You are here

Does Lymph Node Metastasis Have a Negative Prognostic Impact in Patients with NSCLC and M1a Disease?

Journal of Thoracic Oncology, Volume 11, Issue 10, October 2016, Pages 1745 - 1754

Abstract

Objectives

Patients with NSCLC with M1a disease regardless of lymph node status were categorized as stage IV. This study aims to investigate whether the N descriptors in M1a patients could provide clinical information.

Methods

Overall, 39,731 patients with NSCLC with M1a disease were identified from the Surveillance, Epidemiology, and End Results database during 2005–2012. Lung cancer–specific survival (LCSS) was compared among M1a patients stratified by N stage. A Cox proportional hazards regression model was applied to evaluate the prognostic factors. Statistical analyses were performed in all subgroups.

Results

M1a patients without lymph node involvement had the best LCSS, followed by patients with N1 disease; no difference in LCSS was observed between N2 and N3 disease (N0 versus N1, p < 0.001; N1 versus N2, p < 0.001; and N2 versus N3, p = 0.478). Similarly, this trend was observed when patients were subdivided into two temporal cohorts (2005–2008 and 2009–2012) and also when M1a disease was subdivided into contralateral pulmonary nodules and pleural dissemination (malignant pleural effusion [or pericardial effusion] and pleural nodules). In addition, a difference in LCSS between N2 and N3 disease was observed in patients with malignant pleural nodules (p = 0.003). Multivariate analysis showed that lymph node involvement was an independent prognostic factor for M1a patients, and this result was also noticed in all subgroups.

Conclusions

These results provide preliminary evidence that lymph node stage may have clinical significance among patients with NSCLC with M1a disease, adding prognostic information.

Keywords: NSCLC, Staging, M1a disease, SEER.

Introduction

Although the incidence of lung cancer has been stable in the past decade, nearly 40% of new cases were diagnosed at stage IV.1 In 2007, these large numbers of cases were subdivided and a new category of M1a was proposed in the seventh edition of TNM staging.2 Specifically, M1a disease was defined as metastases within the chest cavity, including pleural dissemination (pericardial dissemination) and contralateral pulmonary nodules.2

In clinical practice, lymph node metastasis is regarded as one of the most important prognostic factors for M0 patients whereas M1a patients, regardless of any N status, are categorized as stage IV.3 and 4 Hence, the clinical effect of lymph node status on patients with NSCLC with M1a disease has not been studied extensively. Recently, Iida et al. performed a retrospective study including 329 patients with pleural dissemination and found that N0/N1 status was an independent predictor of better survival.5 Hence, studies with larger sample sizes and more sufficient subgroup analyses of M1a disease are necessary to clarify the prognostic impact of N stage in M1a patients.

Thus, the present study aims to identify whether accurate identification of lymph node status in M1a patients with NSCLC is of clinical value by analyzing the big series from the Surveillance, Epidemiology, and End Results (SEER) database.

Materials and Methods

The Institutional Review Board of Shanghai Pulmonary Hospital approved this study (IRB No. K16-262). All patients in this study were selected from the SEER database between January 2005 and December 2012. The database contains cancer cases from 18 areas of the United States and covers 26% of the U.S. population.6 M1a patients were identified according to the SEER codes as follows: (1) patients with contralateral pulmonary nodules were identified as CS mets at dx 23 and (2) patients with pleural dissemination, including malignant pleural effusion (or pericardial effusion), were identified as CS mets at dx 15, 16, 17, 18, 20, or 21 or CS extension 720 or 790 and pleural nodules were identified as CS mets at dx 24 or CS extension 760. The SEER database also provided the N status of each patient. Although N descriptors from 2005 to 2009 and from 2010 to 2012 were recorded according to the sixth or seventh edition of TNM classification, respectively, the definition of the N descriptor was consistent across these two editions.7 and 8 Specifically, N0 was defined as no regional node metastasis; N1 as metastasis in ipsilateral peribronchial, perihilar and intrapulmonary lymph nodes; N2 as metastasis in ipsilateral mediastinal and/or subcarinal lymph nodes; and N3 as metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph nodes.7 and 8 M1a patients were excluded if N status was recorded as unknown in the SEER database. N status provided by the SEER database could not distinguish between pathological or clinical N staging, but it met the concept of the best N stage, which was defined as the pathological stage if available and clinical stage otherwise.2 Thus, we analyzed the best N stages of the patients included in this study.

Moreover, the demographic features of patients (age, marriage, sex, and race/ethnic group), pathological characteristics of lung cancer (T descriptor according to the seventh edition of TNM classification, location, and histological type), and types of therapeutic strategy (radiotherapy) were collected from the SEER database. Histologic subtypes were divided into adenocarcinoma (SEER codes 8140, 8230, 8255, 8260, 8310, 8333, 8470, 8480, 8481, 8490, and 8550), squamous cell carcinoma (SEER codes 8052, 8070, 8071, 8072, 8073, 8083, and 8084), and other histologic types because of the low incidence (large cell carcinoma and the like).9 The SEER database reported the lung cancer–specific survival (LCSS), which was defined as the interval from diagnosis until death due to lung cancer or until the last follow-up. In this research, LCSS was considered the outcome of interest.

Statistical Analysis

The data were presented as median (range) and percent values. LCSS was evaluated using the Kaplan-Meier method and compared using the log-rank test for all M1a patients, M1a patients during different periods (2005–2008 and 2009–2012), two subgroups of M1a disease (contralateral pulmonary nodules and pleural dissemination), and two subgroups of pleural dissemination (malignant pleural effusion [or pericardial effusion] and pleural nodules) according to N staging. In addition, multivariate the Cox proportional-hazards regression model was applied to adjust for potential confounders in the survival analysis for all M1a patients and those from each subgroup. In this study, a p value less than 0.05 was considered statistically significant. All analyses were conducted using SPSS 19.0 software (IBM, Inc., Armonk, NY).

Results

Overall Analysis

This study included 39,731 patients with NSCLC with M1a disease from the SEER database (Supplementary Fig. 1). Table 1 showed the baseline characteristics of patients, tumors, and therapies for all M1a patients.

Table 1

Baseline Characteristics of Patients with NSCLC with M1a Disease

 

Characteristic M1a Patients
(N = 39,731)
M1a Patients during 2004–2008
(n = 24,801)
M1a Patients during 2009–2012
(n = 14,930)
Median age (range), y 70 (23–103) 70 (23–103) 71 (23–101)
Age group
 ≤65 y 14,202 (35.7) 9070 (36.6) 5132 (34.4)
 >65 y 25,529 (64.3) 15,731 (63.4) 9798 (65.5)
Sex
 Male 21,593 (54.3) 13,627 (54.9) 7966 (53.4)
 Female 18,138 (45.7) 11,174 (45.1) 6964 (46.6)
Marriage
 Yes 20,030 (50.4) 12,637 (51.0) 7393 (49.5)
 No 19,701 (49.6) 12,164 (49.0) 7537 (50.5)
Race/ethnic group
 White 31,091 (78.3) 19,493 (78.6) 11,598 (77.7)
 Black 5081 (12.8) 3098 (12.5) 1983 (13.3)
 Other 3559 (9.0) 2210 (8.9) 1349 (9.0)
Location
 Main bronchus 2456 (6.2) 1,580 (6.4) 876 (5.9)
 Single lobe 28,034 (70.6) 17,378 (70.1) 10,656 (71.4)
 Overlapping lesion 639 (1.6) 401 (1.6) 238 (1.6)
 Unknown 8602 (21.7) 5442 (21.9) 3160 (21.2)
Histological type
 Adenocarcinoma 18,210 (45.8) 10,708 (43.2) 7502 (50.2)
 Squamous cell carcinoma 7625 (19.2) 4381 (17.7) 3244 (21.7)
 Other 13,896 (35.0) 9712 (39.2) 4184 (28.0)
T stage
 T1 5152 (13.0) 3869 (15.6) 1283 (8.6)
 T2 10,514 (26.5) 7651 (30.8) 2863 (19.2)
 T3 5137 (12.9) 3838 (15.5) 1299 (8.7)
 T4 8237 (20.7) 644 (2.6) 7593 (50.9)
 Tx 10,691 (26.9) 8799 (35.5) 1892 (12.7)
N stage
 N0 11,435 (28.8) 6824 (27.5) 4611 (30.9)
 N1 2683 (6.8) 1663 (6.7) 1020 (6.8)
 N2 18,977 (47.8) 12,072 (48.7) 6905 (46.2)
 N3 6636 (16.7) 4242 (17.1) 2394 (16.0)
Radiotherapy
 Yes 11,458 (28.8) 7,492 (30.2) 3966 (26.6)
 No 28,273 (71.2) 17,309 (69.8) 10,964 (73.4)
Follow-up time, mo 5 (0–95) 4 (0–95) 6 (0–47)

Of all the M1a patients, 11,435 patients had their disease diagnosed as N0, 2683 as N1, 18,977 as N2, and 6636 as N3. The survival analysis evaluating the entire cohort showed that patients without lymph node metastasis had a better LCSS (p < 0.001) than did those with N1 disease (Fig. 1A). In addition, the LCSS of M1a patients with N1 disease was significantly higher (p < 0.001) than that of those with N2 disease (Fig. 1A), whereas similar LCSS rates (p = 0.478) were observed between patients with N2 involvement and those with N3 involvement (Fig. 1A). In the multivariate analysis, the results indicated that lymph node metastasis was an independent prognostic factor for M1a patients (N1 versus N0, hazard ratio [HR] = 1.14, 95% confidence interval [CI]: 1.09–1.20, p < 0.001; N2 versus N0, HR = 1.35, 95% CI: 1.31–1.39, p < 0.001; and N3 versus N0, HR = 1.39, 95% CI: 1.34–1.44; p < 0.001) (Table 2).

gr1

Figure 1

Lung cancer–specific survival according to N categories in patients with NSCLC and M1a disease (A), M1a patients during 2005–2008 (B), and M1a patients during 2009–2012 (C).

 

Table 2

Cox Proportional Hazards Regression Model for Lung Cancer–Specific Survival in Patients with NSCLC with M1a Disease

 

Characteristic M1a Patients M1a Patients during 2005–2008 M1a Patients during 2009–2012
Hazard Ratios (95% CI) p Value Hazard Ratios (95% CI) p Value Hazard Ratios (95% CI) p Value
Age
 ≤65 y 1.00 (reference) 1.00 (reference) 1.00 (reference)
 >65 y 1.26 (1.23–1.29) <0.001 1.24 (1.21–1.28) <0.001 1.30 (1.25–1.36) <0.001
Sex
 Male 1.00 (reference) 1.00 (reference) 1.00 (reference)
 Female 0.86 (0.84–0.88) <0.001 0.88 (0.85–0.90) <0.001 0.84 (0.80–0.87) <0.001
Marriage
 Yes 1.00 (reference) 1.00 (reference) 1.00 (reference)
 No 1.17 (1.15–1.20) <0.001 1.16 (1.13–1.19) <0.001 1.21 (1.16–1.26) <0.001
Race/ethnic group
 White 1.00 (reference) 1.00 (reference) 1.00 (reference)
 Black 0.97 (0.94–1.01) 0.103 0.97 (0.93–1.01) 0.145 0.98 (0.92–1.04) 0.454
 Other 0.78 (0.75–0.81) <0.001 0.79 (0.76–0.83) <0.001 0.76 (0.71–0.81) <0.001
Location
 Main bronchus 1.00 (reference) 1.00 (reference) 1.00 (reference)
 Single lobe 0.85 (0.81–0.89) <0.001 0.88 (0.83–0.93) <0.001 0.78 (0.72–0.84) <0.001
 Overlapping lesion 0.98 (0.89–1.08) 0.657 1.05 (0.94–1.18) 0.399 0.85 (0.72–1.00) 0.052
 Unknown 0.94 (0.89–0.99) 0.012 0.95 (0.89–1.01) 0.091 0.91 (0.84–0.99) 0.042
Histological type
 Adenocarcinoma 1.00 (reference) 1.00 (reference) 1.00 (reference)
 Squamous cell carcinoma 1.02 (0.99–1.05) 0.279 0.99 (0.96–1.04) 0.84 1.07 (1.0–1.13) 0.009
 Other 1.15 (1.13–1.18) <0.001 1.12 (1.08–1.15) <0.001 1.23 (1.18–1.29) <0.001
T stage
 T1 1.00 (reference) 1.00 (reference) 1.00 (reference)
 T2 1.13 (1.09–1.17) <0.001 1.11 (1.07–1.16) <0.001 1.21 (1.12–1.31) <0.001
 T3 1.19 (1.14–1.24) <0.001 1.15 (1.10–1.21) <0.001 1.35 (1.23–1.48) <0.001
 T4 1.01 (0.97–1.05) 0.639 0.90 (0.82–0.98) 0.017 1.21 (1.12–1.30) <0.001
 Tx 1.56 (1.50–1.62) <0.001 1.49 (1.43–1.56) <0.001 1.79 (1.64–1.95) <0.001
N stage
 N0 1.00 (reference) 1.00 (reference) 1.00 (reference)
 N1 1.14 (1.09–1.20) <0.001 1.14 (1.07–1.20) <0.001 1.14 (1.05–1.24) 0.002
 N2 1.35 (1.31–1.39) <0.001 1.34 (1.30–1.38) <0.001 1.37 (1.31–1.43) <0.001
 N3 1.39 (1.34–1.44) <0.001 1.39 (1.34–1.45) <0.001 1.40 (1.32–1.48) <0.001
Radiotherapy
 Yes 1.00 (reference) 1.00 (reference) 1.00 (reference)
 No 1.18 (1.15–1.21) <0.001 1.16 (1.1–1.19) <0.001 1.24 (1.19–1.30) <0.001

CI, confidence interval.

Subgroup Analysis of Patients during Different Periods

Of all the M1a patients, 24,801 had their disease diagnosed during 2005–2008 and 14,930 had their disease diagnosed during 2009–2012. Table 1 shows the baseline characteristics of patients, tumors, and therapies for these two groups.

The survival analyses showed that the results for the two subgroups were consistent with those of the overall cohort (Fig. 1B and C). Specifically, M1a patients without lymph node involvement had the best LCSS (N0 versus N1, p = 0.018 for 2005–2008 and p = 0.009 for 2009–2012), followed by patients with N1 disease (N1 versus N2, p < 0.001 for 2005–2008 and p < 0.001 for 2009–2012). No difference in LCSS was observed between N2 disease and N3 disease (N2 versus N3, p = 0.998 for 2005–2008 and p = 0.293 for 2009–2012). In addition, multivariate analysis also confirmed that lymph node metastasis had a negative prognostic effect on patients with NSCLC with M1a disease (N1 versus N0, HR = 1.14, 95% CI: 1.07–1.20, p < 0.001 for 2005–2008 and HR = 1.14, 95% CI: 1.05–1.24, p = 0.002 for 2009–2012), (N2 versus N0, HR = 1.34, 95% CI: 1.30–1.38, p < 0.001 for 2005–2008 and HR = 1.37, 95% CI: 1.31–1.43, p < 0.001 for 2009–2012), and (N3 versus N0, HR = 1.39, 95% CI: 1.34–1.45, p < 0.001 for 2005–2008 and HR = 1.40, 95% CI: 1.32–1.48, p < 0.001 for 2009–2012) (Table 2).

Subgroup Analysis of Patients with Different Subtypes of M1a Disease

Of all M1a patients, 31,294 had pleural dissemination and 8437 had contralateral pulmonary nodules. Patients with pleural dissemination were further divided into two categories, including 29,197 patients with malignant pleural effusion (or pericardial effusion) and 2097 patients with malignant pleural nodules. Supplementary Tables 1 and 2 show the baseline characteristics of patients, tumors, and therapies for these subgroups.

In M1a patients with pleural dissemination, a significant difference in LCSS (p = 0.019) was noticed between those with lymph node negative and those with N1 involvement (Fig. 2A). Moreover, we discovered that pleural dissemination with N1 disease was significantly associated with better LCSS (p < 0.001) compared with N2 disease (Fig. 2A), yet no difference in survival rates was observed between patients with N2 disease and those with N3 disease (p = 0.856) (Fig. 2A). Similar survival results were obtained in the subgroup analysis of M1a patients with contralateral pulmonary nodules. Specifically, N0 patients had a better LCSS, followed by N1 patients, whereas no difference in LCSS was observed between N2 patients and N3 patients (N0 versus N1, p = 0.001; N1 versus N2, p < 0.001; and N2 versus N3, p = 0.361) (Fig. 2B). In the multivariate analysis, lymph node metastasis emerged as a significant prognostic factor for both M1a patients with pleural dissemination and those with contralateral pulmonary nodules (Table 3). Specifically, in patients with pleural dissemination, for N1 versus N0, HR = 1.11 (95% CI: 1.06–1.17, p < 0.001); for N2 versus N0, HR= 1.29 (95% CI: 1.25–1.33, p < 0.001); and for N3 versus N0, HR = 1.35 (95% CI: 1.29–1.40, p < 0.001), whereas in patients with contralateral pulmonary nodule, for N1 versus N0, HR = 1.22 (95% CI: 1.01–1.36, p < 0.001); for N2 versus N0, HR = 1.52 (95% CI: 1.43–1.62, p < 0.001); and for N3 versus N0, HR = 1.61 (95% CI: 1.49–1.73, p < 0.001).

gr2

Figure 2

Lung cancer–specific survival according to N categories in patients with malignant pleural dissemination (A), contralateral lung nodules (B), malignant pleural effusion (or pericardial effusion) (C), and malignant pleural nodules (D).

 

Table 3

Cox Proportional Hazards Regression Model for Lung Cancer–Specific Survival in Patients with NSCLC with Pleural Dissemination or Contralateral Lung Nodules

 

Characteristic Pleural Dissemination Contralateral Lung Nodules
Hazard Ratios (95% CI) p Value Hazard Ratios (95% CI) p Value
Age
 ≤65 y 1.00 (reference) 1.00 (reference)
 >65 y 1.26 (1.23–1.29) <0.001 1.29 (1.23–1.37) <0.001
Sex
 Male 1.00 (reference) 1.00 (reference)
 Female 0.90 (0.88–0.93) <0.001 0.79 (0.75–0.83) <0.001
Marriage
 Yes 1.00 (reference) 1.00 (reference)
 No 1.17 (1.14–1.20) <0.001 1.20 (1.14–1.26) <0.001
Race/ethnic group
 White 1.00 (reference) 1.00 (reference)
 Black 0.96 (0.93–1.00) 0.046 0.98 (0.91–1.05) 0.547
 Other 0.76 (0.72–0.79) <0.001 0.82 (0.75–0.90) <0.001
Location
 Main bronchus 1.00 (reference) 1.00 (reference)
 Single lobe 0.88 (0.84–0.93) <0.001 0.77 (0.69–0.86) <0.001
 Overlapping lesion 1.01 (0.91–1.12) 0.834 0.87 (0.69–1.09) 0.218
 Unknown 0.99 (0.94–1.05) 0.687 0.85 (0.75–0.96) 0.01
Histological type
 Adenocarcinoma 1.00 (reference) 1.00 (reference)
 Squamous cell carcinoma 1.02 (0.98–1.06) 0.298 1.15 (1.08–1.23) <0.001
 Other 1.17 (1.14–1.21) <0.001 1.15 (1.09–1.22) <0.001
T stage
 T1 1.00 (reference) 1.00 (reference)
 T2 1.12 (1.07–1.17) <0.001 1.28 (1.17–1.40) <0.001
 T3 1.34 (1.27–1.41) <0.001 1.34 (1.22–1.47) <0.001
 T4 0.98 (0.94–1.03) 0.47 1.28 (1.17–1.41) <0.001
 Tx 1.40 (1.34–1.46) <0.001 2.34 (2.10–2.61) <0.001
N stage
 N0 1.00 (reference) 1.00 (reference)
 N1 1.11 (1.06–1.17) <0.001 1.22 (1.01–1.36) <0.001
 N2 1.29 (1.25–1.33) <0.001 1.52 (1.43–1.62) <0.001
 N3 1.35 (1.29–1.40) <0.001 1.61 (1.49–1.73) <0.001
Radiotherapy
 Yes 1.00 (reference) 1.00 (reference)
 No 1.23 (1.20–1.26) <0.001 1.16 (1.10–1.23) <0.001

CI, confidence interval.

Survival analyses were also performed, with pleural dissemination divided into malignant pleural effusion (or pericardial effusion) and malignant pleural nodules. We found a difference in LCSS for N0 compared with for N1 in patients with malignant pleural effusion (or pericardial effusion) (p = 0.029) (Fig. 2C). Additionally, N1 patients had a better survival than did N2 patients (p < 0.001) (Fig. 2C), but survival for N2 patients was equivalent to that for N3 patients (p = 0.468) (Fig. 2C). In the other subgroup, we observed that with the upstaging of N category, LCSS decreased significantly in patients with malignant pleural nodules (N0 versus N1, p = 0.032) (N1 versus N2, p = 0.049) (N2 versus N3, p = 0.003) (Fig. 2D). Multivariable analyses suggested that both subgroups of patients without lymph node metastasis had better LCSS (Table 4). Specifically, in patients with malignant pleural effusion (or pericardial effusion), for N1 versus N0, HR = 1.11 (95% CI: 1.05–1.17, p < 0.001); for N2 versus N0, HR = 1.28 (95% CI: 1.24–1.32, p < 0.001); and for N3 versus N0, HR = 1.33 (95% CI: 1.27–1.38, p < 0.001), whereas in patients with malignant pleural nodules, for N1 versus N0, HR = 1.29 (95% CI: 1.06–1.56, p = 0.01); for N2 versus N0, HR = 1.41 (95% CI: 1.25–1.60, p < 0.001); and for N3 versus N, HR = 1.65 (95% CI: 1.41–1.93, p < 0.001).

Table 4

Cox Proportional Hazards Regression Model for Lung Cancer–Specific Survival in Patients with Malignant Pleural Effusion (or Pericardial Effusion) or Pleural Nodules

 

Characteristic Malignant Pleural Effusion Malignant Pleural Nodules
Hazard Ratios (95% CI) p Value Hazard Ratios (95% CI) p Value
Age
 ≤65 y 1.00 (reference) 1.00 (reference)
 >65 y 1.24 (1.21–1.28) <0.001 1.45 (1.31–1.60) <0.001
Sex
 Male 1.00 (reference) 1.00 (reference)
 Female 0.91 (0.88–0.93) <0.001 0.84 (0.76–0.93) 0.001
Marriage
 Yes 1.00 (reference) 1.00 (reference)
 No 1.16 (1.13–1.19) <0.001 1.19 (1.08–1.32) 0.001
Race/ethnic group
 White 1.00 (reference) 1.00 (reference)
 Black 0.97 (0.93–1.01) 0.087 0.90 (0.77–1.05) 0.186
 Other 0.76 (0.73–0.80) <0.001 0.76 (0.65–0.88) <0.001
Location
 Main bronchus 1.00 (reference) 1.00 (reference)
 Single lobe 0.89 (0.84–0.93) <0.001 0.92 (0.72–1.18) 0.509
 Overlapping lesion 1.02 (0.91–1.13) 0.764 0.94 (0.60–1.46) 0.771
 Unknown 0.98 (0.93–1.04) 0.502 1.19 (0.91–1.54) 0.199
Histological type
 Adenocarcinoma 1.00 (reference) 1.00 (reference)
 Squamous cell carcinoma 1.00 (0.96–1.04) 0.949 1.27 (1.09–1.47) 0.002
 Other 1.15 (1.12–1.18) <0.001 1.43 (1.28–1.60) <0.001
T stage
 T1 1.00 (reference) 1.00 (reference)
 T2 1.12 (1.07–1.17) <0.001 1.09 (0.93–1.28) 0.287
 T3 1.33 (1.26–1.40) <0.001 1.45 (1.17–1.80) 0.001
 T4 0.99 (0.95–1.04) 0.813 1.00 (0.84–1.18) 0.981
 Tx 1.39 (1.33–1.45) <0.001 1.44 (1.22–1.71) <0.001
N stage
 N0 1.00 (reference) 1.00 (reference)
 N1 1.11 (1.05–1.17) <0.001 1.29 (1.06–1.56) 0.01
 N2 1.28 (1.24–1.32) <0.001 1.41 (1.25–1.60) <0.001
 N3 1.33 (1.27–1.38) <0.001 1.65 (1.41–1.93) <0.001
Radiotherapy
 Yes 1.00 (reference) 1.00 (reference)
 No 1.26 (1.22–1.29) <0.001 0.91 (0.81–1.02) 0.104

CI, confidence interval.

Discussion

In 2007, International Staging Project on Lung Cancer proposed a new category of M1a in TNM staging.2 This category continues to be used in the forthcoming edition of TNM staging.10 Lymph node involvement is an important demarcation criterion for the staging of M0 patients, whereas M1a patients are all classified as stage IV regardless of any N status. Hence, the clinical value of N descriptors has been neglected and not well studied in M1a patients. However, our study found that the extent of lymph node metastasis also has a prognostic value for M1a patients. Specifically, M1a patients without lymph node involvement had the best survival, followed by those with N1 disease. Those with N2/N3 disease had the worst survival. This trend could be observed in all subgroups of M1a disease.

Although many efforts have been made to find some biomarkers with prognostic value for patients with advanced NSCLC, the high cost of testing and the extra need for tissue samples limited the extensive promotion of these indicators.11 Lymph node metastasis in lung cancer has been well established as a poor prognostic factor, and its pathway of spread through the intrapulmonary (N1), hilar (N1), and mediastinal lymph nodes (N2/N3) has been widely accepted. In 1978, Naruke et al. reported the first lymph node map with the anatomic definitions of 14 lymph node stations.12 Subsequently, the American Thoracic Society, the American Joint Committee on Cancer, and the Union for International Cancer Control modified this map several times, and it has been widely applied in the staging system for lung cancer to define the node levels.13 and 14 Nowadays, N descriptors have been well defined and were hardly revised in the two recent editions of TNM staging.7 and 8 In present clinical practice, accurate lymph node staging is utilized mainly to estimate prognosis, and it also contributes to determining treatment strategies and providing a common language when communicating about patients and enrolling them in trials.15 Our results supported that the prognostic value of lymph node staging extends even to M1a patients and indicated that accurate lymph node evaluation for M1a patients is still necessary to obtain important prognostic information.

Malignant pleural disease was reclassified from T4 to M1a in the seventh edition of TNM staging, and it was the largest subgroup in the M1a category (78% in our study). Recently, Iida et al. retrospectively reviewed 329 M1a patients with pleural dissemination selected from their national database and found that best N status (N0/N1) was as independent prognostic factor of survival when compared with N2/N3.5 In addition, some other studies with small case series,16 and 17 including our previous study,18 also showed that patients with M1a and N0/N1 disease had a better 5-year survival rate than did those with N2/N3 disease. One of the likely explanations for the phenomenon is that patients with early N status may have minor pleural effusion or not diffuse pleural metastatic nodules. In such patients, cancer cells might be well controlled by the comprehensive treatment. In addition, because of the small sample size of the previous studies, the authors failed to make a pairwise survival comparison among patients with different N status. In this present study, we selected a bigger sample size from the SEER database to achieve the larger power; moreover, a sensitivity analysis was also performed to verify the stability of results in subgroups of patients with malignant pleural effusion (or pericardial effusion) or with malignant pleural nodules. On the basis of the aforesaid evidence, it is suggested that early N status in M1a patients is associated with better survival and N descriptors have a predictive value for these patients.

Our study also indicated that M1a patients with contralateral lung nodules and early N status had better long-term cancer-specific survival. In fact, it is difficult to distinguish patients with contralateral lung metastasis from those with synchronous primary NSCLC. Nowadays, the distinction is estimated mainly on the basis of the clinicopathological criteria proposed by Martini and Melamed in 1975.19 Yet, with the rapid development of molecular diagnostic techniques, several studies have shown a high rate (up to 32%) of tumor misclassification when the Martini and Melamed criteria were compared with genomic or mutational analysis.20, 21, and 22 Thus, the misclassification from synchronous primary tumors to intrapulmonary metastases might be the reason for the better survival observed in patients with contralateral nodules and early N status. In addition, Morris et al. also identified 5161 M1a patients with contralateral lung nodules from the SEER database and concluded that N stage (N0/N1 versus N2/N3) may help distinguish contralateral pulmonary metastasis from synchronous primary tumors.23 Hence, the N status of M1a patients with contralateral lung nodules could provide not only prognostic information but also the evidence for differential diagnosis.

N status was evaluated by imaging technology or minimally invasive technology for most M1a patients. A meta-analysis by Dales et al. showed that computed tomography could provide acceptable sensitivity (79%) and specificity (78%) in assessing mediastinal nodal metastasis.24 In addition, another meta-analysis revealed that positron emission tomography imaging is a more sensitive and accurate method for N staging, with a sensitivity of 85% and specificity of 90%.25 Regarding invasive methods for N staging, mediastinoscopy is the current accepted standard.26 However, many studies have indicated that endobronchial ultrasound–guided transbronchial needle aspiration, which is associated with less injury, could achieve comparable outcomes for mediastinal lymph node staging.27 and 28 Thus, with the help of these methods, the lymph node status of M1a patients could be evaluated accurately and credibly.

Several strengths and limitations in this study should be pointed out. One advantage is that the SEER database provided a large number of M1a patients, which allowed us to detect relatively small differences in survival among N0, N1, and N2/N3 disease. In addition, the database contains cases from 18 areas in the United States, avoiding the bias that could have been caused by a single-center study. Thus, the universality of the results should be satisfactory. Thanks to these strengths, the SEER database has frequently been used to study NSCLC staging.2 and 29

On the other hand, SEER database also has its limitations. In this study, the SEER database could not distinguish between pathological and clinical N staging; thus, we could not perform subgroup analyses of pathological versus clinical N staging. In addition, some details of clinical practice regarding chemotherapy, radiotherapy, and surgery were not available. This study was also limited by the lack of some information, including patients’ functional status, comorbidities, and molecular mutation (EGFR). Therefore, further efforts on data collection of some clinical factors are encouraged to confirm our conclusion. Second, because of the difficulty in distinguishing contralateral lung or pleural metastasis from synchronous second primary tumor, our included cases may be confounded by the heterogeneity of patients with second primary tumor who have a better overall survival rate. As a final comment, we included the patients with either pleural dissemination or contralateral lung nodules in this study because the SEER database did not provide a specific code to identify the cases with both pleural dissemination and contralateral lung nodules. With the database improvement, it will be necessary for future studies to verify the prognostic factor of N status for patients with multiple M1a descriptors.

Conclusions

In summary, these results provide preliminary evidence that lymph node stage may have clinical significance among patients with NSCLC with M1a disease, adding prognostic information.

Acknowledgments

This study was supported by grants from the National Natural Science Foundation of China (81570014) and projects of the Science and Technology Commission of Shanghai Municipality (15JC1490900 and 14411962600), Health and Family Planning Commission of Shanghai Municipality (2013ZYJB0003), Shanghai Pujiang Program (15PJD034), and Shanghai Hospital Development Center (SHDC12015116).

Supplementary Data

figs1

Supplementary Figure 1

Download file

Supplementary Tables 1 and 2

References

  • 1 D. Morgensztern, S.H. Ng, F. Gao, R. Govindan. Trends in stage distribution for patients with non-small cell lung cancer: a National Cancer Database survey. J Thorac Oncol. 2010;5:29-33 Crossref
  • 2 P.E. Postmus, E. Brambilla, K. Chansky, et al. The IASLC Lung Cancer Staging Project: proposals for revision of the M descriptors in the forthcoming (seventh) edition of the TNM classification of lung cancer. J Thorac Oncol. 2007;2:686-693 Crossref
  • 3 H. Asamura, K. Chansky, J. Crowley, et al. The International Association for the Study of Lung Cancer Lung Cancer Staging Project: proposals for the revision of the N descriptors in the forthcoming 8th edition of the TNM classification for lung cancer. J Thorac Oncol. 2015;10:1675-1684
  • 4 P. Goldstraw, K. Chansky, J. Crowley, et al. The IASLC Lung Cancer Staging Project: proposals for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for lung cancer. J Thorac Oncol. 2016;11:39-51
  • 5 T. Iida, M. Shiba, I. Yoshino, et al. Surgical intervention for non-small-cell lung cancer patients with pleural carcinomatosis: results from the Japanese Lung Cancer Registry in 2004. J Thorac Oncol. 2015;10:1076-1082 Crossref
  • 6 National Cancer Institute. Surveillance, Epidemiology, and End Results. http://www.seer.cancer.gov. Accessed January 1, 2016.
  • 7 C.F. Mountain. Revisions in the International System for Staging Lung Cancer. Chest. 1997;111:1710-1717 Crossref
  • 8 F.C. Detterbeck, D.J. Boffa, L.T. Tanoue. The new lung cancer staging system. Chest. 2009;136:260-271 Crossref
  • 9 R.R. Veluswamy, N. Ezer, G. Mhango, et al. Limited resection versus lobectomy for older patients with early-stage lung cancer: impact of histology. J Clin Oncol. 2015;33:3447-3453
  • 10 W.E. Eberhardt, A. Mitchell, J. Crowley, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the M descriptors in the forthcoming eighth edition of the TNM classification of lung cancer. J Thorac Oncol. 2015;10:1515-1522
  • 11 J.N. Patel, J.L. Ersek, E.S. Kim. Lung cancer biomarkers, targeted therapies and clinical assays. Transl Lung Cancer Res. 2015;4:503-514
  • 12 T. Naruke, K. Suemasu, S. Ishikawa. Lymph node mapping and curability at various levels of metastasis in resected lung cancer. J Thorac Cardiovasc Surg. 1978;76:832-839
  • 13 American Thoracic Society. Medical section of the American Lung Association. Clinical staging of primary lung cancer. Am Rev Respir Dis. 1983;127:659-664
  • 14 C.F. Mountain. A new international staging system for lung cancer. Chest. 1986;89:225S-233S Crossref
  • 15 S.D. Murgu. Diagnosing and staging lung cancer involving the mediastinum. Chest. 2015;147:1401-1412 Crossref
  • 16 T. Okamoto, T. Iwata, T. Mizobuchi, et al. Pulmonary resection for lung cancer with malignant pleural disease first detected at thoracotomy. Eur J Cardiothorac Surg. 2012;41:25-30
  • 17 Y. Ichinose, R. Tsuchiya, T. Koike, et al. Prognosis of resected non-small cell lung cancer patients with carcinomatous pleuritis of minimal disease. Lung Cancer. 2001;32:55-60 Crossref
  • 18 Y.J. Ren, Y.L. She, C.Y. Dai, G.N. Jiang, K. Fei, C. Chen. Primary tumour resection showed survival benefits for non-small-cell lung cancers with unexpected malignant pleural dissemination. Interact Cardiovasc Thorac Surg. 2016;22:321-326
  • 19 N. Martini, M.R. Melamed. Multiple primary lung cancers. J Thorac Cardiovasc Surg. 1975;70:606-612
  • 20 J. Huang, C. Behrens, I. Wistuba, A.F. Gazdar, J. Jagirdar. Molecular analysis of synchronous and metachronous tumors of the lung: impact on management and prognosis. Ann Diagn Pathol. 2001;5:321-329 Crossref
  • 21 T. Mitsudomi, Y. Yatabe, T. Koshikawa, et al. Mutations of the P53 tumor suppressor gene as clonal marker for multiple primary lung cancers. J Thorac Cardiovasc Surg. 1997;114:354-360 Crossref
  • 22 N. Girard, I. Ostrovnaya, C. Lau, et al. Genomic and mutational profiling to assess clonal relationships between multiple non-small cell lung cancers. Clin Cancer Res. 2009;15:5184-5190 Crossref
  • 23 Z.S. Morris, D.M. Cannon, B.A. Morris, S.M. Bentzen, K.R. Kozak. Impact of a contralateral tumor nodule on survival in non-small-cell lung cancer. J Thorac Oncol. 2015;10:1608-1615
  • 24 R.E. Dales, R.M. Stark, S. Raman. Computed tomography to stage lung cancer. Approaching a controversy using meta-analysis. Am Rev Respir Dis. 1990;141:1096-1101 Crossref
  • 25 M.K. Gould, W.G. Kuschner, C.E. Rydzak, et al. Test performance of positron emission tomography and computed tomography for mediastinal staging in patients with non-small-cell lung cancer: a meta-analysis. Ann Intern Med. 2003;139:879-892 Crossref
  • 26 N. Navani, S.G. Spiro, S.M. Janes. Mediastinal staging of NSCLC with endoscopic and endobronchial ultrasound. Nat Rev Clin Oncol. 2009;6:278-286 Crossref
  • 27 K. Yasufuku, A. Pierre, G. Darling, et al. A prospective controlled trial of endobronchial ultrasound-guided transbronchial needle aspiration compared with mediastinoscopy for mediastinal lymph node staging of lung cancer. J Thorac Cardiovasc Surg. 2011;142:1393-1400
  • 28 S.W. Um, H.K. Kim, S.H. Jung, et al. Endobronchial ultrasound versus mediastinoscopy for mediastinal nodal staging of non-small-cell lung cancer. J Thorac Oncol. 2015;10:331-337 Crossref
  • 29 R. Rami-Porta, D. Ball, J. Crowley, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the T descriptors in the forthcoming (seventh) edition of the TNM classification for lung cancer. J Thorac Oncol. 2007;2:593-602 Crossref

Footnotes

Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China

Corresponding author. Address for correspondence: Chang Chen, MD, PhD, Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200443, People's Republic of China.

Drs. Dai and Ren equally contributed to this work.

Disclosure: The authors declare no conflict of interest.