortality were evaluated as two alternative outcomes of interest. The covariates in the initial models included age, sex, race, tumor grade, histology and size, as well as surgery type. Tumor size was dichotomized at 30 mm to distinguish stage IA (T1N0M0) disease from stage IB (T2N0M0) disease.20

Backwards stepwise Cox regression analysis was used to arrive at the final model. The results of the multivariate survival analyses are presented as hazard ratios (HRs) with the corresponding 95% confidence intervals (CIs). Stratified analysis was used for those variables that violated the proportional hazard assumption.


   Results
TOP
 Abstract
 Introduction
 Methods and Materials
 Results
Discussion
 References
 
A total of 16,800 patients met the inclusion criteria. There were 6,714 deaths (40%) at the end of the 5-year follow-up period. Patients with lung cancer-specific mortality comprised 22.6% of all deaths. The patient characteristics and associated median survival times are summarized in Table 1 . Patients with one to four LNs examined during surgery constituted the largest proportion of cases (41.8%). Patients with 5 to 8, 9 to 12, 13 to 16, and > 16 LNs evaluated represented 30.3%, 14.7%, 5.8%, and 7.5%, respectively. The majority of patients (82%) were white, and just over one half (53%) were men. Most patients (54%) were 45 to 70 years of age (mean, 68.4 years). Analysis by histologic type showed that 28% of all lung cancers in this data set were squamous cell carcinomas, 6% were large call carcinomas, and the remaining majority (56%) were adenocarcinomas. With respect to other pathologic cancer characteristics, 9,183 tumors (55%) were relatively small (≤ 30 mm in diameter) and the majority (69%) were grades II and III.


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  		Table 1.. Distribution of Clinical and Demographic Patient Characteristics by Number of LNs Examined During Surgery*

 
Figure 1 demonstrates life table survival curves by the number of LNs evaluated during surgery. Compared to the lowest group (1 to 4 LNs), there appears to be statistically significant albeit modest improvement in survival with the maximum survival observed in the 13- to 16-LN group.



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  		Figure 1.. Kaplan-Meier survival curves by number of LNs evaluated.

 
These findings are further confirmed by the multivariate analysis that controlled for potentially confounding predictors of postoperative survival (Table 2 ). As the proportional hazards assumption was not valid for radiation therapy (RT), the final model was stratified based on the RT status, and the relationship between the number of LNs and survival was evaluated separately for patients who did and did not receive RT. The final Cox model controlled for age, gender, tumor size, grade, and histology. As shown in Table 2, the overall survival analysis for patients without RT demonstrated that in comparison to the reference group (one to four LNs), patients with five to eight LNs examined during surgery had a modest but statistically significant increase in survival (HR, 0.90; 95% CI, 0.84 to 0.97). Similar results for 9 to 12 LNs and 13 to 16 LNs produced further increases in survival (HR, 0.86 [95% CI, 0.79 to 0.95], and HR, 0.78 [95% CI, 0.68 to0.90], respectively). There appeared to be no incremental improvement after evaluating > 16 LNs (HR, 0.85; 95% CI, 0.75 to 0.96). The corresponding results for lung cancer-specific mortality were not substantially different (Table 2). The results for those who received RT were also similar, with slightly more pronounced HR estimates but wider CIs (Table 2).


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  		Table 2.. Cox Multivariate Survival Analysis by Number of LNs Evaluated*

 

   Discussion
TOP
 Abstract
 Introduction
 Methods and Materials
 Results
 Discussion
References
 
Our analysis shows that increasing number of LNs evaluated during definitive surgery for stage I NSCLC is associated with a statistically significant increase in survival, which peaks at approximately 13 to 16 LNs. When compared to the reference group (1 to 4 LNs), an evaluation of 5 to 8 LNs, 9 to 12 LNs, and 13 to 16 LNs among patients who did not undergo RT conferred a 12%, 15%, and 26% improvement in lung cancer-specific survival, respectively. The results were similar for both cancer-specific and overall survival, indicating that mortality from causes other than lung cancer is not associated with the number of LNs examined during surgery.

It is important to point out that the statistical significance of these results is hardly surprising because the study population was so large (n = 16,800). For this reason, a more important issue is the clinical significance of the reported 15 to 25% increase in survival. We addressed this question by calculating the median survival among patients with different numbers of LNs evaluated during surgery. As shown in Figure 2 , the median survival among patients with only one to two LNs examined was approximately 65 months. As the number of LNs increased so did survival, with the maximum of 97 months in a group with 11 to 12 LNs examined. Thus, an optimal evaluation of the nodal status may be associated with up to 2 additional years of median postoperative life expectancy.



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  		Figure 2.. Median postoperative survival by number of lymph nodes evaluated.

 
The most plausible explanation for the observed inverse association between the number of LNs examined and postoperative mortality is staging error. It is possible that a certain proportion of patients classified as node negative (stage I) may in fact be node positive. As the number of LNs examined increases, the probability of missing a positive LN decreases and so does the proportion of stage II or stage IIIA patients misclassified as having stage I disease.

It is also possible that a more extensive LN dissection in and of itself leads to improved survival. However, the contribution of extensive LN dissection to patient survival cannot be quantified in the absence of more detailed information, which is more likely to be available from randomized clinical trials. For example, one aim of the ongoing collaborative trial of the American College of Surgeons Oncology Group (ACOSOG Z0030) is to compare patient survival following complete mediastinal LN dissection vs LN sampling for N0 or nonhilar N1 NSCLC.21

While interpreting the results of our analysis, it is important to consider strengths and limitations of the SEER data set. The large sample size enables SEER-based studies to have sufficient power of detecting relatively moderate associations and permits complex multivariate analyses. The population-based, as opposed to institution-based, recruitment of cases increases the external validity and generalizability of findings. Rigorous data extraction and coding procedures permit pooling of data across different time periods and geographic locations. However, potential shortcomings of the SEER data include lack of more detailed clinical information related to exact tumor location, specific surgical technique used, surgeon training and experience, and details of RT and adjuvant therapy.

One additional source of uncertainty in this study is the variability in reporting the number of LNs examined during surgery. Nodal tissue rarely is extracted completely intact, and instead comes out in fragments. For this reason, it is possible that that some of the LNs in our data set were in fact fragments and the true number of LNs examined may have been overestimated. However, if such misclassification is random (ie, not related to survival), this would bias the results toward null. In other words, the true association may be in fact somewhat stronger than what is reported in our study.

Additional research is expected to shed more light on the potential underlying mechanism of the observed association between postoperative survival and the number of LNs evaluated during surgery. Alternative methods of detecting micrometastases, such as intraoperative 99mTc sentinel LN mapping22 and positron emission tomography,23 both of which are currently undergoing clinical evaluation, are expected to improve our ability to correctly determine NSCLC stage.

In summary, our results indicate that a sufficient number of LNs is necessary for routine surgical staging of early stage NSCLC. Although there is no clear optimal number, our data support a conclusion that an evaluation of nodal status should include somewhere from 11 to 16 LNs until alternative noninvasive methods of detecting nodal micrometastases can be perfected.


   Footnotes
 
Abbreviations: CI = confidence interval; HR = hazard ratio; LN = lymph node; NSCLC = non-small cell lung cancer; RT = radiation therapy; SEER = Surveillance, Epidemiology, and End Results

This study was presented at the 46th Annual Meeting of the American Society for Therapeutic Radiology and Oncology, October 6, 2004, Atlanta, GA.

Received for publication January 8, 2005. Accepted for publication March 13, 2005.


   References
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 Introduction
 Methods and Materials
 Results
 Discussion
 References
 

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