Eur J Cardiothorac Surg 2003;24:994-1001
© 2003 Elsevier Science NL
Long-term results of pathological stage I non-small cell lung cancer: validation of using the number of totally removed lymph nodes as a staging control
Yu-Chung Wua,
Chien-Fu Jeff Linb,
Wen-Hu Hsua,
Biing-Shiun Huanga,
Min-Hsiung Huanga,
Liang-Shun Wanga*
a Division of Thoracic Surgery, Department of Surgery, Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei 11217, Taiwan
b Biostatistics Task Force, Taipei Veterans General Hospital and National Yang-Ming Medical College, Taipei, Taiwan
Received 21 May 2003;
received in revised form 15 August 2003;
accepted 20 August 2003.
* Corresponding author. Tel.: +886-2-2875-7060; fax: +886-2-2873-1488
e-mail: lswang{at}vghtpe.gov.tw
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Abstract
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Objective: The number of totally removed lymph nodes during thoracotomy was used alternatively to represent the quality of lymphadenectomy in patients with pathologic stage I non-small cell lung cancer (NSCLC). We combined this new parameter with other well-established prognostic factors and performed multivariate survival analyses to validate its usage as a stage control. Methods: Three hundred and twenty-one patients who underwent complete surgical resection for stage I NSCLC were reviewed retrospectively. Aside from the number of lymph nodes removed during thoracotomy, other well-known clinical and histopathological factors were also included as possible prognostic factors for analysis. Two survival analyses, overall death and cancer-related death as study end-point, were performed, using the Kaplan–Meier method and multivariable Cox's proportional hazard regression analysis. Stepwise method of variable selection was employed to choose the ‘best’ Cox proportional hazard model in each survival analysis. Results: The overall 5- and 10-year survival rates were 48 and 35%, and the cancer-related 5- and 10-year survival rate was 63.3 and 58.3%, respectively. The number of totally removed lymph nodes during thoracotomy, tumor size and smoking history in multivariable analysis significantly affected both overall and cancer-related survival rates. Cell type of adenocarcinoma or large cell carcinoma was associated with a worse cancer-related survival compared with other histological types. Conclusions: The quality of lymphadenectomy, represented quantitatively by the number of totally removed lymph nodes during thoracotomy, may impact on a more accurate tumor stage, and will affect the survival rate for patients with stage I NSCLC as well as other well known clinical and histopathological factors.
Key Words: Non small cell lung cancer • Prognostic factors
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1. Introduction
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To date, surgery is still the first choice of treatment for localized non-small cell lung cancer (NSCLC) if the patient's physical condition is feasible. However, the result of surgical treatment remains unsatisfactory. The previous studies have shown a 5-year survival rate in stage I NSCLC ranging from 55 to 77.6% [1–6]. Inadequacies of staging system and heterogeneity among patient groups have also been proposed [5]. New molecular prognostic factors [7] in addition to the well-established clinicopathological factors were then intensively investigated to refine the present TNM system. However, the discrepancy in results and inconsistency in methodology have limited their role in clinical application. TNM staging system is still the most important prognostic factor while treating the patients or selecting patients for a clinical trial.
Mediastinal lymph node removal, whether defined by complete dissection or sampling, has been well accepted as a part of standard procedures in lung cancer surgery to ensure the accuracy of N-status and potential survival benefit as well [8]. More recent data revealed that detection of micrometastatic tumors in node-negative lung cancer [9,10] provided a more accurate assessment of tumor staging and has prognostic implications. Therefore, theoretically, a more aggressive attitude in locoregional lymph node removal during the operative process will increase the probability of micrometastatic lymph node clearance, which will at least reflect the accuracy of the staging process and will influence the survival, especially in early-stage tumors. Taken together, in this study we established a novel parameter, the number of totally removed lymph nodes during thoracotomy, which was used alternatively to represent the quality of lymphadenectomy in a quantitative fashion. We evaluated this new variable and other well-known prognostic factors in our surgicopathological stage I NSCLC patients to define their clinical and prognostic significance.
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2. Patients and methods
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Between July 1980 and June 1990, a total of 321 consecutive patients who underwent surgery for NSCLC at the Division of Thoracic Surgery, Veterans General Hospital in Taipei with a final pathological stage defined as ISS stage I were reviewed retrospectively. Cell types of mixed or undetermined histology were excluded for analysis. The preoperative staging workup included serum biochemistry tests, chest and upper abdomen computed tomography scans, bronchoscopic examination and nuclear medicine survey (bone and brain). Mediastinoscopy was not a routine procedure in the preoperative staging workup unless enlarged lymph nodes (diameter over 1.0 cm) were observed on the contralateral side of mediastinum from the computed tomography scan. Patients of suspicious distant metastasis (i.e. abnormal uptake of nuclear medicine scan) were also excluded for further analysis. All patients received a complete tumor resection with microscopically tumor-free margin (R0), whereas the extension of pulmonary mesenchymal resection and mediastinal lymph node removal were decided according to the preference of the operators and the general physical condition of the patients. The number of lymph nodes removed during thoracotomy was defined as how many pieces of lymph nodes had been dissected or sampled by the surgeon during the thoracotomy (including those sent for frozen diagnosis) and examined by the pathologist. The nodes harvested from mediastinoscopy were not included in this study. None of our patients received pre- or postoperative chemotherapy or radiotherapy as an adjuvant. All patients were followed regularly on an outpatient basis. Follow-up data obtained consisted of chest radiography, bone and brain nuclear medical scans, and abdominal sonography for a period of 3–4 months for the first 2 years, 6 months until 5 years, then annually for the rest of life. The overall survival is defined from the date of operation to the date of death, including surgical mortality. The cancer-related survival is defined from the date of operation to the date of death related to the primary lung cancer. Patients who did not respond twice for communication over a period of 1.5 were defined as lost to follow-up. The first noted neogrowth from the same hemithorax was defined as local recurrence, others as distant metastasis. A second primary lung cancer was defined according to the criteria of Martini et al. [4]. Patients who developed a second primary cancer were then treated as censored subjects in cancer-related survival analysis.
2.1. Statistical analysis
All subjects were included in this analysis. Variables in the analysis included age, gender, Karnofsky performance scale, history of smoking, presentation of symptoms, cough, hemoptysis, chest pain, body weight loss (defined as loss excess 10% of ideal body weight), presentation of preoperative histopathological diagnosis, cell type, tumor location (central or peripheral), type of resection (pneumonectomy, lobectomy and sleeve lobectomy, bilobectomy, and lesser resection), tumor size (greatest dimension of tumor), T-status (T1 or T2), the number of lymph nodes removed during thoracotomy, differentiation of tumor cell (well, moderate, poor), and vascular or lymphatic vessel invasion. Data were entered and analyzed with PC SAS (SAS Institute, Cary, NC). However, not every subject had complete measurements for all variables that included possible prognostic factors and important outcomes. Data were represented as mean and standard deviation (SD; for continuous variables) or percentage (for categorical variables). Survival probability was calculated by Kaplan–Meier method [11]. The log-rank test was used in univariate survival analysis to compare different survival probabilities among different levels within each categorical variable (prognostic factor). The univariate Cox's proportional hazard model was used for each continuous variable (prognostic factor). The P-value was set at 0.05 in advance for each univariate analysis. It depended on clinical experience and statistical analysis to decide whether continuous variables should be categorized. Possible prognostic factors associated with survival probability at a significance level of 0.20 or less were considered in a multivariable Cox's proportional hazard regression analysis [12]. Variable selection with a stepwise method was employed to choose the ‘best’ model, with the significance criterion for a prognostic factor entering and remaining at the significance level 0.05 in the ‘best’ model. The final model was checked by available diagnostic statistics including graphics and residual analysis.
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3. Results
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3.1. Follow-up and causes of death
Three hundred and twenty-one patients were included in this study with mean age (±SD) 63±8 years (range 27–80). The mean (±SD) of Karnofsky performance scales was 90±2%, and 308 patients had scales equal to or above 90%. Surgical procedures included 66 pneumonectomies, 42 bilobectomies, 196 lobectomies, and four sleeve lobectomies. The number of pneumonectomies in this old series was rather high, due to the fact that some surgeons in principle preferred to have a wide excision than alternative bronchoplastic procedures at that period if the tumor was centrally located or across the fissures. Thirteen patients with inadequate cardiopulmonary function were scaled 80% and received fewer resections (11 wedge resections and two segmental resections) than standard lobectomies. Thirty-one (9.7%) major complications occurred and resulted in ten surgical mortalities (3%). The mean (±SD) number of removed lymph nodes was 11±7.8 (range 0–45). Complete follow-up data were obtained through July 30, 1995. The mean (±SD) follow-up period was 61±46 months, ranging from 0 (surgical mortality) to 175.6 months. One hundred and three patients (32%) were alive at the end of the study. One hundred patients had event-free survival and three had tumor recurrence (two local recurrences and one brain metastasis). These three patients remained stable after radiotherapy. Eighteen patients (5.6%) were lost to follow-up during the study period. All surviving patients were followed at least 56 months (range 56.6–176). The causes of death and follow-up results are shown in Table 1.
3.2. Overall survival
The 5- and 10-year overall survival rates were 49 and 36% (T1: 60%, 43%; T2: 41%, 30%), respectively. In univariate analysis (shown in Tables 2 and 3), statistically significant prognostic factors of overall death were the presence of symptoms, the presence of hemoptysis, the presence of cough, smoking history, body weight loss, the presence of preoperative histopathological diagnosis, the number of removed lymph nodes equal to or less than 15, cell type and tumor size. The multivariable analysis showed that significant prognostic factors of overall survival were the number of removed lymph nodes equal to or less than 15, tumor size, and smoking history over 20 pack-years. The number of removed lymph nodes equal to or less than 15 had 1.66 times (95% confidence interval (CI): 1.12, 2.38) higher risk ratio of overall death after adjustment of other risk factors. The tumor size (as continuous variable) had 1.10 times (95% CI: 1.05, 1.16) higher risk ratio of overall death for each increase of 1 cm after adjustment of other risk factors. The smoking history over 20 pack-years had 1.61 times (95% CI: 1.22, 2.12) higher risk ratio of overall death after adjustment of other risk factors. The Kaplan–Meier survival estimates with overall death as study end point are shown in Fig. 1
.The overall survival estimates stratified by the number of removed lymph nodes, tumor size, smoking history and cell type are shown in Fig. 2
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Table 3. Univariate analysis of pathological stage I non-small cell lung cancer according to surgical and histopathological factors
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Fig. 1. Kaplan–Meier survival estimates are displayed to compare the difference by using overall death or cancer-related death as study end-point in patients with pathological stage I non-small cell lung cancer. Vertical cross-marks denote censored observation at last follow-up.
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Fig. 2. Overall Kaplan–Meier survival estimates stratified by the number of removed lymph nodes (A), tumor size (B), smoking history (C) and cell type (D) in patients with pathological stage I non-small cell lung cancer. Vertical cross-marks denote censored observation at last follow-up. The P-value was obtained from the result of multivariable analysis; NS, not significant at a level of 0.05.
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3.3. Cancer-related survival
The 5- and 10-year cancer-related survival rate was 63.3 and 58.3% (T1: 71.4%, 56.9%; T2: 62.7%, 55%), respectively. In univariate analysis (Tables 2 and 3), statistically significant risk factors of cancer-related death included the presence of symptoms, the presence of hemoptysis, smoking history, presence of preoperative histopathological diagnosis, the number of removed lymph nodes equal to or less than 15, cell type, tumor size and tumor cell differentiation. The multivariable analysis showed that significant prognostic factors of cancer-related death were the number of removed lymph nodes equal to or less than 15, tumor size, smoking history over 20 pack-years, and cell type of adenocarcinoma or large cell carcinoma. The number of removed lymph nodes equal to or less than 15 had a 1.53 times (95% CI: 1.05, 2.22) higher risk ratio in cancer-related death after adjustment of other risk factors. The cell type of adenocarcinoma had 2.27 times (95% CI: 1.47, 3.49) and large cell carcinoma 3.16 times (95% CI: 1.47, 6.77) higher risk ratio in cancer-related death after adjustment of other risk factors. The tumor size (as continuous variable) had 1.15 (95% CI: 1.08, 1.22) times higher risk for each increase of 1 cm in cancer-related death after adjustment of other risk factors. The smoking history over 20 pack-years had 2.14 times (95% CI: 1.42, 3.23) higher risk in cancer-related death after adjustment of other risk factors. The Kaplan–Meier survival estimates with cancer-related death as study end point are shown in Fig. 1.The cancer-related survival estimates stratified by the number of removed lymph nodes, tumor size, smoking history and cell type are shown in Fig. 3
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Fig. 3. Cancer-related Kaplan–Meier survival estimates stratified by the number of removed lymph nodes (A), tumor size (B), smoking history (C) and cell type (D) in patients with pathological stage I non-small cell lung cancer. Vertical cross-marks denote censored observation at last follow-up. The P-value was obtained from the result of multivariable analysis; NS, not significant at q level of 0.05.
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4. Discussion
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4.1. The number of totally removed lymph nodes during thoracotomy affects the survival
During thoracotomy, surgeons need to choose among various methods of lymphadenectomy from a nonsystematic sampling to a complete systematic dissection [13–20]. This decision-making depends largely on the preference of the surgeons and occasionally on the general condition of the patients and the characteristics of the target lymph nodes. Although nonsystematic lymph node sampling has never been clearly defined, it was thought ‘inadequate’ for accurate tumor staging [19,20]. Investigators have also compared systematic ‘sampling’ with ‘dissection’ groups by using non-randomized [16] and small-scale randomized trials [17]. However, a large-scale, multicenter randomized trial is still awaited to solve the debate. A recent study [9] in completely resected stage I NSCLC revealed that micrometastatic tumor cells could be detected in 1.7% of pathological ‘negative’ lymph nodes and 27.7% of patients. It implicated that a more aggressive attitude toward lymph node removal during thoracotomy will increase the probability of micrometastatic lymph node detection and clearance. Therefore in this study, we used a new variable, the number of totally removed lymph nodes during thoracotomy, to alternatively represent the quality of lymphadenectomy and compared it with other well-established prognostic factors to test to what degree it affects survival for stage I NSCLC. The number of lymph nodes removed during thoracotomy was used as a continuous variable and in univariate analysis (data not shown) it revealed that any cutoff value between 8 and 15 could be set to divide the series into two significant subgroups. A cutoff value of 15 was selected because it provided the most stable and significant models in multivariable analyses and model selection. A further analysis showed no difference in the pattern of failure (local or distant metastases) whether the number of lymph nodes removed was more or less than 15 (data not shown). Clinically, this result suggested that the removal of less than 15 lymph nodes could be interpreted as ‘inadequate’ lymphadenectomy for a proper staging process and would affect the results of survival adversely. However, limited by the retrospective nature and insufficient description in lymphadenectomy in our series, we do not further analyze whether ‘adequate’ lymphadenectomy (defined by removal of more than 15 lymph nodes) represented ‘systematic lymph node sampling’ or others. A prospective study with thorough descriptions regarding how and how many lymph nodes have been removed in each lymph node station is needed to answer that question. Therefore, in this study, the number of lymph nodes referred to the number of lymph nodes that were totally removed or partially sampled by the surgeon during thoracotomy and examined by the pathologist. Nevertheless, the ‘best number’ of lymph nodes removed during thoracotomy should be adjusted according to individual experience.
The number of totally removed lymph nodes could also explain, at least in part, the survival variations or selection bias from the historical series of pathological stage I NSCLC. Without selection, the 5-year cancer-related survival rate in our whole series was 63%. By selecting patients removed with more than eight lymph nodes (n=181) we can achieve a 67% 5-year survival rate, close to the mean of historical series [5]. With more than 15 lymph nodes removed (n=65), the patients could achieve 77% of the 5-year survival, a result compatible with the recent series emphasizing the procedure of systemic or radical mediastinal lymph node dissection [4,6]. In contrast, in patients with not more than eight lymph nodes removed (n=140) the 5-year survival was 58%, close to the lower limit of surgical series [2]. Taken together, these data proved that the procedure of lymphadenectomy during thoracotomy alone could have a nearly 20% variation to affect the 5-year survival rate in our series. This survival variation can be explained by micrometastatic tumor cell detection or clearance in pathologically negative removed lymph nodes. An improvement of microscopic examination, multisection with or without special immunohistochemistry staining, in each removed lymph node could more accurately detect the presence of nodal micrometastases. Thus, a prospective protocol is needed to evaluate whether there is a difference between these two groups in detection of micrometastatic tumor cells in lymph nodes and the influence in outcome measurement.
4.2. Cell type affects cancer-related but not overall survival
In our study, cell type was a unique prognostic factor in cancer-related survival but not in overall survival. Compared with squamous cell carcinoma, the cell types of adenocarcinoma and large cell had a 2.27 times (95% CI: 1.47, 3.49) and 3.16 times (95% CI: 1.47, 6.77) higher risk ratio, respectively, in cancer-related death. Interestingly, in the overall survival model cell type was not a prognostic factor. It might be possible that the high-risk cell types of adenocarcinoma or large cell carcinoma in cancer-related death could be ‘diluted’ or even ‘reversed’ by other causes of death if the follow-up period was long enough. However, owing to the limited number of cases and heterogeneity of non-cancer-related death, our evidence was not strong enough to support this assumption. The data also revealed a different survival distribution among different cell types studied. As most of the analyses in early stage lung cancer either subgrouped cell types into squamous and non-squamous [6,21–24] or combined adenocarcinoma with bronchioloalveolar cell [7,8], we suggested that each cell type should be analyzed with a sufficient sample size.
4.3. Tumor size and smoking affect both overall and cancer-related survival
Tumor size may be the most well-accepted prognostic factor in stage I NSCLC. Therefore, the new international staging system for lung cancer [1] further classified stage I disease into IA and IB. One of the criteria used was tumor size, with a cutoff value at 3 cm. However, our study showed that tumor size, while treated as a continuous variable, had more statistical power than a binomial variable (<3 cm or >3 cm; T1 or T2). This result is consistent with the suggestion that other criteria of T2 (extension to hilar region, invasion of visceral pleural, and partial atelectasis) failed to provide more prognostic information than tumor size alone, and the validity of classifying tumor size by a cutoff point of 3 cm is also questionable [8]. Because the risk ratio of tumor size was similar in both overall and cancer-related death (1.1 and 1.09), a 3-cm tumor had 1.2 times and a 5-cm tumor a 1.5 times higher risk ratio of death than a 1-cm tumor.
Smoking has long been identified as a risk factor of lung cancer development. Our study also demonstrated it as an independent prognostic factor to predict survival in pathological stage I NSCLC. Harpole et al. [3] have reported a prognostic model of recurrence and death in stage I NSCLC, in which smoking history revealed no survival differences among four subgroups of patients. However, 80% of their patients had smoked more than 20 pack-years, which might affect the statistical power. More recently, Fujisawa et al. [6] have demonstrated that smoking before surgery could predict poor long-term survival in patients with stage I NSCLC. A cutoff value of 30 pack-years was used in their multivariable analyses and showed the statistical significance of smoking history in the overall survival model but not in the cancer-related model. In view of these different results, smoking history may be an important poor-prognosis factor of long-term overall survival of stage I NSCLC, but its impact on tumor recurrence or cancer-related death needs further investigation.
4.4. Clinical decision based on survival models including procedure of lymph node removal
A clinical decision could be established based on the procedure of lymphadenectomy and other prognostic factors. For example, a heavy smoker with a 5-cm large cell carcinoma who underwent a thoracotomy to remove a lobe of lung and seven lymph nodes runs a 10 times higher risk of death from primary treatment failure than a non-smoker with a 1-cm squamous cell carcinoma who underwent a lobectomy with16 lymph nodes removed. Thus, for the low-risk group (i.e. risk ratio less than 5) the goal of surgical treatment should be addressed at how to decrease the pulmonary complication and to preserve parenchyma as well for the high possibility of a second primary cancer. These patients can be followed without adjuvant therapy. More attention should be focused on the possibility of a second primary cancer and chemoprevention. For the high-risk group (i.e. risk ratio over or equal to 5), a more aggressive attitude for local and systemic control should be taken. Any clinical trial with the goal of better primary disease control should be considered first. A more intensive follow-up protocol and early detection of treatment failure are necessary in the first 5 years.
In conclusion, the number of totally removed lymph nodes during thoracotomy can be used alternatively as a simple surgical factor that represents the quality of mediastinal lymphadenectomy, which will affect the results of survival in patients with stage I NSCLC. Any lymphadenectomy procedure that harvests less than 15 lymph nodes could be regarded as inadequate for tumor staging and locoregional control of the lesion and bearing an adverse effect in survival. Moreover, both overall and cancer-related survival rates were significantly affected by tumor size and smoking history, while cell type of adenocarcinoma or large cell carcinoma was a poor prognostic factor in cancer-related survival.
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Acknowledgments
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This work was supported by grant from VGH89-223, Veterans General Hospital in Taipei and NSC 89-2314-B-075-084, National Science Council, Taiwan.
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Top
Abstract
1. Introduction
