- Email: [email protected]
Prognostic Significance of the Number of Metastatic pN2 Lymph Nodes in Stage IIIA-N2 Non–Small-Cell Lung Cancer After Curative Resection
Original Study
Prognostic Significance of the Number of Metastatic pN2 Lymph Nodes in Stage IIIA-N2 NoneSmall-Cell Lung Cancer After Curative Resection Changhoon Yoo,1 Shinkyo Yoon,1 Dae Ho Lee,1 Seung-Il Park,2 Dong Kwan Kim,2 Yong-Hee Kim,2 Hyeong Ryul Kim,2 Se Hoon Choi,2 Woo Sung Kim,3 Chang-Min Choi,1,3 Se Jin Jang,4 Si Yeol Song,5 Su Ssan Kim,5 Eun Kyung Choi,5 Jae Cheol Lee,1 Cheolwon Suh,1 Jung-Shin Lee,1 Sang-We Kim1 Abstract Stage IIIA-N2 nonesmall cell lung cancer (NSCLC) shows prognostic heterogeneity. We investigated the prognostic relevance of the number of metastatic pN2 nodes in patients with IIIA-N2 NSCLC. The criteria for the number of pN2 used in this study were significantly associated with the survival outcomes after surgery and may improve the accuracy of prognostic prediction in this subgroup of patients. Introduction: There have been controversies regarding the prognostic relevance of the number of positive N2 nodes in pathologic stage IIIA-N2 nonesmall-cell lung cancer (NSCLC). We examine prognosis of patients with pathologic stage IIIA-N2 with classifying the number of positive N2 nodes into subgroups. Methods: From January 1997 to December 2004, 250 patients were diagnosed with pathologic stage IIIA-N2 disease. All patients underwent mediastinal lymph node dissection. After excluding 44 patients with preoperative chemotherapy, incomplete resection, and postsurgical mortality, 206 patients were included in the analysis. Patients were classified according to the number of positive N2 lymph nodes (N2a: 1 [n ¼ 83], N2b: 2-4 [n ¼ 82], N2c: 5 [n ¼ 41]), and its correlation with survival outcomes were investigated. Results: With a median follow-up of 96.3 months, 5-year disease-free survival (DFS) was 27.2% (95% confidence interval [CI], 21.6-33.7), and 5-year overall survival (OS) was 37.7% (95% CI, 31.5-44.7) in all patients. The number of metastatic N2 lymph nodes was associated with DFS (P < .001) and OS (P ¼ .01). In the N2a, N2b, and N2c groups, 5-year DFS rates were 38%, 24%, and 5%, respectively, and 5-year OS rates were 47%, 35%, and 24%, respectively. In a multivariate analysis, the number of metastatic N2 lymph nodes was an independent prognostic factor for DFS and OS. Conclusion: Stratification of patients according to the number of metastatic N2 lymph nodes may improve the accuracy of prognostic prediction among patients with curatively resected stage IIIA-N2 NSCLC. Clinical Lung Cancer, Vol. -, No. -, 1-8 ª 2015 Elsevier Inc. All rights reserved. Keywords: Adjuvant treatment, N2, Nonesmall-cell lung cancer, Prognosis, Stage IIIA
Introduction Stage IIIA-N2 nonesmall-cell lung cancer (NSCLC) is a potentially operable, locally advanced disease. Because pathologically This study was presented in part as a poster at the 2010 ASCO Annual Meeting, June 4-9, 2010, Chicago, IL, USA. 1
Department of Oncology 2 Department of Thoracic Surgery 3 Department of Pulmonology and Critical Care Medicine 4 Department of Pathology 5 Department of Radiation Oncology Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
1525-7304/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cllc.2015.04.004
confirmed N2 (pN2) disease is classified according to the presence of mediastinal nodal metastasis regardless of its extent, it includes a broad spectrum of presentations, from occult disease to multiple Submitted: Feb 25, 2015; Revised: Apr 4, 2015; Accepted: Apr 14, 2015 Address for correspondence: Sang-We Kim, MD, PhD, Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea Fax: þ82-2-3010-6961; e-mail contact: [email protected]
Clinical Lung Cancer Month 2015
-1
Prognostic Significance of pN2 Lymph Nodes mediastinal nodal metastases. As a consequence, stage IIIA-N2 NSCLC has been linked to a variable prognosis in previous studies, with 5-year survival rates ranging from 6% to 35%.1,2 Although cisplatin-based adjuvant chemotherapy has led to significant improvements in survival in patients with resected NSCLC, particularly stage II and IIIA disease,3-5 the optimal management of stage IIIA-pN2 disease remains largely unknown, mainly as a result of the prognostic heterogeneity of this patient subgroup. With the hypothesis that the extent of pN2 metastasis may have prognostic relevance in patients with curatively resected stage IIIA-N2 NSCLC, several subclassifications of patients with pN2 disease have been proposed to improve staging—for example, based on skip pN2 metastasis6,7 or pN2 nodal station numbers.8-12 Although the prognostic implication of the number of metastatic lymph nodes in resected NSCLC has been explored in previous studies, its relevance in pathologic stage IIIA-N2 disease has not been clearly demonstrated.13-15 To investigate this, we retrospectively assessed whether the risk of disease relapse and survival after complete surgical resection could be stratified according to the number of metastatic pN2 lymph nodes in patients with IIIA-N2 NSCLC.
Materials and Methods Patients Between January 1997 and December 2004, 250 patients with pathologically confirmed stage IIIA-N2 NSCLC were selected for inclusion from a prospectively collected patient database of the Asan Medical Center, Seoul, Korea. According to the preoperative staging assessment, all patients were determined to have curatively resectable disease by the attending surgeons. Of these, 44 patients were excluded as a result of preoperative induction chemotherapy (n ¼ 28), incomplete resection (n ¼ 11), and immediate postsurgical mortality (defined as death within 30 days after surgery, n ¼ 5). The remaining 206 patients with stage IIIA-N2 NSCLC were included in this retrospective analysis. This study was approved by the Asan Medical Center institutional review board.
Preoperative Staging The initial staging was based on medical history, physical examination, complete blood counts, blood chemistry with electrolytes, chest x-ray, computed tomography (CT) of the chest and upper abdomen, biopsy, bronchoscopy, pulmonary function testing, and radionuclide bone scanning. In January 2002, 18F-fluorodeoxyglucose positron emission tomography (PET) was added to these routine modalities. Mediastinoscopy, transbronchial needle aspiration, endoscopic esophageal ultrasound-guided fine needle aspiration were performed for preoperative staging of lymph nodes, if clinically indicated. Staging using ultrasound-guided bronchoscopy with fine needle aspiration was not available during the study period. Brain CT or magnetic resonance imaging was performed in clinically indicated cases.
Treatment and Surveillance
2
-
The extent of surgical resection was determined by the operating surgeons. Complete mediastinal lymph node dissection was performed in all patients. Because the operating surgeons labeled
Clinical Lung Cancer Month 2015
dissected lymph nodes, meticulous pathologic examination of lymph nodes could be performed. Tumors were staged according to the American Joint Committee on Cancer, 6th edition,16 and lymph node levels were classified according to the American Thoracic Society numbering system.17 Because the role of adjuvant treatment was not clearly established during the study period, patients were enrolled onto the clinical trials of postoperative treatment if they were eligible. Study treatments in those trials included 2 cycles of MVP (mitomycin, vinblastine, and cisplatin), chemotherapy followed by radiotherapy,18 or radiotherapy with or without subsequent 4 cycles of NP (vinorelbine 25 mg/m2 on days 1 and 8, and cisplatin 60 mg/m2 on day 8). Radiotherapy was provided in a total dose of 50.4 Gy with a daily dose of 1.8 Gy. A chest CT scan was performed every 6 months during the first 2 years after surgery and every 1 year thereafter, or at any time when disease recurrence was suspected clinically. Treatment modalities and chemotherapeutic regimens in relapsed cases were at the discretion of the attending physician.
pN2 Subclassification To stratify outcomes according to the extent of pN2 metastasis, we grouped the patients according to the number of metastatic pN2 lymph nodes (group N2a, 1 node; group N2b, 2 to 4 nodes; group N2c, 5 or more nodes), skip pN2 lymph node metastasis (with or without concomitant pN1 disease),6 and the number of pN2 lymph node stations (single vs. multiple).
Statistical Analysis Disease-free survival (DFS) denotes the time from surgery to relapse or death from any cause. Overall survival (OS) was defined as the time from surgery to death from any cause. Clinically significant weight loss was defined as unintended weight loss > 10% within 6 months from diagnosis. Survival probability was estimated using the Kaplan-Meier method and compared by a log-rank test. A multivariate Cox proportional hazard regression model for the prognostic significance of pN2 subclassification included clinicopathologic variables that showed a potential correlation with survival outcomes (P < .2) in univariate analyses. A 2-sided P value of < .05 was considered to be statistically significant, and 95% confidence intervals (CI) were reported. SPSS software, version 18.0 (IBM), was used for all statistical analyses.
Results Patient Characteristics The patients’ baseline characteristics are summarized in Table 1. The median age was 59 years, and 145 patients (71%) were male. Significant weight loss was reported in 34 patients (17%) at the time of diagnosis. In 73 patients (35%), PET scan was performed for initial clinical staging. N2 nodal metastasis was predicted in 68 patients (33%) at the preoperative staging assessment, and pneumonectomy was performed in 43 patients (21%). According to the number of pN2 metastases, 83 patients (40%) were in the N2a group, 82 (40%) in the N2b group, and 41 (20%) in the N2c group. The median number of dissected lymph nodes (mediastinal lymph nodes) was 25 (15) in group N2a, 25 (16) in group N2b, and 29 (21) in group N2c. Skip pN2 and multiple-station
Changhoon Yoo et al Table 1 Baseline Clinicopathologic Characteristics of 206 Patients
Table 1 Continued Characteristic
Characteristic
Value
Sex Male
145 (70%)
Female
61 (30%)
Age, years, median [range]
59 [27-84]
ECOG performance status 0
72 (35%)
1
129 (63%)
2 Weight loss
Value
Adjuvant treatment No
28 (13%)
Radiotherapy alone
59 (29%)
Sequential chemotherapy and radiotherapy
119 (58%)
Abbreviations: ECOG ¼ Eastern Cooperative Oncology Group; PET ¼ positron emission tomography. a Unintentional loss of > 10% of normal body weight over a period of 6 months.
5 (2%) a
No
172 (83%)
Yes
34 (17%)
Smoking Current or ex-smoker Nonsmoker
141 (68%) 65 (32%)
pN2 Subclassification and Survival
Pathology Squamous cell carcinoma Adenocarcinoma Other
76 (37%) 111 (54%) 19 (9%)
PET for initial staging Yes
73 (35%)
No
133 (65%)
Clinical T stage cT1
40 (19%)
cT2
139 (68%)
cT3
26 (13%)
cT4
1 (<1%)
Clinical N stage cN0
92 (45%)
cN1
46 (22%)
cN2
68 (33%)
Surgical type Segmentectomy
2 (1%)
Lobectomy
143 (69%)
Bilobectomy
18 (9%)
Pneumonectomy
43 (21%)
Pathologic T stage pT1
41 (20%)
pT2
142 (69%)
pT3
23 (11%)
No. of metastatic pN2 lymph nodes 83 (40%)
2-4
82 (40%)
5
41 (20%)
pN2 lymph node station Multiple levels
With a median follow-up duration of 96.3 months, median DFS was 22.5 months (95% CI, 18.1-26.9), and median OS was 41.3 months (95% CI, 35.4-47.2) among all patients. The 5-year DFS rate was 27.2% (95% CI, 21.6-33.7), and the 5-year OS rate was 37.7% (95% CI, 31.5-44.7). The subclassification of patients according to the number of metastatic pN2 lymph nodes was significantly associated with DFS (P < .001; Figure 1A) and OS (P ¼ .01; Figure 1B). In groups N2a, N2b, and N2c, the 5-year DFS rates were 38%, 24%, and 5%, respectively, and the 5-year OS rates were 47%, 35%, and 24%, respectively. We also evaluated the prognostic relevance of the previously used pN2 subclassifications. Although skip pN2 metastasis was not associated with DFS (P ¼ .39) or OS (P ¼ .68), the number of pN2 nodal stations were significantly related with DFS (P ¼ .002) or OS (P ¼ .03). The 5-year DFS and OS rates were, respectively, 34% and 45% in patients with single-station pN2 disease, and 12% and 26% in patients with multiple-station pN2 disease (Figure 2). The number of metastatic pN2 lymph nodes and pN2 nodal stations were significantly correlated (P < .001; Supplemental Table 1 in the online version). In groups N2a, N2b, and N2c, metastasis in multiple pN2 stations was observed in 0, 49%, and 83%, respectively. In patients with single pN2 station nodal disease, 37% (49 of 132) had involvements of metastasis on more than 1 mediastinal lymph node.
Multivariate Analysis for DFS and OS
1
Single level
pN2 metastasis was observed in 56 (27%) and 74 (36%) patients, respectively. After surgical resection, 119 patients (58%) received postoperative sequential chemotherapy with radiotherapy, 59 patients (29%) received only radiotherapy, and 28 patients (13%) did not receive any adjuvant treatment.
132 (64%) 74 (36%)
Skip pN2 metastasis No
150 (73%)
Yes
56 (27%)
Multivariate analyses were performed to test the association between the number of metastatic N2 lymph nodes and DFS (Table 2) and OS (Table 3). Other clinicopathologic factors, such as age, sex, weight loss, surgical type, pathologic T stage, histology, and adjuvant therapy were used as covariates. The number of metastatic pN2 lymph nodes was found to be an independent predictor of prognosis in stage IIIA-N2 NSCLC patients in the multivariate model (for DFS, N2b vs. N2a, hazard ratio [HR], 1.50 [95% CI, 1.05-2.15], P ¼ .03, and N2c vs. N2a, HR, 2.87 [95% CI, 1.85-4.47], P < .001; for OS, N2b vs. N2a, HR, 1.62 [95% CI, 1.11-2.36],
Clinical Lung Cancer Month 2015
-3
Prognostic Significance of pN2 Lymph Nodes Figure 1 Disease-Free Survival (A) and Overall Survival (B) According to Number of Metastatic pN2 Lymph Nodes
4
-
P ¼ .01, and N2c vs. N2a, HR, 2.15 [95% CI, 1.38-3.37], P ¼ .001). In addition, pathologic T stage and adjuvant therapy were significant predictors of both DFS and OS, while old age (> 60 years) was a significant predictor of OS. Other multivariate models were developed with the inclusion of pN2 nodal stations instead of the number of metastatic pN2 lymph nodes (Supplemental Tables 2 and 3 in the online version). The
Clinical Lung Cancer Month 2015
pN2 nodal stations also remained significant for DFS (multiple levels vs. single level, HR, 1.69 [95% CI, 1.20-2.38], P ¼ .03) and OS (HR, 1.49 [95% CI, 1.08-2.07], P ¼ .02).
Discussion The prognosis of patients with resected stage IIIA-N2 NSCLC is heterogeneous, and better prognostic prediction is required for
Changhoon Yoo et al Figure 2 Disease-Free Survival (A) and Overall Survival (B) According to Number of Metastatic pN2 Stations
tailored therapy in this group of patients. However, many researchers have indicated that in patients with NSCLC, the current tumor, node, metastasis staging classification system does not accurately reflect the extent of mediastinal nodal metastasis that may be closely associated with survival outcomes. To circumvent this problem, a variety of pN2 subclassifications have been introduced.6-12 In this study, we found the prognostic relevance of the number of metastatic pN2 lymph nodes (1 node vs. 2 to 4 nodes vs. 5 nodes) in patients with stage IIIA-N2 NSCLC after curative
resection. Furthermore, this parameter was the strongest predictor of survival outcomes among all the investigated clinicopathologic characteristics. Our results suggest that this strategy for patient stratification might be useful to improve the accuracy of prognostic prediction. The prognostic implication of the number of metastatic lymph nodes in resected NSCLC has been explored in previous studies.13-15 These studies, which included all stages of resected NSCLC, have suggested that the classification using the number of
Clinical Lung Cancer Month 2015
-5
Prognostic Significance of pN2 Lymph Nodes Table 2 Univariate and Multivariate Analyses for Disease-Free Survival Univariate Analysis Characteristic
cHR
95% CI
Multivariate Analysis P
aHR
95% CI
P
0.52-1.04
.08
Age 60 years
1.00
e
>60 years
1.28
0.94-1.74
.12
Sex Male
1.00
e
Female
0.83
0.60-1.16
1.00 .28
0.73 1.00
e
.04
1.45
0.97-2.16
Weight loss No
1.00
e
Yes
1.52
1.03-2.25
Segmentectomy, lobectomy, bilobectomy
1.00
e
Pneumonectomy
1.08
0.74-1.56
.07
Surgical type .69
Pathologic T stage pT1/2
1.00
e
pT3
1.71
1.07-2.74
1.00
e
.02
1.66
1.02-2.71
.04
No. of metastatic pN2 lymph nodes N2a (1)
1.00
e
1.00
e
N2b (2-4)
1.45
1.01-2.06
.04
1.50
1.05-2.15
.03
N2c (5)
2.28
1.50-3.46
<.001
2.87
1.85-4.47
<.001
Histology Squamous cell carcinoma
1.00
e
Adenocarcinoma
1.24
0.89-1.74
Others
1.17
0.66-2.07
Adjuvant treatment
.20 .60 .01
No
1.00
e
1.00
e
Radiotherapy alone
0.80
0.48-1.33
.38
0.85
0.50-1.45
.55
Sequential chemotherapy and radiotherapy
0.54
0.33-0.86
.01
0.46
0.28-0.75
.002
Abbreviations: aHR ¼ adjusted hazard ratio; cHR ¼ crude hazard ratio; CI ¼ confidence interval.
6
-
metastatic lymph nodes might be a better discriminant than the current location-based pN classification. However, the significance of the number of metastatic lymph nodes seemed to be prominent in patients with pN2 NSCLC rather than pN1 NSCLC.13,14 This may indicate that the location of metastatic lymph nodes should not be disregarded, and subclassification using the number of metastatic lymph nodes might be more suitable in pN2 disease that has more heterogeneous prognostic features. Stratification according to the number of tumor-involved lymph nodes is a current standard for staging of other types of cancers, such as those of stomach, breast, and colon. Because current nodal staging for NSCLC is based only on the location of metastatic lymph nodes, this may not accurately reflect the impact of tumor burden in mediastinal nodal metastasis in pN2 disease. Our findings demonstrate that stratification of patients with stage IIIA-N2 according to the extent of mediastinal node involvement improves the prediction of clinical outcomes. This may help physicians select therapeutic strategies according to the risk of recurrence and may enhance the efficacy of clinical trials investigating novel treatments for this group of patients. However, there are still concerns for staging using the number of metastatic lymph nodes because
Clinical Lung Cancer Month 2015
lymphadenectomy is not conducted identically between surgeons and varies geographically. Moreover, the estimation of number of metastatic lymph nodes is largely dependent on the pathologists and surgeons, and inter- or intraobserver variations might be large, particularly in cases of fragmented nodes or a conglomerate of matted nodes. These limitations might be addressed in the future studies. The prognostic utility of the metastatic patterns in mediastinal nodes has been studied extensively in stage IIIA-N2 NSCLC. Staging according to skip mediastinal metastasis (determined by the presence of concomitant pN1 disease) and metastatic pN2 station (determined by the number of metastatic pN2 stations) has also been investigated and showed a correlation with prognosis in multiple retrospective studies.1,9-12,19-21 Although skip mediastinal metastasis did not show significant association with survival outcomes, metastatic pN2 stations was an independent prognostic factor for DFS and OS in our study. However, the magnitude of impact of the number of metastatic pN2 lymph nodes on DFS and OS (ie, HR) was greater than that of the metastatic pN2 station. In addition, patients with lower or higher risk of relapse or death could be found with subclassification using the number of metastatic pN2
Changhoon Yoo et al Table 3 Univariate and Multivariate Analyses for Overall Survival Univariate Analysis Characteristic
cHR
95% CI
Multivariate Analysis P
aHR
.01
1.42
95% CI
P
1.02-1.97
.04
Age 60 years
1.00
e
>60 years
1.49
1.08-2.04
1.00
Sex Male
1.00
e
Female
0.80
0.56-1.13
.20
Weight loss No
1.00
e
Yes
1.41
0.94-2.11
Segmentectomy, lobectomy, bilobectomy
1.00
e
Pneumonectomy
1.20
0.83-1.74
.10
Surgical type .34
Pathologic T stage pT1/2
1.00
e
pT3
1.75
1.09-2.80
1.00
e
.02
1.66
1.02-2.70
.04
No. of metastatic pN2 lymph nodes N2a (1)
1.00
e
1.00
e
N2b (2-4)
1.50
1.04-2.17
.03
1.62
1.11-2.36
.01
N2c (5)
1.83
1.19-2.80
.006
2.15
1.38-3.37
.001
Histology Squamous cell carcinoma
1.00
e
Adenocarcinoma
1.13
0.80-1.59
.49
Other
1.39
0.78-2.48
.26
Adjuvant treatment No
1.00
e
1.00
e
Radiotherapy alone
0.82
0.49-1.39
.47
0.81
0.46-1.41
.46
Sequential chemotherapy and radiotherapy
0.61
0.38-0.98
.04
0.59
0.36-0.99
.05
Abbreviations: aHR ¼ adjusted hazard ratio; cHR ¼ crude hazard ratio; CI ¼ confidence interval.
lymph nodes (5-year DFS ranged from 5% to 38% and 5-year OS ranged from 24% to 47%) compared to the metastatic pN2 stations (5-year DFS ranged from 12% to 34% and 5-year OS ranged from 26% to 45%). Because 37% of patients with single pN2 station nodal disease showed metastasis on multiple pN2 lymph nodes, the number of metastatic pN2 lymph nodes might have an advantage, at least in the identification of low-risk patients with minimal tumor burden on the mediastinal nodes. Although adjuvant chemotherapy and/or radiotherapy has been recommended for medically fit patients with completely resected stage IIIA-N2 NSCLC, the optimal therapeutic strategies and best chemotherapeutic regimens are yet to be defined as a result of a lack of evidence from randomized phase 3 trials.22 In this study, patients who received adjuvant chemoradiotherapy had significantly longer DFS than those who did not receive any adjuvant treatment, whereas radiotherapy alone did not have a significant impact on DFS. However, these findings should be interpreted cautiously because our analysis was performed retrospectively, and it was not intended to compare the efficacy of different treatment modalities. The strengths of our study include the relatively large sample size, a homogeneous study population that included only patients after
complete resection without previous neoadjuvant treatments, and a long-term follow-up. It should be remembered, however, that the study design was retrospective and based on a single center, which has the potential to introduce bias.
Conclusion The number of metastatic pN2 lymph nodes is an independent predictor of DFS and OS in patients with stage IIIA-N2 NSCLC after curative surgery. This may have an application in clinical practice and trials, where risk stratification is important. Further studies to validate this pN2 subclassification in other populations are warranted.
Clinical Practice Points Pathologic IIIA-N2 NSCLC shows heterogeneous prognosis. Although the number of positive N2 nodal stations is known as
prognostic factor, there have been controversies regarding the number of positive N2 nodes. We found that the number of positive N2 nodes (1 vs. 2 to 4 vs. 5) was significantly correlated with survival outcomes after curative surgery.
Clinical Lung Cancer Month 2015
-7
Prognostic Significance of pN2 Lymph Nodes The optimal management of IIIA-N2 disease remains largely
unknown, mainly as a result of the prognostic heterogeneity of this patient subgroup. Our results suggest that the number of positive N2 nodes might be useful to improve the accuracy of prognostic prediction as well as for risk stratification in clinical practice and trials.
Disclosure The authors have stated that they have no conflicts of interest.
Supplemental Data Supplemental tables accompanying this article can be found in the online version at http://dx.doi.org/10.1016/j.cllc.2015.04.004.
References 1. Vansteenkiste JF, De Leyn PR, Deneffe GJ, et al. Clinical prognostic factors in surgically treated stage IIIAeN2 nonesmall cell lung cancer: analysis of the literature. Lung Cancer 1998; 19:3-13. 2. Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of Malignant Tumours. J Thorac Oncol 2007; 2:706-14. 3. Arriagada R, Bergman B, Dunant A, et al. Cisplatin-based adjuvant chemotherapy in patients with completely resected nonesmall-cell lung cancer. N Engl J Med 2004; 350:351-60. 4. Winton T, Livingston R, Johnson D, et al. Vinorelbine plus cisplatin vs. observation in resected nonesmall-cell lung cancer. N Engl J Med 2005; 352: 2589-97. 5. Douillard JY, Rosell R, De Lena M, et al. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IBeIIIA nonesmallcell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol 2006; 7:719-27. 6. Riquet M, Assouad J, Bagan P, et al. Skip mediastinal lymph node metastasis and lung cancer: a particular N2 subgroup with a better prognosis. Ann Thorac Surg 2005; 79:225-33.
8
-
Clinical Lung Cancer Month 2015
7. Ilic N, Petricevic A, Arar D, et al. Skip mediastinal nodal metastases in the IIIa/N2 nonesmall cell lung cancer. J Thorac Oncol 2007; 2:1018-21. 8. Vansteenkiste JF, De Leyn PR, Deneffe GJ, et al. Survival and prognostic factors in resected N2 nonesmall cell lung cancer: a study of 140 cases. Leuven Lung Cancer Group. Ann Thorac Surg 1997; 63:1441-50. 9. Casali C, Stefani A, Natali P, et al. Prognostic factors in surgically resected N2 nonesmall cell lung cancer: the importance of patterns of mediastinal lymph nodes metastases. Eur J Cardiothorac Surg 2005; 28:33-8. 10. Keller SM, Vangel MG, Wagner H, et al. Prolonged survival in patients with resected nonesmall cell lung cancer and single-level N2 disease. J Thorac Cardiovasc Surg 2004; 128:130-7. 11. Andre F, Grunenwald D, Pignon JP, et al. Survival of patients with resected N2 nonesmall-cell lung cancer: evidence for a subclassification and implications. J Clin Oncol 2000; 18:2981-9. 12. Ichinose Y, Kato H, Koike T, et al. Completely resected stage IIIA nonesmall cell lung cancer: the significance of primary tumor location and N2 station. J Thorac Cardiovasc Surg 2001; 122:803-8. 13. Wei S, Asamura H, Kawachi R, et al. Which is the better prognostic factor for resected nonesmall cell lung cancer: the number of metastatic lymph nodes or the currently used nodal stage classification? J Thorac Oncol 2011; 6:310-8. 14. Fukui T, Mori S, Yokoi K, et al. Significance of the number of positive lymph nodes in resected nonesmall cell lung cancer. J Thorac Oncol 2006; 1:120-5. 15. Lee JG, Lee CY, Park IK, et al. Number of metastatic lymph nodes in resected nonesmall cell lung cancer predicts patient survival. Ann Thorac Surg 2008; 85: 211-5. 16. Sobin L, Wittekind CH. TNM Classification of Malignant Tumours. 6th ed. New York, NY: Wiley-Liss; 2002. 17. Tisi GM, Friedman PJ, Peters RM, et al. American Thoracic Society; Medical Section of the American Lung Association. Clinical staging of primary lung cancer. Am Rev Respir Dis 1983; 127:659-64. 18. Lee SW, Choi EK, Chung WK, et al. Postoperative adjuvant chemotherapy and radiotherapy for stage II and III nonesmall cell lung cancer (NSCLC). Lung Cancer 2002; 37:65-71. 19. Kang CH, Ra YJ, Kim YT, et al. The impact of multiple metastatic nodal stations on survival in patients with resectable N1 and N2 nonsmall-cell lung cancer. Ann Thorac Surg 2008; 86:1092-7. 20. Sonobe M, Date H, Wada H, et al. Prognostic factors after complete resection of pN2 nonesmall cell lung cancer. J Thorac Cardiovasc Surg 2013; 146:788-95. 21. Nakagiri T, Sawabata N, Funaki S, et al. Validation of pN2 sub-classifications in patients with pathological stage IIIA N2 nonesmall cell lung cancer. Interact Cardiovasc Thorac Surg 2011; 12:733-8. 22. Vansteenkiste J, De Ruysscher D, Eberhardt WE, et al. Early and locally advanced nonesmall-cell lung cancer (NSCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013; 24(suppl 6):vi89-98.
Changhoon Yoo et al Supplementary Table S1 Distribution of pN2 Subgroups by the Number of Metastatic pN2 Lymph Nodes and pN2 Nodal Stations No. of Metastatic pN2 Lymph Nodes N2a (n[83) N2b (n[82) N2c (n[41)
Total
pN2 nodal stations Single level
83 (100%)
42 (51%)
7 (17%)
132
0
40 (49%)
34 (83%)
74
Multiple levels
Supplementary Table S2 Univariate and Multivariate Analyses for Disease-Free Survival With Inclusion of the pN2 Nodal Stations Univariate Analysis cHR
95% CI
60 years
1.00
e
>60 years
1.28
0.94-1.74
Multivariate Analysis P-Value
95% CI
P-Value
0.63
0.43-0.92
.02
1.00
e
1.58
1.05-2.37
1.00
e
.02
1.67
1.00-2.78
1.00
e
.002
1.69
1.20-2.38
.03
aHR
Age .12
Sex Male
1.00
e
Female
0.83
0.60-1.16
No
1.00
e
Yes
1.52
1.03-2.25
1.00 .28
Weight loss .04
.03
Surgical type Segmentectomy/lobectomy/bilobectomy
1.00
e
Pneumonectomy
1.08
0.74-1.56
pT1/2
1.00
e
pT3
1.71
1.07-2.74
.69
Pathologic T stage .05
pN2 nodal stations Single level
1.00
e
Multiple levels
1.65
1.20-2.26
Squamous cell carcinoma
1.00
e
Adenocarcinoma
1.24
0.89-1.74
.20
1.67
1.13-2.47
.01
Others
1.17
0.66-2.07
.60
1.32
0.71-2.47
.39
Histology
Adjuvant treatment
1.00
.01
None
1.00
e
1.00
e
Radiotherapy alone
0.80
0.48-1.33
.38
0.77
0.45-1.33
.35
Sequential chemotherapy and radiotherapy
0.54
0.33-0.86
.01
0.47
0.28-0.77
.003
Abbreviations: cHR ¼ crude hazard ratio; aHR ¼ adjusted hazard ratio; CI ¼ confidence interval.
Clinical Lung Cancer Month 2015
- 8.e1
Prognostic Significance of pN2 Lymph Nodes Supplementary Table S3 Univariate and Multivariate Analyses for Overall Survival With Inclusion of the pN2 Nodal Stations Univariate Analysis cHR
95% CI
Multivariate Analysis P-Value
aHR
.01
1.64
95% CI
P-Value
1.19-2.27
.003
Age 60 years
1.00
e
>60 years
1.49
1.08-2.04
1.00
Sex Male
1.00
e
Female
0.80
0.56-1.13
.20
Weight loss No
1.00
e
Yes
1.41
0.94-2.11
.10
1.00
e
1.51
1.00-2.27
.05
Surgical type Segmentectomy/lobectomy/bilobectomy
1.00
e
Pneumonectomy
1.20
0.83-1.74
.34
Pathologic T stage pT1/2
1.00
e
pT3
1.75
1.09-2.80
.02
pN2 nodal stations Single level
1.00
e
Multiple levels
1.43
1.03-1.97
.03
Histology Squamous cell carcinoma
1.00
e
Adenocarcinoma
1.13
0.80-1.59
.49
Others
1.39
0.78-2.48
.26
Adjuvant treatment No
1.00
e
Radiotherapy alone
0.82
0.49-1.39
.47
Sequential chemotherapy and radiotherapy
0.61
0.38-0.98
.04
Abbreviations: cHR ¼ crude hazard ratio; aHR ¼ adjusted hazard ratio; CI ¼ confidence interval.
8.e2
-
Clinical Lung Cancer Month 2015
1.00
e
1.49
1.08-2.07
.02
Prognostic Significance of the Number of Metastatic pN2 Lymph Nodes in Stage IIIA-N2 NoneSmall-Cell Lung Cancer After Curative Resection Changhoon Yoo,1 Shinkyo Yoon,1 Dae Ho Lee,1 Seung-Il Park,2 Dong Kwan Kim,2 Yong-Hee Kim,2 Hyeong Ryul Kim,2 Se Hoon Choi,2 Woo Sung Kim,3 Chang-Min Choi,1,3 Se Jin Jang,4 Si Yeol Song,5 Su Ssan Kim,5 Eun Kyung Choi,5 Jae Cheol Lee,1 Cheolwon Suh,1 Jung-Shin Lee,1 Sang-We Kim1 Abstract Stage IIIA-N2 nonesmall cell lung cancer (NSCLC) shows prognostic heterogeneity. We investigated the prognostic relevance of the number of metastatic pN2 nodes in patients with IIIA-N2 NSCLC. The criteria for the number of pN2 used in this study were significantly associated with the survival outcomes after surgery and may improve the accuracy of prognostic prediction in this subgroup of patients. Introduction: There have been controversies regarding the prognostic relevance of the number of positive N2 nodes in pathologic stage IIIA-N2 nonesmall-cell lung cancer (NSCLC). We examine prognosis of patients with pathologic stage IIIA-N2 with classifying the number of positive N2 nodes into subgroups. Methods: From January 1997 to December 2004, 250 patients were diagnosed with pathologic stage IIIA-N2 disease. All patients underwent mediastinal lymph node dissection. After excluding 44 patients with preoperative chemotherapy, incomplete resection, and postsurgical mortality, 206 patients were included in the analysis. Patients were classified according to the number of positive N2 lymph nodes (N2a: 1 [n ¼ 83], N2b: 2-4 [n ¼ 82], N2c: 5 [n ¼ 41]), and its correlation with survival outcomes were investigated. Results: With a median follow-up of 96.3 months, 5-year disease-free survival (DFS) was 27.2% (95% confidence interval [CI], 21.6-33.7), and 5-year overall survival (OS) was 37.7% (95% CI, 31.5-44.7) in all patients. The number of metastatic N2 lymph nodes was associated with DFS (P < .001) and OS (P ¼ .01). In the N2a, N2b, and N2c groups, 5-year DFS rates were 38%, 24%, and 5%, respectively, and 5-year OS rates were 47%, 35%, and 24%, respectively. In a multivariate analysis, the number of metastatic N2 lymph nodes was an independent prognostic factor for DFS and OS. Conclusion: Stratification of patients according to the number of metastatic N2 lymph nodes may improve the accuracy of prognostic prediction among patients with curatively resected stage IIIA-N2 NSCLC. Clinical Lung Cancer, Vol. -, No. -, 1-8 ª 2015 Elsevier Inc. All rights reserved. Keywords: Adjuvant treatment, N2, Nonesmall-cell lung cancer, Prognosis, Stage IIIA
Introduction Stage IIIA-N2 nonesmall-cell lung cancer (NSCLC) is a potentially operable, locally advanced disease. Because pathologically This study was presented in part as a poster at the 2010 ASCO Annual Meeting, June 4-9, 2010, Chicago, IL, USA. 1
Department of Oncology 2 Department of Thoracic Surgery 3 Department of Pulmonology and Critical Care Medicine 4 Department of Pathology 5 Department of Radiation Oncology Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
1525-7304/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cllc.2015.04.004
confirmed N2 (pN2) disease is classified according to the presence of mediastinal nodal metastasis regardless of its extent, it includes a broad spectrum of presentations, from occult disease to multiple Submitted: Feb 25, 2015; Revised: Apr 4, 2015; Accepted: Apr 14, 2015 Address for correspondence: Sang-We Kim, MD, PhD, Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea Fax: þ82-2-3010-6961; e-mail contact: [email protected]
Clinical Lung Cancer Month 2015
-1
Prognostic Significance of pN2 Lymph Nodes mediastinal nodal metastases. As a consequence, stage IIIA-N2 NSCLC has been linked to a variable prognosis in previous studies, with 5-year survival rates ranging from 6% to 35%.1,2 Although cisplatin-based adjuvant chemotherapy has led to significant improvements in survival in patients with resected NSCLC, particularly stage II and IIIA disease,3-5 the optimal management of stage IIIA-pN2 disease remains largely unknown, mainly as a result of the prognostic heterogeneity of this patient subgroup. With the hypothesis that the extent of pN2 metastasis may have prognostic relevance in patients with curatively resected stage IIIA-N2 NSCLC, several subclassifications of patients with pN2 disease have been proposed to improve staging—for example, based on skip pN2 metastasis6,7 or pN2 nodal station numbers.8-12 Although the prognostic implication of the number of metastatic lymph nodes in resected NSCLC has been explored in previous studies, its relevance in pathologic stage IIIA-N2 disease has not been clearly demonstrated.13-15 To investigate this, we retrospectively assessed whether the risk of disease relapse and survival after complete surgical resection could be stratified according to the number of metastatic pN2 lymph nodes in patients with IIIA-N2 NSCLC.
Materials and Methods Patients Between January 1997 and December 2004, 250 patients with pathologically confirmed stage IIIA-N2 NSCLC were selected for inclusion from a prospectively collected patient database of the Asan Medical Center, Seoul, Korea. According to the preoperative staging assessment, all patients were determined to have curatively resectable disease by the attending surgeons. Of these, 44 patients were excluded as a result of preoperative induction chemotherapy (n ¼ 28), incomplete resection (n ¼ 11), and immediate postsurgical mortality (defined as death within 30 days after surgery, n ¼ 5). The remaining 206 patients with stage IIIA-N2 NSCLC were included in this retrospective analysis. This study was approved by the Asan Medical Center institutional review board.
Preoperative Staging The initial staging was based on medical history, physical examination, complete blood counts, blood chemistry with electrolytes, chest x-ray, computed tomography (CT) of the chest and upper abdomen, biopsy, bronchoscopy, pulmonary function testing, and radionuclide bone scanning. In January 2002, 18F-fluorodeoxyglucose positron emission tomography (PET) was added to these routine modalities. Mediastinoscopy, transbronchial needle aspiration, endoscopic esophageal ultrasound-guided fine needle aspiration were performed for preoperative staging of lymph nodes, if clinically indicated. Staging using ultrasound-guided bronchoscopy with fine needle aspiration was not available during the study period. Brain CT or magnetic resonance imaging was performed in clinically indicated cases.
Treatment and Surveillance
2
-
The extent of surgical resection was determined by the operating surgeons. Complete mediastinal lymph node dissection was performed in all patients. Because the operating surgeons labeled
Clinical Lung Cancer Month 2015
dissected lymph nodes, meticulous pathologic examination of lymph nodes could be performed. Tumors were staged according to the American Joint Committee on Cancer, 6th edition,16 and lymph node levels were classified according to the American Thoracic Society numbering system.17 Because the role of adjuvant treatment was not clearly established during the study period, patients were enrolled onto the clinical trials of postoperative treatment if they were eligible. Study treatments in those trials included 2 cycles of MVP (mitomycin, vinblastine, and cisplatin), chemotherapy followed by radiotherapy,18 or radiotherapy with or without subsequent 4 cycles of NP (vinorelbine 25 mg/m2 on days 1 and 8, and cisplatin 60 mg/m2 on day 8). Radiotherapy was provided in a total dose of 50.4 Gy with a daily dose of 1.8 Gy. A chest CT scan was performed every 6 months during the first 2 years after surgery and every 1 year thereafter, or at any time when disease recurrence was suspected clinically. Treatment modalities and chemotherapeutic regimens in relapsed cases were at the discretion of the attending physician.
pN2 Subclassification To stratify outcomes according to the extent of pN2 metastasis, we grouped the patients according to the number of metastatic pN2 lymph nodes (group N2a, 1 node; group N2b, 2 to 4 nodes; group N2c, 5 or more nodes), skip pN2 lymph node metastasis (with or without concomitant pN1 disease),6 and the number of pN2 lymph node stations (single vs. multiple).
Statistical Analysis Disease-free survival (DFS) denotes the time from surgery to relapse or death from any cause. Overall survival (OS) was defined as the time from surgery to death from any cause. Clinically significant weight loss was defined as unintended weight loss > 10% within 6 months from diagnosis. Survival probability was estimated using the Kaplan-Meier method and compared by a log-rank test. A multivariate Cox proportional hazard regression model for the prognostic significance of pN2 subclassification included clinicopathologic variables that showed a potential correlation with survival outcomes (P < .2) in univariate analyses. A 2-sided P value of < .05 was considered to be statistically significant, and 95% confidence intervals (CI) were reported. SPSS software, version 18.0 (IBM), was used for all statistical analyses.
Results Patient Characteristics The patients’ baseline characteristics are summarized in Table 1. The median age was 59 years, and 145 patients (71%) were male. Significant weight loss was reported in 34 patients (17%) at the time of diagnosis. In 73 patients (35%), PET scan was performed for initial clinical staging. N2 nodal metastasis was predicted in 68 patients (33%) at the preoperative staging assessment, and pneumonectomy was performed in 43 patients (21%). According to the number of pN2 metastases, 83 patients (40%) were in the N2a group, 82 (40%) in the N2b group, and 41 (20%) in the N2c group. The median number of dissected lymph nodes (mediastinal lymph nodes) was 25 (15) in group N2a, 25 (16) in group N2b, and 29 (21) in group N2c. Skip pN2 and multiple-station
Changhoon Yoo et al Table 1 Baseline Clinicopathologic Characteristics of 206 Patients
Table 1 Continued Characteristic
Characteristic
Value
Sex Male
145 (70%)
Female
61 (30%)
Age, years, median [range]
59 [27-84]
ECOG performance status 0
72 (35%)
1
129 (63%)
2 Weight loss
Value
Adjuvant treatment No
28 (13%)
Radiotherapy alone
59 (29%)
Sequential chemotherapy and radiotherapy
119 (58%)
Abbreviations: ECOG ¼ Eastern Cooperative Oncology Group; PET ¼ positron emission tomography. a Unintentional loss of > 10% of normal body weight over a period of 6 months.
5 (2%) a
No
172 (83%)
Yes
34 (17%)
Smoking Current or ex-smoker Nonsmoker
141 (68%) 65 (32%)
pN2 Subclassification and Survival
Pathology Squamous cell carcinoma Adenocarcinoma Other
76 (37%) 111 (54%) 19 (9%)
PET for initial staging Yes
73 (35%)
No
133 (65%)
Clinical T stage cT1
40 (19%)
cT2
139 (68%)
cT3
26 (13%)
cT4
1 (<1%)
Clinical N stage cN0
92 (45%)
cN1
46 (22%)
cN2
68 (33%)
Surgical type Segmentectomy
2 (1%)
Lobectomy
143 (69%)
Bilobectomy
18 (9%)
Pneumonectomy
43 (21%)
Pathologic T stage pT1
41 (20%)
pT2
142 (69%)
pT3
23 (11%)
No. of metastatic pN2 lymph nodes 83 (40%)
2-4
82 (40%)
5
41 (20%)
pN2 lymph node station Multiple levels
With a median follow-up duration of 96.3 months, median DFS was 22.5 months (95% CI, 18.1-26.9), and median OS was 41.3 months (95% CI, 35.4-47.2) among all patients. The 5-year DFS rate was 27.2% (95% CI, 21.6-33.7), and the 5-year OS rate was 37.7% (95% CI, 31.5-44.7). The subclassification of patients according to the number of metastatic pN2 lymph nodes was significantly associated with DFS (P < .001; Figure 1A) and OS (P ¼ .01; Figure 1B). In groups N2a, N2b, and N2c, the 5-year DFS rates were 38%, 24%, and 5%, respectively, and the 5-year OS rates were 47%, 35%, and 24%, respectively. We also evaluated the prognostic relevance of the previously used pN2 subclassifications. Although skip pN2 metastasis was not associated with DFS (P ¼ .39) or OS (P ¼ .68), the number of pN2 nodal stations were significantly related with DFS (P ¼ .002) or OS (P ¼ .03). The 5-year DFS and OS rates were, respectively, 34% and 45% in patients with single-station pN2 disease, and 12% and 26% in patients with multiple-station pN2 disease (Figure 2). The number of metastatic pN2 lymph nodes and pN2 nodal stations were significantly correlated (P < .001; Supplemental Table 1 in the online version). In groups N2a, N2b, and N2c, metastasis in multiple pN2 stations was observed in 0, 49%, and 83%, respectively. In patients with single pN2 station nodal disease, 37% (49 of 132) had involvements of metastasis on more than 1 mediastinal lymph node.
Multivariate Analysis for DFS and OS
1
Single level
pN2 metastasis was observed in 56 (27%) and 74 (36%) patients, respectively. After surgical resection, 119 patients (58%) received postoperative sequential chemotherapy with radiotherapy, 59 patients (29%) received only radiotherapy, and 28 patients (13%) did not receive any adjuvant treatment.
132 (64%) 74 (36%)
Skip pN2 metastasis No
150 (73%)
Yes
56 (27%)
Multivariate analyses were performed to test the association between the number of metastatic N2 lymph nodes and DFS (Table 2) and OS (Table 3). Other clinicopathologic factors, such as age, sex, weight loss, surgical type, pathologic T stage, histology, and adjuvant therapy were used as covariates. The number of metastatic pN2 lymph nodes was found to be an independent predictor of prognosis in stage IIIA-N2 NSCLC patients in the multivariate model (for DFS, N2b vs. N2a, hazard ratio [HR], 1.50 [95% CI, 1.05-2.15], P ¼ .03, and N2c vs. N2a, HR, 2.87 [95% CI, 1.85-4.47], P < .001; for OS, N2b vs. N2a, HR, 1.62 [95% CI, 1.11-2.36],
Clinical Lung Cancer Month 2015
-3
Prognostic Significance of pN2 Lymph Nodes Figure 1 Disease-Free Survival (A) and Overall Survival (B) According to Number of Metastatic pN2 Lymph Nodes
4
-
P ¼ .01, and N2c vs. N2a, HR, 2.15 [95% CI, 1.38-3.37], P ¼ .001). In addition, pathologic T stage and adjuvant therapy were significant predictors of both DFS and OS, while old age (> 60 years) was a significant predictor of OS. Other multivariate models were developed with the inclusion of pN2 nodal stations instead of the number of metastatic pN2 lymph nodes (Supplemental Tables 2 and 3 in the online version). The
Clinical Lung Cancer Month 2015
pN2 nodal stations also remained significant for DFS (multiple levels vs. single level, HR, 1.69 [95% CI, 1.20-2.38], P ¼ .03) and OS (HR, 1.49 [95% CI, 1.08-2.07], P ¼ .02).
Discussion The prognosis of patients with resected stage IIIA-N2 NSCLC is heterogeneous, and better prognostic prediction is required for
Changhoon Yoo et al Figure 2 Disease-Free Survival (A) and Overall Survival (B) According to Number of Metastatic pN2 Stations
tailored therapy in this group of patients. However, many researchers have indicated that in patients with NSCLC, the current tumor, node, metastasis staging classification system does not accurately reflect the extent of mediastinal nodal metastasis that may be closely associated with survival outcomes. To circumvent this problem, a variety of pN2 subclassifications have been introduced.6-12 In this study, we found the prognostic relevance of the number of metastatic pN2 lymph nodes (1 node vs. 2 to 4 nodes vs. 5 nodes) in patients with stage IIIA-N2 NSCLC after curative
resection. Furthermore, this parameter was the strongest predictor of survival outcomes among all the investigated clinicopathologic characteristics. Our results suggest that this strategy for patient stratification might be useful to improve the accuracy of prognostic prediction. The prognostic implication of the number of metastatic lymph nodes in resected NSCLC has been explored in previous studies.13-15 These studies, which included all stages of resected NSCLC, have suggested that the classification using the number of
Clinical Lung Cancer Month 2015
-5
Prognostic Significance of pN2 Lymph Nodes Table 2 Univariate and Multivariate Analyses for Disease-Free Survival Univariate Analysis Characteristic
cHR
95% CI
Multivariate Analysis P
aHR
95% CI
P
0.52-1.04
.08
Age 60 years
1.00
e
>60 years
1.28
0.94-1.74
.12
Sex Male
1.00
e
Female
0.83
0.60-1.16
1.00 .28
0.73 1.00
e
.04
1.45
0.97-2.16
Weight loss No
1.00
e
Yes
1.52
1.03-2.25
Segmentectomy, lobectomy, bilobectomy
1.00
e
Pneumonectomy
1.08
0.74-1.56
.07
Surgical type .69
Pathologic T stage pT1/2
1.00
e
pT3
1.71
1.07-2.74
1.00
e
.02
1.66
1.02-2.71
.04
No. of metastatic pN2 lymph nodes N2a (1)
1.00
e
1.00
e
N2b (2-4)
1.45
1.01-2.06
.04
1.50
1.05-2.15
.03
N2c (5)
2.28
1.50-3.46
<.001
2.87
1.85-4.47
<.001
Histology Squamous cell carcinoma
1.00
e
Adenocarcinoma
1.24
0.89-1.74
Others
1.17
0.66-2.07
Adjuvant treatment
.20 .60 .01
No
1.00
e
1.00
e
Radiotherapy alone
0.80
0.48-1.33
.38
0.85
0.50-1.45
.55
Sequential chemotherapy and radiotherapy
0.54
0.33-0.86
.01
0.46
0.28-0.75
.002
Abbreviations: aHR ¼ adjusted hazard ratio; cHR ¼ crude hazard ratio; CI ¼ confidence interval.
6
-
metastatic lymph nodes might be a better discriminant than the current location-based pN classification. However, the significance of the number of metastatic lymph nodes seemed to be prominent in patients with pN2 NSCLC rather than pN1 NSCLC.13,14 This may indicate that the location of metastatic lymph nodes should not be disregarded, and subclassification using the number of metastatic lymph nodes might be more suitable in pN2 disease that has more heterogeneous prognostic features. Stratification according to the number of tumor-involved lymph nodes is a current standard for staging of other types of cancers, such as those of stomach, breast, and colon. Because current nodal staging for NSCLC is based only on the location of metastatic lymph nodes, this may not accurately reflect the impact of tumor burden in mediastinal nodal metastasis in pN2 disease. Our findings demonstrate that stratification of patients with stage IIIA-N2 according to the extent of mediastinal node involvement improves the prediction of clinical outcomes. This may help physicians select therapeutic strategies according to the risk of recurrence and may enhance the efficacy of clinical trials investigating novel treatments for this group of patients. However, there are still concerns for staging using the number of metastatic lymph nodes because
Clinical Lung Cancer Month 2015
lymphadenectomy is not conducted identically between surgeons and varies geographically. Moreover, the estimation of number of metastatic lymph nodes is largely dependent on the pathologists and surgeons, and inter- or intraobserver variations might be large, particularly in cases of fragmented nodes or a conglomerate of matted nodes. These limitations might be addressed in the future studies. The prognostic utility of the metastatic patterns in mediastinal nodes has been studied extensively in stage IIIA-N2 NSCLC. Staging according to skip mediastinal metastasis (determined by the presence of concomitant pN1 disease) and metastatic pN2 station (determined by the number of metastatic pN2 stations) has also been investigated and showed a correlation with prognosis in multiple retrospective studies.1,9-12,19-21 Although skip mediastinal metastasis did not show significant association with survival outcomes, metastatic pN2 stations was an independent prognostic factor for DFS and OS in our study. However, the magnitude of impact of the number of metastatic pN2 lymph nodes on DFS and OS (ie, HR) was greater than that of the metastatic pN2 station. In addition, patients with lower or higher risk of relapse or death could be found with subclassification using the number of metastatic pN2
Changhoon Yoo et al Table 3 Univariate and Multivariate Analyses for Overall Survival Univariate Analysis Characteristic
cHR
95% CI
Multivariate Analysis P
aHR
.01
1.42
95% CI
P
1.02-1.97
.04
Age 60 years
1.00
e
>60 years
1.49
1.08-2.04
1.00
Sex Male
1.00
e
Female
0.80
0.56-1.13
.20
Weight loss No
1.00
e
Yes
1.41
0.94-2.11
Segmentectomy, lobectomy, bilobectomy
1.00
e
Pneumonectomy
1.20
0.83-1.74
.10
Surgical type .34
Pathologic T stage pT1/2
1.00
e
pT3
1.75
1.09-2.80
1.00
e
.02
1.66
1.02-2.70
.04
No. of metastatic pN2 lymph nodes N2a (1)
1.00
e
1.00
e
N2b (2-4)
1.50
1.04-2.17
.03
1.62
1.11-2.36
.01
N2c (5)
1.83
1.19-2.80
.006
2.15
1.38-3.37
.001
Histology Squamous cell carcinoma
1.00
e
Adenocarcinoma
1.13
0.80-1.59
.49
Other
1.39
0.78-2.48
.26
Adjuvant treatment No
1.00
e
1.00
e
Radiotherapy alone
0.82
0.49-1.39
.47
0.81
0.46-1.41
.46
Sequential chemotherapy and radiotherapy
0.61
0.38-0.98
.04
0.59
0.36-0.99
.05
Abbreviations: aHR ¼ adjusted hazard ratio; cHR ¼ crude hazard ratio; CI ¼ confidence interval.
lymph nodes (5-year DFS ranged from 5% to 38% and 5-year OS ranged from 24% to 47%) compared to the metastatic pN2 stations (5-year DFS ranged from 12% to 34% and 5-year OS ranged from 26% to 45%). Because 37% of patients with single pN2 station nodal disease showed metastasis on multiple pN2 lymph nodes, the number of metastatic pN2 lymph nodes might have an advantage, at least in the identification of low-risk patients with minimal tumor burden on the mediastinal nodes. Although adjuvant chemotherapy and/or radiotherapy has been recommended for medically fit patients with completely resected stage IIIA-N2 NSCLC, the optimal therapeutic strategies and best chemotherapeutic regimens are yet to be defined as a result of a lack of evidence from randomized phase 3 trials.22 In this study, patients who received adjuvant chemoradiotherapy had significantly longer DFS than those who did not receive any adjuvant treatment, whereas radiotherapy alone did not have a significant impact on DFS. However, these findings should be interpreted cautiously because our analysis was performed retrospectively, and it was not intended to compare the efficacy of different treatment modalities. The strengths of our study include the relatively large sample size, a homogeneous study population that included only patients after
complete resection without previous neoadjuvant treatments, and a long-term follow-up. It should be remembered, however, that the study design was retrospective and based on a single center, which has the potential to introduce bias.
Conclusion The number of metastatic pN2 lymph nodes is an independent predictor of DFS and OS in patients with stage IIIA-N2 NSCLC after curative surgery. This may have an application in clinical practice and trials, where risk stratification is important. Further studies to validate this pN2 subclassification in other populations are warranted.
Clinical Practice Points Pathologic IIIA-N2 NSCLC shows heterogeneous prognosis. Although the number of positive N2 nodal stations is known as
prognostic factor, there have been controversies regarding the number of positive N2 nodes. We found that the number of positive N2 nodes (1 vs. 2 to 4 vs. 5) was significantly correlated with survival outcomes after curative surgery.
Clinical Lung Cancer Month 2015
-7
Prognostic Significance of pN2 Lymph Nodes The optimal management of IIIA-N2 disease remains largely
unknown, mainly as a result of the prognostic heterogeneity of this patient subgroup. Our results suggest that the number of positive N2 nodes might be useful to improve the accuracy of prognostic prediction as well as for risk stratification in clinical practice and trials.
Disclosure The authors have stated that they have no conflicts of interest.
Supplemental Data Supplemental tables accompanying this article can be found in the online version at http://dx.doi.org/10.1016/j.cllc.2015.04.004.
References 1. Vansteenkiste JF, De Leyn PR, Deneffe GJ, et al. Clinical prognostic factors in surgically treated stage IIIAeN2 nonesmall cell lung cancer: analysis of the literature. Lung Cancer 1998; 19:3-13. 2. Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of Malignant Tumours. J Thorac Oncol 2007; 2:706-14. 3. Arriagada R, Bergman B, Dunant A, et al. Cisplatin-based adjuvant chemotherapy in patients with completely resected nonesmall-cell lung cancer. N Engl J Med 2004; 350:351-60. 4. Winton T, Livingston R, Johnson D, et al. Vinorelbine plus cisplatin vs. observation in resected nonesmall-cell lung cancer. N Engl J Med 2005; 352: 2589-97. 5. Douillard JY, Rosell R, De Lena M, et al. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IBeIIIA nonesmallcell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol 2006; 7:719-27. 6. Riquet M, Assouad J, Bagan P, et al. Skip mediastinal lymph node metastasis and lung cancer: a particular N2 subgroup with a better prognosis. Ann Thorac Surg 2005; 79:225-33.
8
-
Clinical Lung Cancer Month 2015
7. Ilic N, Petricevic A, Arar D, et al. Skip mediastinal nodal metastases in the IIIa/N2 nonesmall cell lung cancer. J Thorac Oncol 2007; 2:1018-21. 8. Vansteenkiste JF, De Leyn PR, Deneffe GJ, et al. Survival and prognostic factors in resected N2 nonesmall cell lung cancer: a study of 140 cases. Leuven Lung Cancer Group. Ann Thorac Surg 1997; 63:1441-50. 9. Casali C, Stefani A, Natali P, et al. Prognostic factors in surgically resected N2 nonesmall cell lung cancer: the importance of patterns of mediastinal lymph nodes metastases. Eur J Cardiothorac Surg 2005; 28:33-8. 10. Keller SM, Vangel MG, Wagner H, et al. Prolonged survival in patients with resected nonesmall cell lung cancer and single-level N2 disease. J Thorac Cardiovasc Surg 2004; 128:130-7. 11. Andre F, Grunenwald D, Pignon JP, et al. Survival of patients with resected N2 nonesmall-cell lung cancer: evidence for a subclassification and implications. J Clin Oncol 2000; 18:2981-9. 12. Ichinose Y, Kato H, Koike T, et al. Completely resected stage IIIA nonesmall cell lung cancer: the significance of primary tumor location and N2 station. J Thorac Cardiovasc Surg 2001; 122:803-8. 13. Wei S, Asamura H, Kawachi R, et al. Which is the better prognostic factor for resected nonesmall cell lung cancer: the number of metastatic lymph nodes or the currently used nodal stage classification? J Thorac Oncol 2011; 6:310-8. 14. Fukui T, Mori S, Yokoi K, et al. Significance of the number of positive lymph nodes in resected nonesmall cell lung cancer. J Thorac Oncol 2006; 1:120-5. 15. Lee JG, Lee CY, Park IK, et al. Number of metastatic lymph nodes in resected nonesmall cell lung cancer predicts patient survival. Ann Thorac Surg 2008; 85: 211-5. 16. Sobin L, Wittekind CH. TNM Classification of Malignant Tumours. 6th ed. New York, NY: Wiley-Liss; 2002. 17. Tisi GM, Friedman PJ, Peters RM, et al. American Thoracic Society; Medical Section of the American Lung Association. Clinical staging of primary lung cancer. Am Rev Respir Dis 1983; 127:659-64. 18. Lee SW, Choi EK, Chung WK, et al. Postoperative adjuvant chemotherapy and radiotherapy for stage II and III nonesmall cell lung cancer (NSCLC). Lung Cancer 2002; 37:65-71. 19. Kang CH, Ra YJ, Kim YT, et al. The impact of multiple metastatic nodal stations on survival in patients with resectable N1 and N2 nonsmall-cell lung cancer. Ann Thorac Surg 2008; 86:1092-7. 20. Sonobe M, Date H, Wada H, et al. Prognostic factors after complete resection of pN2 nonesmall cell lung cancer. J Thorac Cardiovasc Surg 2013; 146:788-95. 21. Nakagiri T, Sawabata N, Funaki S, et al. Validation of pN2 sub-classifications in patients with pathological stage IIIA N2 nonesmall cell lung cancer. Interact Cardiovasc Thorac Surg 2011; 12:733-8. 22. Vansteenkiste J, De Ruysscher D, Eberhardt WE, et al. Early and locally advanced nonesmall-cell lung cancer (NSCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013; 24(suppl 6):vi89-98.
Changhoon Yoo et al Supplementary Table S1 Distribution of pN2 Subgroups by the Number of Metastatic pN2 Lymph Nodes and pN2 Nodal Stations No. of Metastatic pN2 Lymph Nodes N2a (n[83) N2b (n[82) N2c (n[41)
Total
pN2 nodal stations Single level
83 (100%)
42 (51%)
7 (17%)
132
0
40 (49%)
34 (83%)
74
Multiple levels
Supplementary Table S2 Univariate and Multivariate Analyses for Disease-Free Survival With Inclusion of the pN2 Nodal Stations Univariate Analysis cHR
95% CI
60 years
1.00
e
>60 years
1.28
0.94-1.74
Multivariate Analysis P-Value
95% CI
P-Value
0.63
0.43-0.92
.02
1.00
e
1.58
1.05-2.37
1.00
e
.02
1.67
1.00-2.78
1.00
e
.002
1.69
1.20-2.38
.03
aHR
Age .12
Sex Male
1.00
e
Female
0.83
0.60-1.16
No
1.00
e
Yes
1.52
1.03-2.25
1.00 .28
Weight loss .04
.03
Surgical type Segmentectomy/lobectomy/bilobectomy
1.00
e
Pneumonectomy
1.08
0.74-1.56
pT1/2
1.00
e
pT3
1.71
1.07-2.74
.69
Pathologic T stage .05
pN2 nodal stations Single level
1.00
e
Multiple levels
1.65
1.20-2.26
Squamous cell carcinoma
1.00
e
Adenocarcinoma
1.24
0.89-1.74
.20
1.67
1.13-2.47
.01
Others
1.17
0.66-2.07
.60
1.32
0.71-2.47
.39
Histology
Adjuvant treatment
1.00
.01
None
1.00
e
1.00
e
Radiotherapy alone
0.80
0.48-1.33
.38
0.77
0.45-1.33
.35
Sequential chemotherapy and radiotherapy
0.54
0.33-0.86
.01
0.47
0.28-0.77
.003
Abbreviations: cHR ¼ crude hazard ratio; aHR ¼ adjusted hazard ratio; CI ¼ confidence interval.
Clinical Lung Cancer Month 2015
- 8.e1
Prognostic Significance of pN2 Lymph Nodes Supplementary Table S3 Univariate and Multivariate Analyses for Overall Survival With Inclusion of the pN2 Nodal Stations Univariate Analysis cHR
95% CI
Multivariate Analysis P-Value
aHR
.01
1.64
95% CI
P-Value
1.19-2.27
.003
Age 60 years
1.00
e
>60 years
1.49
1.08-2.04
1.00
Sex Male
1.00
e
Female
0.80
0.56-1.13
.20
Weight loss No
1.00
e
Yes
1.41
0.94-2.11
.10
1.00
e
1.51
1.00-2.27
.05
Surgical type Segmentectomy/lobectomy/bilobectomy
1.00
e
Pneumonectomy
1.20
0.83-1.74
.34
Pathologic T stage pT1/2
1.00
e
pT3
1.75
1.09-2.80
.02
pN2 nodal stations Single level
1.00
e
Multiple levels
1.43
1.03-1.97
.03
Histology Squamous cell carcinoma
1.00
e
Adenocarcinoma
1.13
0.80-1.59
.49
Others
1.39
0.78-2.48
.26
Adjuvant treatment No
1.00
e
Radiotherapy alone
0.82
0.49-1.39
.47
Sequential chemotherapy and radiotherapy
0.61
0.38-0.98
.04
Abbreviations: cHR ¼ crude hazard ratio; aHR ¼ adjusted hazard ratio; CI ¼ confidence interval.
8.e2
-
Clinical Lung Cancer Month 2015
1.00
e
1.49
1.08-2.07
.02