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Characteristics of clinical N0 metastatic non-small cell lung cancer
Lung Cancer 89 (2015) 71–75
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Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Characteristics of clinical N0 metastatic non-small cell lung cancer Tomohiro Tamura a , Koichi Kurishima b , Hiroko Watanabe a , Toshihiro Shiozawa a , Kensuke Nakazawa a , Hiroichi Ishikawa b , Hiroaki Satoh c,∗ , Nobuyuki Hizawa a a b c
Division of Respiratory Medicine, Faculty of Medicine, University of Tsukuba, Japan Division of Respiratory Medicine, Tsukuba Medical Center, Japan Division of Respiratory Medicine, Mito Medical Center, University of Tsukuba, Mito, Japan
a r t i c l e
i n f o
Article history: Received 5 February 2015 Received in revised form 25 March 2015 Accepted 4 April 2015 Keywords: Non-small-cell lung cancer Clinical N0 Metastasis Survival Metastatic site Adrenal gland Prognostic factor
a b s t r a c t Objectives: Non-small cell lung cancer (NSCLC) patients who have clinically no mediastinal lymph node metastasis but have distant metastasis are occasionally found in clinical practice. Such clinical N0 metastatic NSCLC may be a different subtype from the clinical N1–3 patients with regional lymph node metastasis. The aim of this study was to evaluate the prognosis, clinical features, and incidence of clinical N0 NSCLC patients with metastasis. Methods: All metastatic NSCLC patients (n = 761) diagnosed at our hospitals from April 1999 to August 2012 were retrospectively analyzed. They were divided into two groups: N0 and N1–3. Staging was recorded according to the UICC 7th edition of the TNM classification. Differences between the two groups were analyzed using a Chi-square test. Prognostic factors were analyzed by the Kaplan–Meier method and Cox proportional hazards analysis. A probability value less than 0.05 was considered to be significant. Results: A total of 761 patients with NSCLC were registered. 124 patients (16.3%) were N0 and 637 (83.7%) were N1–3. There were no differences between the two groups in age, sex, smoking history, performance status, and histological type. The ratio of adrenal gland metastasis was low in the N0 group (N0 7.3%, N1–3 13.4%, p = 0.002). Median survival time was longer in the N0 group (N0 11.9 months vs N1–3 7.2 months, p < 0.001). N0 was an independent favorable prognostic factor. Conclusion: Metastatic NSCLC patients with clinical N0 had a favorable prognosis and a lower ratio of adrenal gland metastasis than those with clinical N1–3. Our results suggest that a certain type of adrenal metastasis may result from direct lymphatic spread from a primary lung tumor. About one sixth of metastatic NSCLC cases are clinical N0. Therefore, clinical evaluations for detecting metastasis are important even in clinical N0 patients. © 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths [1]. Approximately 30–40% of patients with NSCLC present with distant metastatic disease at the time of diagnosis [2,3]. The metastatic spread of NSCLC is thought to be both lymphogenous and hematogenous [4,5]. Interestingly, patients who have clinically no mediastinal lymph node metastasis but have distant metastasis are occasionally found in practical clinic. They seem to have no lymphogenous metastasis. Such clinical N0 metastatic NSCLC patients
∗ Corresponding author at: Division of Respiratory Medicine, Mito Medical Center, University of Tsukuba, Miya-machi 3-2-7, Mito, Ibaraki 310-0015, Japan. Tel.: +81 29 231 2371; fax: +81 29 853 3320. E-mail address: [email protected] (H. Satoh). http://dx.doi.org/10.1016/j.lungcan.2015.04.002 0169-5002/© 2015 Elsevier Ireland Ltd. All rights reserved.
may be a different subtype from the clinical N1–3 patients with regional lymph node metastasis. The aim of this study was to evaluate the prognosis, clinical features, and incidence of clinical N0 NSCLC patients with metastasis. 2. Patients and methods 2.1. Patient population Clinicopathological data for all the consecutive patients with metastatic NSCLC were obtained by retrospective review from the databases of University of Tsukuba Hospital and Tsukuba Medical Center Hospital and its Regional Cancer Center. All the patients were diagnosed pathologically and treated between April 1999 and August 2012 at these two tertiary hospitals. A total of 761 patients were identified and included in the analysis. Pathological diagnosis was defined by the WHO classification [6]. Demographic data,
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including age, gender, and PS, were retrieved from their medical records along with the specific details of their cancer. This study conformed to the Ethical Guidelines for Clinical Studies of the Ministry of Health, Labor and Welfare of Japan. 2.2. Staging A staging procedure was performed for all the patients prior to any treatment, using head computed tomography (CT) or magnetic resonance imaging (MRI), bone scintigraphy, as well as ultrasonography and/or abdominal CT. Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) imaging was performed in recent years. The patients were staged according to the Union for International Cancer Control (7th edition) TNM classification [7]. A chest CT findings of lymph nodes with a short axis size exceeding 1.0 cm was considered indicative of metastasis [8,9], which is the most widely accepted criterion. PET/CT played only a subsidiary role due to the lack of standardized criteria [10]. Staging was evaluated by conference of respiratory specialists. Consolidation/tumor (C/T) ratio was measured when tumor size were smaller than or equal to 2 cm. 2.3. Statistical analysis The entire patient population was divided into two groups according to their clinical mediastinal lymph node status: clinical N0 (cN0) group and clinical N1–3 (cN1–3) group. Length of survival was defined as the interval in months from date of initial therapy or supportive care until date of death or date of last follow-up. Differences between the two groups in distribution of characteristics (age, sex, smoking habit, PS, histology, therapy, and metastatic site) were analyzed using a Chi-square test. The Kaplan–Meier method was used to assess survival curves and the log-rank test to evaluate the statistical significance of differences between the two groups [11]. The Cox proportional hazard model was used to study the effects of nodal status on survival while adjusting for other important factors. A probability value less than 0.05 was considered to be significant. All the statistical analyses were performed using StatView software for Windows, version 5.0 (SAS Institute Inc., Cary, NC, USA).
Table 1 Characteristics of 761 patients with stage IV non-small cell lung cancer. Age (years)
Median: 69, range: 21–96
Gender Male Female
529 (69.5%) 232 (30.5%)
Smoking habit Present Absent
558 (73.3%) 203 (26.7%)
Histology Adenocarcinoma Squamous cell carcinoma Large cell carcinoma Others
571 (75.0%) 165 (21.7%) 19 (2.5%) 6 (0.8%)
Treatment Active treatment Surgery Chemotherapy and radiotherapy Molecular targeted agentsa Best supportive care only
496 (65.2%) 18 (2.4%) 478 (62.8%) 176 (23.1%) 265 (34.8%)
Clinical N stage cN0 cN1–3 cN1 cN2 cN3
124 (16.3%) 637 (83.7%) 62 (8.1%) 289 (38.0%) 286 (37.6%)
a
Molecular targeted agents included gefitnib and erlotinib.
chemoradiotherapy followed by lobectomy and wedge resection, 1 had pneumonectomy, and 1 had partial resection. No patient underwent surgical resection of both primary and metastatic tumor. Among the 18 patients, pleural effusion and/or pleural dissemination were detected in 15 patients. Pleural involvement was found in 2 patients. Adrenal metastasis existed in one patient who underwent surgery to control the symptom of hemoptysis. Molecular targeted agents (gefitinib and erlotinib) were administered in 176 (23.1%) patients. EGFR mutation was evaluated only in 174 (22.9%) patients and detected in 60 patients. Table 2 shows the comparison of clinicopathological features between cN0 group and cN1–3 group. There were no differences between the two groups in age, gender, smoking habit, performance status, histological type, and treatment.
3. Results 3.1. Demographics A total of 761 patients with metastatic NSCLC were registered during the 14-year period. The characteristics of these patients are summarized in Table 1. There were 529 (69.5%) men and 232 (30.5%) women, with a median age of 69 years (range, 21–96 years). Among the patients, 124 patients (16.3%) were cN0 and 637 (83.7%) were cN1–3 stage. Among the 124 patients with cN0, tumor sizes were distributed as follows: 10 smaller than or equal to 2 cm; 104 larger than 2 cm; 4 non-measurable; 6 not recorded. C/T ratio was measured in 6 of 10 patients whose tumor size were ≤2 cm. Two of the 6 patients had ground-glass opacity with the C/T ratio of 53–61%, and 4 patients had solid tumor. Pathological staging was performed only in 18 (2.4%) patients who underwent surgery. Among them, 8 patients were cN0 and only one patient was upstaged to pathological N1–3, resulting in the negative predictive value of 87.5%. Ten patients were cN1–3 and one patient was diagnosed as pathological N0 disease. The sensitivity and specificity of lymph node metastasis was 90.0% and 87.5%, respectively. Four hundred ninety-six (65.2%) patients had some active treatment. Surgery was performed in 18 (2.4%) patients. The type of surgical treatment was as follows: 13 had lobectomy, 2 had lobectomy and partial resection, 1 had preoperative concurrent
3.2. Metastatic status Table 3 shows the comparison of metastatic status between cN0 group and cN1–3 group. The cN0 group had significantly less adrenal gland metastasis. While 117 (18.4%) out of 637 cN1–3 patients had adrenal gland metastasis, only 9 (7.3%) out of 124 cN0 patients had adrenal gland metastasis (p = 0.002). The ratio of extrathoracic lymph node metastasis was also significantly low in the cN0 group (2.4% vs 10.5%, p = 0.004). The cN0 group had significantly fewer metastatic sites. While 332 (50.5%) out of cN1–3 patients had a single metastatic site, 80 (64.5%) of the cN0 patients had a single metastatic site (p = 0.004).
Table 2 Comparison of clinicopathological features between cN0 and cN1–3 stage IV nonsmall lung cancer patients. Variable
cN0 (n = 124)
cN1–3 (n = 637)
p-Value
Age <70 Gender: female Smoking habit: absent Performance status: 0–1 Histology: adenocarcinoma Treatment: active treatment
64 (51.6%) 38 (30.6%) 35 (28.2%) 73 (58.9%) 98 (79.0%) 79 (63.7%)
346 (54.3%) 194 (30.5%) 168 (26.4%) 352 (55.3%) 473 (74.3%) 417 (65.5%)
0.580 0.966 0.669 0.458 0.260 0.708
T. Tamura et al. / Lung Cancer 89 (2015) 71–75 Table 3 Comparison of metastatic status between cN0 and cN1–3 stage IV non-small lung cancer patients. cN0 (n = 124)
cN1–3 (n = 637)
p-Value
Metastatic site Bone Brain Liver Adrenal glands Extrathoracic lymph nodes Lungs Pleural/pericardial fluid
39 (31.5%) 29 (23.4%) 12 (9.7%) 9 (7.3%) 3 (2.4%) 35 (28.2%) 47 (37.9%)
225 (35.3%) 191 (30.0%) 87 (13.7%) 117 (18.4%) 67 (10.5%) 205 (32.2%) 246 (38.6%)
0.407 0.138 0.228 0.002 0.004 0.385 0.881
Number of metastatic sites Single site Multiple site
80 (64.5%) 44 (35.5%)
332 (50.5%) 305 (49.5%)
0.004
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Among the 60 patients with EGFR mutation, there are trend of longer median survival time in N0 group (N0 37.9 months vs N1–3 27.0 months), although the result was not statistically significant. 3.4. Prognostic factors Table 4 summarizes the relationship between clinical variables and survival. In univariate analysis, clinical N0, age less than 70 years old, female, no smoking habit, good PS (PS 0–1), histology of adenocarcinoma, active treatment, absence of metastasis in bone, liver, adrenal gland and extrathoracic lymph nodes, and metastasis to a single site were favorable prognostic factors. In multivariate analysis, clinical N0, female, good PS (PS 0–1), histology of adenocarcinoma, active treatment, absence of liver and adrenal gland metastasis, and metastasis to a single site were favorable prognostic factors. Clinical N0 in metastatic NSCLC was an independent favorable prognostic factor (p < 0.001). 4. Discussion
Fig. 1. Survival curves of each clinical N stage group. Median survival of the cN0, cN1, cN2, and cN3 groups was 11.9, 9.1, 7.2, and 6.7 months, respectively.
3.3. Survival Fig. 1 shows the comparison of survival in each of the four clinical N stage groups. Median survival of the cN0, cN1, cN2, and cN3 groups was 11.9, 9.1, 7.2, and 6.7 months, respectively. When we compare the cN0 and cN1–3 groups, median survival of the cN0 and cN1–3 group was 11.9 and 7.2 months (Fig. 2). Median survival time was significantly longer in the cN0 group (p < 0.001). Among the 496 patients who received active treatment, median survival of the cN0 and cN1–3 group was 18.3 and 11.4 months (p < 0.001).
Fig. 2. Survival curves compared between cN0 group and cN1–3 group. Median survival of the cN0 and cN1–3 groups was 11.9 and 7.2 months (p < 0.001).
In the present study, we demonstrate the following three points. First, the cN0 group in metastatic NSCLC had a longer median survival time than the cN1–3 group, and cN0 was an independent favorable prognostic factor in multivariate analysis. Second, the cN0 group had less adrenal gland metastasis than the cN1–3 group. Third, the cN0 group accounted for 16.3% of stage IV NSCLC. These finding suggests that clinical N0 has distinct behavior that differs from clinical N1–3 patients with regional lymph node metastasis. This analysis is unique in that it examines consecutive unselected stage IV NSCLC patients diagnosed in a regional cancer center. There are only a few reports regarding the association between prognosis and regional lymph node status in metastatic NSCLC patients, although it has been confirmed that survival curves show clear differences in outcome for each of the clinical N categories in patients with no clinical evidence of metastatic disease [12]. In patients with oligometastasis who are treated with locally ablative therapies, N status has been found to be a significant prognostic factor for survival in several retrospective studies [13–16]. Recently, Ashworth et al. reported that intrathoracic nodal status is one of the key determinants of long-term survival in oligometastatic NSCLC patients receiving ablative treatment at all sites of the disease [17]. In our present study, the cN0 group had longer median survival time and cN0 was an independent favorable prognostic factor in multivariate analysis. Interestingly, the survival curves show distinct differences between cN0 and other groups, while those of cN1, cN2, and cN3 group overlap. In previous reports, Okamoto et al., using multivariate analysis, revealed that early N status (N0, N1) was an important factor for long term survivors in 222 NSCLC patients with stage IV disease [18]. This finding is compatible with our results. On the other hand, Li et al. reported that N staging was not an independent prognostic factor in 1214 advanced NSCLC patients who received gemcitabine in combination with platinum, although disease stage (stage IIIB or IV), PS, gemcitabine-platinum regimen, and T stage were independent predictors of survival [19]. This discrepancy may be due to the fact that the study included both stage IIIB and stage IV patients while our study registered only stage IV patients. We also analyzed the clinical features of cN0 NSCLC patients and found that the cN0 group had less adrenal gland metastasis. This finding suggests that adrenal metastatic spread is associated with lymphatic routes. Several researchers indicated that isolated adrenal metastasis may result from direct lymphatic spread from a primary lung tumor and is sometimes considered to be a regional extension [20]. In the early stages adrenal metastases from NSCLC may develop mainly by lymphogenous, and later mainly by
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Table 4 Univariate and multivariate analyses of prognostic factors in patients with stage IV non-small cell lung cancer. Variables
Univariate analysis (log-rank test)
Multivariate analysis (Cox’s proportional hazards model)
p-Value
Hazard ratio
cN0 Age <70 years Female Smoking habit: absent Performance status: 0–1 Histology: adenocarcinoma Therapy: active treatment
<0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001
0.60 1.05 0.67 0.82 0.49 0.69 0.32
0.47–0.76 0.88–1.25 0.52–0.87 0.63–1.08 0.40–0.59 0.57–0.84 0.26–0.40
<0.001 0.592 0.002 0.158 <0.001 <0.001 <0.001
Metastatic site Bone: absent Liver: absent Adrenal gland: absent Extrathoracic lymph node: absent
0.021 <0.001 <0.001 0.005
0.89 0.74 0.71 0.79
0.74–1.08 0.57–0.95 0.57–0.89 0.59–1.04
0.240 0.017 0.002 0.096
Number of metastatic site Single
<0.001
0.62
0.50–0.76
<0.001
95%CI
p-Value
95%CI: 95% confidence interval.
hematogenous routes [21,22]. Nevertheless the lymphatic spread theory of adrenal metastases has not been widely accepted. Our results may support this theory. It is noteworthy that 16.3% of metastatic NSCLC patients were cN0. Japan Lung Cancer Society recommends full staging using PET/CT and brain MRI or CT except for ≤2 cm nodules with the consolidation/tumor (C/T) ratio smaller than 25%, because such nodules hardly metastasize to other sites [23]. In our study, 10 of the 124 cN0 metastatic NSCL patients had primary lesion of ≤2 cm, but no patients had ≤2 cm nodules with the C/T ratio ≤25%. Furthermore, 3 of the 10 patients had multiple pulmonary metastases. Five had apparent pleural effusion. Therefore, clinical evaluation for detecting metastases is important even in clinical N0 patients except for ≤2 cm nodules with the C/T ratio smaller than 25%. In spite of these significant findings, this study has limitations. The first is inherent to its retrospective design, which is necessarily complicated by lead time and length time biases. Second, we could not examine the detailed classification of histological type and EGFR mutation status because of the small amount of specimens collected by transbronchial lung biopsy or cytology. Moreover, The EGFR mutation analysis has become available since 2007 under the Japanese National Health Insurance program. Previously diagnosed patients were not examined for the EGFR mutations. Rebiopsy for the evaluation of EGFR mutations were rarely performed because of the disagreement of bronchoscopy. The availability of molecular targeted drugs contributed to the paradigm shift of therapeutic strategies in non-squamous NSCLC during the study period. In our study, there are trend of longer survival in N0 group than N1–3 group among the 60 patients who are confirmed to have EGFR mutations, although the result was not statistically significant due to small number of patients. Third, there is little information on pathological staging. Most of the patients had no indication for surgical treatment; hence, staging was made by diagnostic imaging methods. In previous reports, the sensitivity of CT for mediastinal nodes was 52–75%, with a specificity of 66–68% [24–27]. For PET/CT, sensitivity and specificity were 74–85% and 85–90%, respectively [10,28–30]. Merrit et al. reported that 10–25% of the patients who underwent lobectomy for clinical N0 lung carcinoma were upstaged to pathological N1 or N2 [31]. Regardless of these limitations, we believe that our findings have clinical importance for the management of future NSCLC patients of unselected groups. Our results confirmed that an aggressive treatment strategy might be considered for selected metastatic NSCLC patients with N0 status. Considering the results of multivariate analysis of favorable prognostic factors, patients with metastasis to a single site except for liver and adrenal gland would benefit from
an aggressive therapy. Furthermore, although molecular targeted drugs contributed to the paradigm shift of therapeutic strategies, approximately half of the NSCLC patients who have neither EGFR mutation nor ALK rearrangement still do not benefit from molecular targeted agents [32–34]. Thus, we do feel that the data in this study are beneficial even in this era of molecular-targeted therapy. Based on this retrospective study, we plan to perform a prospective study of an aggressive treatment against metastatic NSCLC patients with N0 including information of gene mutations and usage of molecular targeted drugs. In conclusion, metastatic NSCLC patients with clinical N0 had favorable prognosis. About one sixth of metastatic NSCLC were clinical N0. No clinical characteristics other than less adrenal gland metastasis were found. Therefore, clinical evaluations for detecting metastases are important even in clinical N0 patients. Conflict of interest statement None of the authors have any conflict of interest to declare. References [1] Allemani C, Weir HK, Carreira H, Harewood R, Spika D, Wang XS, et al. Global surveillance of cancer survival 1995–2009: analysis of individual data for 25 676 887 patients from 279 population-based registries in 67 countries (CONCORD-2). Lancet 2015;385:977–1010. [2] Matsuda A, Matsuda T, Shibata A, Katanoda K, Sobue T, Nishimoto H. A study of 25 population-based cancer registries for the Monitoring of Cancer Incidence in Japan (MCIJ) project. Jpn J Clin Oncol 2014;44:388–96. [3] Little AG, Gay EG, Gaspar LE, Stewart AK. National survey of non-small cell lung cancer in the United States: epidemiology, pathology and patterns of care. Lung Cancer 2007;57:253–60. [4] Warren S, Gates O. Lung cancer and metastasis. Arch Pathol 1964;78:467–73. [5] Onuigbo WI. A history of hematogenous metastasis. Cancer Res 1961;21:1077–85. [6] World Health Organizations. Histological typing of lung and pleural tumours. In: International histological classification of tumours. 3rd ed. Geneva: Springer; 1999. [7] Goldstraw P, Crowley J, Chansky K, Giroux DJ, Groome PA, Rami-Porta R, 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. [8] Glazer GM, Gross BH, Quint LE, Francis IR, Bookstein FL, Orringer MB. Normal mediastinal lymph nodes: number and size according to American Thoracic Society mapping. AJR Am J Roentgenol 1985;144:261–5. [9] Kiyono K, Sone S, Sakai F, Imai Y, Watanabe T, Izuno I, et al. The number and size of normal mediastinal lymph nodes: a postmortem study. AJR Am J Roentgenol 1988;150:771–6. [10] Silvestri GA, Gould MK, Margolis ML, Tanoue LT, McCrory D, Toloza E, et al. Noninvasive staging of non-small cell lung cancer: ACCP evidenced-based clinical practice guidelines (2nd edition). Chest 2007;132(3 Suppl.):178S–201S.
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Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Characteristics of clinical N0 metastatic non-small cell lung cancer Tomohiro Tamura a , Koichi Kurishima b , Hiroko Watanabe a , Toshihiro Shiozawa a , Kensuke Nakazawa a , Hiroichi Ishikawa b , Hiroaki Satoh c,∗ , Nobuyuki Hizawa a a b c
Division of Respiratory Medicine, Faculty of Medicine, University of Tsukuba, Japan Division of Respiratory Medicine, Tsukuba Medical Center, Japan Division of Respiratory Medicine, Mito Medical Center, University of Tsukuba, Mito, Japan
a r t i c l e
i n f o
Article history: Received 5 February 2015 Received in revised form 25 March 2015 Accepted 4 April 2015 Keywords: Non-small-cell lung cancer Clinical N0 Metastasis Survival Metastatic site Adrenal gland Prognostic factor
a b s t r a c t Objectives: Non-small cell lung cancer (NSCLC) patients who have clinically no mediastinal lymph node metastasis but have distant metastasis are occasionally found in clinical practice. Such clinical N0 metastatic NSCLC may be a different subtype from the clinical N1–3 patients with regional lymph node metastasis. The aim of this study was to evaluate the prognosis, clinical features, and incidence of clinical N0 NSCLC patients with metastasis. Methods: All metastatic NSCLC patients (n = 761) diagnosed at our hospitals from April 1999 to August 2012 were retrospectively analyzed. They were divided into two groups: N0 and N1–3. Staging was recorded according to the UICC 7th edition of the TNM classification. Differences between the two groups were analyzed using a Chi-square test. Prognostic factors were analyzed by the Kaplan–Meier method and Cox proportional hazards analysis. A probability value less than 0.05 was considered to be significant. Results: A total of 761 patients with NSCLC were registered. 124 patients (16.3%) were N0 and 637 (83.7%) were N1–3. There were no differences between the two groups in age, sex, smoking history, performance status, and histological type. The ratio of adrenal gland metastasis was low in the N0 group (N0 7.3%, N1–3 13.4%, p = 0.002). Median survival time was longer in the N0 group (N0 11.9 months vs N1–3 7.2 months, p < 0.001). N0 was an independent favorable prognostic factor. Conclusion: Metastatic NSCLC patients with clinical N0 had a favorable prognosis and a lower ratio of adrenal gland metastasis than those with clinical N1–3. Our results suggest that a certain type of adrenal metastasis may result from direct lymphatic spread from a primary lung tumor. About one sixth of metastatic NSCLC cases are clinical N0. Therefore, clinical evaluations for detecting metastasis are important even in clinical N0 patients. © 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths [1]. Approximately 30–40% of patients with NSCLC present with distant metastatic disease at the time of diagnosis [2,3]. The metastatic spread of NSCLC is thought to be both lymphogenous and hematogenous [4,5]. Interestingly, patients who have clinically no mediastinal lymph node metastasis but have distant metastasis are occasionally found in practical clinic. They seem to have no lymphogenous metastasis. Such clinical N0 metastatic NSCLC patients
∗ Corresponding author at: Division of Respiratory Medicine, Mito Medical Center, University of Tsukuba, Miya-machi 3-2-7, Mito, Ibaraki 310-0015, Japan. Tel.: +81 29 231 2371; fax: +81 29 853 3320. E-mail address: [email protected] (H. Satoh). http://dx.doi.org/10.1016/j.lungcan.2015.04.002 0169-5002/© 2015 Elsevier Ireland Ltd. All rights reserved.
may be a different subtype from the clinical N1–3 patients with regional lymph node metastasis. The aim of this study was to evaluate the prognosis, clinical features, and incidence of clinical N0 NSCLC patients with metastasis. 2. Patients and methods 2.1. Patient population Clinicopathological data for all the consecutive patients with metastatic NSCLC were obtained by retrospective review from the databases of University of Tsukuba Hospital and Tsukuba Medical Center Hospital and its Regional Cancer Center. All the patients were diagnosed pathologically and treated between April 1999 and August 2012 at these two tertiary hospitals. A total of 761 patients were identified and included in the analysis. Pathological diagnosis was defined by the WHO classification [6]. Demographic data,
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including age, gender, and PS, were retrieved from their medical records along with the specific details of their cancer. This study conformed to the Ethical Guidelines for Clinical Studies of the Ministry of Health, Labor and Welfare of Japan. 2.2. Staging A staging procedure was performed for all the patients prior to any treatment, using head computed tomography (CT) or magnetic resonance imaging (MRI), bone scintigraphy, as well as ultrasonography and/or abdominal CT. Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) imaging was performed in recent years. The patients were staged according to the Union for International Cancer Control (7th edition) TNM classification [7]. A chest CT findings of lymph nodes with a short axis size exceeding 1.0 cm was considered indicative of metastasis [8,9], which is the most widely accepted criterion. PET/CT played only a subsidiary role due to the lack of standardized criteria [10]. Staging was evaluated by conference of respiratory specialists. Consolidation/tumor (C/T) ratio was measured when tumor size were smaller than or equal to 2 cm. 2.3. Statistical analysis The entire patient population was divided into two groups according to their clinical mediastinal lymph node status: clinical N0 (cN0) group and clinical N1–3 (cN1–3) group. Length of survival was defined as the interval in months from date of initial therapy or supportive care until date of death or date of last follow-up. Differences between the two groups in distribution of characteristics (age, sex, smoking habit, PS, histology, therapy, and metastatic site) were analyzed using a Chi-square test. The Kaplan–Meier method was used to assess survival curves and the log-rank test to evaluate the statistical significance of differences between the two groups [11]. The Cox proportional hazard model was used to study the effects of nodal status on survival while adjusting for other important factors. A probability value less than 0.05 was considered to be significant. All the statistical analyses were performed using StatView software for Windows, version 5.0 (SAS Institute Inc., Cary, NC, USA).
Table 1 Characteristics of 761 patients with stage IV non-small cell lung cancer. Age (years)
Median: 69, range: 21–96
Gender Male Female
529 (69.5%) 232 (30.5%)
Smoking habit Present Absent
558 (73.3%) 203 (26.7%)
Histology Adenocarcinoma Squamous cell carcinoma Large cell carcinoma Others
571 (75.0%) 165 (21.7%) 19 (2.5%) 6 (0.8%)
Treatment Active treatment Surgery Chemotherapy and radiotherapy Molecular targeted agentsa Best supportive care only
496 (65.2%) 18 (2.4%) 478 (62.8%) 176 (23.1%) 265 (34.8%)
Clinical N stage cN0 cN1–3 cN1 cN2 cN3
124 (16.3%) 637 (83.7%) 62 (8.1%) 289 (38.0%) 286 (37.6%)
a
Molecular targeted agents included gefitnib and erlotinib.
chemoradiotherapy followed by lobectomy and wedge resection, 1 had pneumonectomy, and 1 had partial resection. No patient underwent surgical resection of both primary and metastatic tumor. Among the 18 patients, pleural effusion and/or pleural dissemination were detected in 15 patients. Pleural involvement was found in 2 patients. Adrenal metastasis existed in one patient who underwent surgery to control the symptom of hemoptysis. Molecular targeted agents (gefitinib and erlotinib) were administered in 176 (23.1%) patients. EGFR mutation was evaluated only in 174 (22.9%) patients and detected in 60 patients. Table 2 shows the comparison of clinicopathological features between cN0 group and cN1–3 group. There were no differences between the two groups in age, gender, smoking habit, performance status, histological type, and treatment.
3. Results 3.1. Demographics A total of 761 patients with metastatic NSCLC were registered during the 14-year period. The characteristics of these patients are summarized in Table 1. There were 529 (69.5%) men and 232 (30.5%) women, with a median age of 69 years (range, 21–96 years). Among the patients, 124 patients (16.3%) were cN0 and 637 (83.7%) were cN1–3 stage. Among the 124 patients with cN0, tumor sizes were distributed as follows: 10 smaller than or equal to 2 cm; 104 larger than 2 cm; 4 non-measurable; 6 not recorded. C/T ratio was measured in 6 of 10 patients whose tumor size were ≤2 cm. Two of the 6 patients had ground-glass opacity with the C/T ratio of 53–61%, and 4 patients had solid tumor. Pathological staging was performed only in 18 (2.4%) patients who underwent surgery. Among them, 8 patients were cN0 and only one patient was upstaged to pathological N1–3, resulting in the negative predictive value of 87.5%. Ten patients were cN1–3 and one patient was diagnosed as pathological N0 disease. The sensitivity and specificity of lymph node metastasis was 90.0% and 87.5%, respectively. Four hundred ninety-six (65.2%) patients had some active treatment. Surgery was performed in 18 (2.4%) patients. The type of surgical treatment was as follows: 13 had lobectomy, 2 had lobectomy and partial resection, 1 had preoperative concurrent
3.2. Metastatic status Table 3 shows the comparison of metastatic status between cN0 group and cN1–3 group. The cN0 group had significantly less adrenal gland metastasis. While 117 (18.4%) out of 637 cN1–3 patients had adrenal gland metastasis, only 9 (7.3%) out of 124 cN0 patients had adrenal gland metastasis (p = 0.002). The ratio of extrathoracic lymph node metastasis was also significantly low in the cN0 group (2.4% vs 10.5%, p = 0.004). The cN0 group had significantly fewer metastatic sites. While 332 (50.5%) out of cN1–3 patients had a single metastatic site, 80 (64.5%) of the cN0 patients had a single metastatic site (p = 0.004).
Table 2 Comparison of clinicopathological features between cN0 and cN1–3 stage IV nonsmall lung cancer patients. Variable
cN0 (n = 124)
cN1–3 (n = 637)
p-Value
Age <70 Gender: female Smoking habit: absent Performance status: 0–1 Histology: adenocarcinoma Treatment: active treatment
64 (51.6%) 38 (30.6%) 35 (28.2%) 73 (58.9%) 98 (79.0%) 79 (63.7%)
346 (54.3%) 194 (30.5%) 168 (26.4%) 352 (55.3%) 473 (74.3%) 417 (65.5%)
0.580 0.966 0.669 0.458 0.260 0.708
T. Tamura et al. / Lung Cancer 89 (2015) 71–75 Table 3 Comparison of metastatic status between cN0 and cN1–3 stage IV non-small lung cancer patients. cN0 (n = 124)
cN1–3 (n = 637)
p-Value
Metastatic site Bone Brain Liver Adrenal glands Extrathoracic lymph nodes Lungs Pleural/pericardial fluid
39 (31.5%) 29 (23.4%) 12 (9.7%) 9 (7.3%) 3 (2.4%) 35 (28.2%) 47 (37.9%)
225 (35.3%) 191 (30.0%) 87 (13.7%) 117 (18.4%) 67 (10.5%) 205 (32.2%) 246 (38.6%)
0.407 0.138 0.228 0.002 0.004 0.385 0.881
Number of metastatic sites Single site Multiple site
80 (64.5%) 44 (35.5%)
332 (50.5%) 305 (49.5%)
0.004
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Among the 60 patients with EGFR mutation, there are trend of longer median survival time in N0 group (N0 37.9 months vs N1–3 27.0 months), although the result was not statistically significant. 3.4. Prognostic factors Table 4 summarizes the relationship between clinical variables and survival. In univariate analysis, clinical N0, age less than 70 years old, female, no smoking habit, good PS (PS 0–1), histology of adenocarcinoma, active treatment, absence of metastasis in bone, liver, adrenal gland and extrathoracic lymph nodes, and metastasis to a single site were favorable prognostic factors. In multivariate analysis, clinical N0, female, good PS (PS 0–1), histology of adenocarcinoma, active treatment, absence of liver and adrenal gland metastasis, and metastasis to a single site were favorable prognostic factors. Clinical N0 in metastatic NSCLC was an independent favorable prognostic factor (p < 0.001). 4. Discussion
Fig. 1. Survival curves of each clinical N stage group. Median survival of the cN0, cN1, cN2, and cN3 groups was 11.9, 9.1, 7.2, and 6.7 months, respectively.
3.3. Survival Fig. 1 shows the comparison of survival in each of the four clinical N stage groups. Median survival of the cN0, cN1, cN2, and cN3 groups was 11.9, 9.1, 7.2, and 6.7 months, respectively. When we compare the cN0 and cN1–3 groups, median survival of the cN0 and cN1–3 group was 11.9 and 7.2 months (Fig. 2). Median survival time was significantly longer in the cN0 group (p < 0.001). Among the 496 patients who received active treatment, median survival of the cN0 and cN1–3 group was 18.3 and 11.4 months (p < 0.001).
Fig. 2. Survival curves compared between cN0 group and cN1–3 group. Median survival of the cN0 and cN1–3 groups was 11.9 and 7.2 months (p < 0.001).
In the present study, we demonstrate the following three points. First, the cN0 group in metastatic NSCLC had a longer median survival time than the cN1–3 group, and cN0 was an independent favorable prognostic factor in multivariate analysis. Second, the cN0 group had less adrenal gland metastasis than the cN1–3 group. Third, the cN0 group accounted for 16.3% of stage IV NSCLC. These finding suggests that clinical N0 has distinct behavior that differs from clinical N1–3 patients with regional lymph node metastasis. This analysis is unique in that it examines consecutive unselected stage IV NSCLC patients diagnosed in a regional cancer center. There are only a few reports regarding the association between prognosis and regional lymph node status in metastatic NSCLC patients, although it has been confirmed that survival curves show clear differences in outcome for each of the clinical N categories in patients with no clinical evidence of metastatic disease [12]. In patients with oligometastasis who are treated with locally ablative therapies, N status has been found to be a significant prognostic factor for survival in several retrospective studies [13–16]. Recently, Ashworth et al. reported that intrathoracic nodal status is one of the key determinants of long-term survival in oligometastatic NSCLC patients receiving ablative treatment at all sites of the disease [17]. In our present study, the cN0 group had longer median survival time and cN0 was an independent favorable prognostic factor in multivariate analysis. Interestingly, the survival curves show distinct differences between cN0 and other groups, while those of cN1, cN2, and cN3 group overlap. In previous reports, Okamoto et al., using multivariate analysis, revealed that early N status (N0, N1) was an important factor for long term survivors in 222 NSCLC patients with stage IV disease [18]. This finding is compatible with our results. On the other hand, Li et al. reported that N staging was not an independent prognostic factor in 1214 advanced NSCLC patients who received gemcitabine in combination with platinum, although disease stage (stage IIIB or IV), PS, gemcitabine-platinum regimen, and T stage were independent predictors of survival [19]. This discrepancy may be due to the fact that the study included both stage IIIB and stage IV patients while our study registered only stage IV patients. We also analyzed the clinical features of cN0 NSCLC patients and found that the cN0 group had less adrenal gland metastasis. This finding suggests that adrenal metastatic spread is associated with lymphatic routes. Several researchers indicated that isolated adrenal metastasis may result from direct lymphatic spread from a primary lung tumor and is sometimes considered to be a regional extension [20]. In the early stages adrenal metastases from NSCLC may develop mainly by lymphogenous, and later mainly by
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Table 4 Univariate and multivariate analyses of prognostic factors in patients with stage IV non-small cell lung cancer. Variables
Univariate analysis (log-rank test)
Multivariate analysis (Cox’s proportional hazards model)
p-Value
Hazard ratio
cN0 Age <70 years Female Smoking habit: absent Performance status: 0–1 Histology: adenocarcinoma Therapy: active treatment
<0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001
0.60 1.05 0.67 0.82 0.49 0.69 0.32
0.47–0.76 0.88–1.25 0.52–0.87 0.63–1.08 0.40–0.59 0.57–0.84 0.26–0.40
<0.001 0.592 0.002 0.158 <0.001 <0.001 <0.001
Metastatic site Bone: absent Liver: absent Adrenal gland: absent Extrathoracic lymph node: absent
0.021 <0.001 <0.001 0.005
0.89 0.74 0.71 0.79
0.74–1.08 0.57–0.95 0.57–0.89 0.59–1.04
0.240 0.017 0.002 0.096
Number of metastatic site Single
<0.001
0.62
0.50–0.76
<0.001
95%CI
p-Value
95%CI: 95% confidence interval.
hematogenous routes [21,22]. Nevertheless the lymphatic spread theory of adrenal metastases has not been widely accepted. Our results may support this theory. It is noteworthy that 16.3% of metastatic NSCLC patients were cN0. Japan Lung Cancer Society recommends full staging using PET/CT and brain MRI or CT except for ≤2 cm nodules with the consolidation/tumor (C/T) ratio smaller than 25%, because such nodules hardly metastasize to other sites [23]. In our study, 10 of the 124 cN0 metastatic NSCL patients had primary lesion of ≤2 cm, but no patients had ≤2 cm nodules with the C/T ratio ≤25%. Furthermore, 3 of the 10 patients had multiple pulmonary metastases. Five had apparent pleural effusion. Therefore, clinical evaluation for detecting metastases is important even in clinical N0 patients except for ≤2 cm nodules with the C/T ratio smaller than 25%. In spite of these significant findings, this study has limitations. The first is inherent to its retrospective design, which is necessarily complicated by lead time and length time biases. Second, we could not examine the detailed classification of histological type and EGFR mutation status because of the small amount of specimens collected by transbronchial lung biopsy or cytology. Moreover, The EGFR mutation analysis has become available since 2007 under the Japanese National Health Insurance program. Previously diagnosed patients were not examined for the EGFR mutations. Rebiopsy for the evaluation of EGFR mutations were rarely performed because of the disagreement of bronchoscopy. The availability of molecular targeted drugs contributed to the paradigm shift of therapeutic strategies in non-squamous NSCLC during the study period. In our study, there are trend of longer survival in N0 group than N1–3 group among the 60 patients who are confirmed to have EGFR mutations, although the result was not statistically significant due to small number of patients. Third, there is little information on pathological staging. Most of the patients had no indication for surgical treatment; hence, staging was made by diagnostic imaging methods. In previous reports, the sensitivity of CT for mediastinal nodes was 52–75%, with a specificity of 66–68% [24–27]. For PET/CT, sensitivity and specificity were 74–85% and 85–90%, respectively [10,28–30]. Merrit et al. reported that 10–25% of the patients who underwent lobectomy for clinical N0 lung carcinoma were upstaged to pathological N1 or N2 [31]. Regardless of these limitations, we believe that our findings have clinical importance for the management of future NSCLC patients of unselected groups. Our results confirmed that an aggressive treatment strategy might be considered for selected metastatic NSCLC patients with N0 status. Considering the results of multivariate analysis of favorable prognostic factors, patients with metastasis to a single site except for liver and adrenal gland would benefit from
an aggressive therapy. Furthermore, although molecular targeted drugs contributed to the paradigm shift of therapeutic strategies, approximately half of the NSCLC patients who have neither EGFR mutation nor ALK rearrangement still do not benefit from molecular targeted agents [32–34]. Thus, we do feel that the data in this study are beneficial even in this era of molecular-targeted therapy. Based on this retrospective study, we plan to perform a prospective study of an aggressive treatment against metastatic NSCLC patients with N0 including information of gene mutations and usage of molecular targeted drugs. In conclusion, metastatic NSCLC patients with clinical N0 had favorable prognosis. About one sixth of metastatic NSCLC were clinical N0. No clinical characteristics other than less adrenal gland metastasis were found. Therefore, clinical evaluations for detecting metastases are important even in clinical N0 patients. Conflict of interest statement None of the authors have any conflict of interest to declare. References [1] Allemani C, Weir HK, Carreira H, Harewood R, Spika D, Wang XS, et al. Global surveillance of cancer survival 1995–2009: analysis of individual data for 25 676 887 patients from 279 population-based registries in 67 countries (CONCORD-2). Lancet 2015;385:977–1010. [2] Matsuda A, Matsuda T, Shibata A, Katanoda K, Sobue T, Nishimoto H. A study of 25 population-based cancer registries for the Monitoring of Cancer Incidence in Japan (MCIJ) project. Jpn J Clin Oncol 2014;44:388–96. [3] Little AG, Gay EG, Gaspar LE, Stewart AK. National survey of non-small cell lung cancer in the United States: epidemiology, pathology and patterns of care. Lung Cancer 2007;57:253–60. [4] Warren S, Gates O. Lung cancer and metastasis. Arch Pathol 1964;78:467–73. [5] Onuigbo WI. A history of hematogenous metastasis. Cancer Res 1961;21:1077–85. [6] World Health Organizations. Histological typing of lung and pleural tumours. In: International histological classification of tumours. 3rd ed. Geneva: Springer; 1999. [7] Goldstraw P, Crowley J, Chansky K, Giroux DJ, Groome PA, Rami-Porta R, 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. [8] Glazer GM, Gross BH, Quint LE, Francis IR, Bookstein FL, Orringer MB. Normal mediastinal lymph nodes: number and size according to American Thoracic Society mapping. AJR Am J Roentgenol 1985;144:261–5. [9] Kiyono K, Sone S, Sakai F, Imai Y, Watanabe T, Izuno I, et al. The number and size of normal mediastinal lymph nodes: a postmortem study. AJR Am J Roentgenol 1988;150:771–6. [10] Silvestri GA, Gould MK, Margolis ML, Tanoue LT, McCrory D, Toloza E, et al. Noninvasive staging of non-small cell lung cancer: ACCP evidenced-based clinical practice guidelines (2nd edition). Chest 2007;132(3 Suppl.):178S–201S.
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