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Korean J Thorac Cardiovasc Surg 2020; 53(3): 114-120

Published online June 5, 2020 https://doi.org/10.5090/kjtcs.2020.53.3.114

Copyright © Journal of Chest Surgery.

The Role of Primary Tumor Resection in Patients with Pleural Metastasis Encountered at the Time of Surgery

Samina Park , M.D., Yongwoo Chung , M.D., Hyun Joo Lee , M.D., In Kyu Park , M.D., Chang Hyun Kang , M.D., Young Tae Kim , M.D.

Department of Thoracic and Cardiovascular Surgery, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea

Correspondence to:Young Tae Kim
Tel 82-2-2072-3161
Fax 82-2-764-3664
E-mail ytkim@snu.ac.kr
ORCID
https://orcid.org/0000-0001-9006-4881

Received: October 10, 2019; Revised: November 11, 2019; Accepted: November 22, 2019

This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properlycited.

Background: Evidence is lacking on whether the resection of lung parenchymal cancer improves the survival of patients with unexpected pleural metastasis encountered during surgery. We conducted a single-center retrospective study to determine the role of lung resection in the long-term survival of these patients.
Methods: Among 4683 patients who underwent lung surgery between 1995 and 2014, 132 (2.8%) had pleural metastasis. After excluding 2 patients who had incomplete medical records, 130 patients’ data were collected. Only a diagnostic pleural and/or lung biopsy was performed in 90 patients, while the lung parenchymal mass was resected in 40 patients.
Results: The mean follow-up duration was 29.8 months. The 5-year survival rate of the resection group (34.7%±9.4%) was superior to that of the biopsy group (15.9%±4.3%, p=0.016). Multivariate Cox regression analysis demonstrated that primary tumor resection (p=0.041), systemic treatment (p<0.001), lower clinical N stage (p=0.018), and adenocarcinoma histology (p=0.009) were significant predictors of a favorable outcome. Interestingly, primary tumor resection only played a significant prognostic role in patients who received systemic treatment.
Conclusion: When pleural metastasis is unexpectedly encountered during surgical exploration, resection in conjunction with systemic treatment may improve long-term survival, especially in adenocarcinoma patients without lymph node metastasis.

Keywords: Lung neoplasms, Non-small-cell lung carcinoma, Pleural metastasis

Approximately 40% of cases of non–small cell lung cancer (NSCLC) are metastatic at the time of diagnosis [1]. Pleural dissemination, which refers to malignant pleural effusion and/or pleural nodules, is identified in 1%–7.5% of NSCLCs and is a component of the M1a descriptor [1,2]. The median survival duration of patients with M1a disease is 8–11.5 months [2,3]. Owing to the poor prognosis of pleural dissemination, with a 2% 5-year survival rate, NSCLC with pleural dissemination was reclassified from T4 to M1a in the seventh edition of the tumor-node-metastasis (TNM) staging system [2].

NSCLC with a solitary metastasis may be treated by resecting both the primary and metastatic lesions, with a favorable survival rate [4,5]. Consequently, it was proposed for the eighth edition of the TNM staging system that metastasis at a single site or single organ should be distinguished from other distant metastatic lung cancer [3]. A contralateral lung nodule (the other M1a descriptor) may sometimes also be a surgical candidate. In contrast, NSCLC with pleural metastasis is not a candidate for surgical resection according to standard treatment guidelines, as pleural dissemination is not amenable to complete resection [6]; therefore, the M1a category was not revised for the eighth edition of the TNM staging system [3]. However, several studies have reported reasonable survival outcomes after surgical resection of the primary tumor in patients with pleural dissemination [7,-11]. Therefore, it remains unclear whether resection of the primary tumor can improve survival in patients with pleural metastasis encountered at the time of surgery [12].

We aimed to evaluate the role of primary tumor resection in patients with pleural dissemination of NSCLC and to identify other predictors of long-term survival.

Patients

Among 4,683 patients who underwent lung surgery between 1995 and 2014, 132 (2.8%) were identified as having clinical M0 stage disease and found to have unexpected pleural metastasis at the time of surgery. After excluding 2 patients whose medical records were not complete, 130 patients’ data were collected. Survival data were confirmed using medical records, telephone surveys, and the national insurance database. Data were analyzed to test the role of lung resection in long-term survival and to identify other predictors of patients’ prognosis. The primary tumor was not resected in 90 patients, in whom only a diagnostic pleural biopsy was performed, whereas the primary lung mass was resected in 40 patients. Systemic treatment (cytotoxic chemotherapy and/or tyrosine kinase inhibitors) was administered to 110 patients (84.6%). Several clinical variables were analyzed to identify factors that could have influenced the long-term survival of these 2 groups. This study was reviewed and approved by the Institutional Review Board at Seoul National University Hospital (IRB approval no., H-1602-050-739). The recommendations of the Declaration of Helsinki for biomedical research involving human subjects were followed. Informed consent was waived.

Statistical analysis

Categorical variables are presented as numbers and percentages. Continuous variables are presented as means and standard deviations. Statistical analysis was performed using IBM SPSS ver. 22.0 (IBM Corp., Armonk, NY, USA). In the univariate analysis, categorical variables were compared using the chi-square test and the Fisher exact test. Continuous variables were compared using the Student t-test. Survival curves were obtained using the Kaplan-Meier method and compared between the 2 groups using the log-rank test. Prognostic factors for survival were analyzed with a Cox proportional hazard ratio model fit with a backward selection method. The proportional hazards assumption, tested by a log minus log plot, was satisfied. Variables with p≤0.1 in the univariate analysis were included in the multivariate analysis. Interactions between any 2 variables in the multivariate models were tested. A p-value of ≤0.05 was considered to indicate statistical significance in both the univariate and multivariate analyses.

Clinicopathologic characteristics

Patients’ characteristics are described in Table 1. The study population had a male predominance (total, 130; male-to-female ratio, 75:55) and most patients had adenocarcinoma (n=109, 83.8%). The mean age was 61.5 years. The mean follow-up duration was 29.8±23.7 months. There were no cases of surgery-related mortality. Of the 65 patients tested for epidermal growth factor receptor (EGFR) mutation status, 50.5% were positive. Clinical variables including age, sex, tumor size, tumor location, histologic cell type, systemic treatment, clinical T stage, clinical N stage, EGFR mutation status, and preoperative pulmonary function were similar between the 2 groups.

Survival

The overall 5-year survival rate was 20.1% (Fig. 1). The median survival time was estimated at 26.3 months. Patients who received systemic treatment survived longer than those who did not (5-year survival rate, 22.3% versus 6.2%; p<0.001). The 5-year survival rate of the resection group was superior to that of the biopsy group (5-year survival rate, 34.7% versus 15.9%; p=0.016) (Fig. 2). There was no significant difference in survival according to the extent of resection (p=0.719). When patients were stratified according to whether they received systemic treatment, the survival curves of the 2 groups showed different patterns. A protective role of primary tumor resection was only observed in patients who received systemic treatment (Fig. 3A). In the systemic treatment group, patients who underwent primary tumor resection showed better survival outcomes than those who underwent biopsy (5-year survival rate, 40.0% versus 17.2%; p=0.009). However, among patients who did not receive chemotherapy, the median survival time was extremely poor in both groups (resection group versus biopsy group: 11.8 months versus 8.3 months), indicating that resection failed to improve survival (p=0.775) (Fig. 3B).

Prognostic factors for long-term survival

In the univariate analysis, clinical N stage and adenocarcinoma histology were additional significant factors associated with favorable survival outcomes, whereas age, sex, and clinical T stage were not significant (Table 2). In the multivariate Cox regression analysis, primary tumor resection, systemic treatment, clinical N0 stage, and adenocarcinoma histology remained significant factors associated with favorable outcomes (Table 3).

Interaction analysis

A significant interaction was found between primary tumor resection and systemic treatment (p=0.017). This demonstrated a differential effect of systemic treatment on the impact of primary tumor resection. After adjusting for interaction between primary tumor resection and systemic treatment, clinical N0 stage (hazard ratio [HR], 1.811; 95% confidence interval [CI], 1.158–2.832; p=0.009) and adenocarcinoma histology (HR, 0.344; 95% CI, 0.172–0.689; p=0.003) remained significant predictors of favorable survival. We then estimated the HRs for mortality according to whether primary tumor resection was performed. The HR of systemic treatment decreased from 0.296 (95% CI, 0.158–0.555; p<0.001) to 0.069 (95% CI, 0.024–0.200; p<0.001), suggesting that resection of the primary tumor may significantly strengthen the effect of systemic treatment (Table 3).

Although the mainstay of treatment in patients with advanced-stage cancer is systemic chemotherapy [13], our study showed that surgery can yield an additional survival benefit in carefully selected patients. Metastasis to a single organ, such as the adrenal gland or brain, can be treated with resection of the primary tumor and local management of the metastatic lesion, either with surgery or with a gamma knife. Therefore, the recent eighth edition of the TNM staging system for lung cancer proposed a subclassification of the M description based on the number of metastatic lesions and sites [3]. Oligometastasis in the brain, liver, bone, adrenal gland, skin, and distant lymph nodes, which can be managed with aggressive local treatment, has a survival rate similar to that of M1a disease and better than that of cases with multiple metastases to a single organ [3,14]. These outcomes contributed to the subclassification of the M stage, which was divided into M1a and M1b, corresponding to a distinction between stage IV and stage IVa, in the eighth edition [3].

Pleural dissemination, which accounts for 13%–14% of all cases of metastatic lung cancer, remained in the M1a category [2,3], and the role of primary tumor resection in cases of pleural dissemination has not been established. Unlike brain or adrenal metastases, complete resection is not possible in pleural dissemination, with the exception of extra-pleural pneumonectomy. Yokoi et al. [15] reported a 5-year survival rate as high as 54.5% after extra-pleural pneumonectomy in carefully selected patients. More recent studies have reported that surgical resection of the primary tumor in NSCLC with pleural dissemination was beneficial in selected patients, particularly in those with N0 status, T1-2 disease, and adenocarcinoma histology [7,-10,16,17]. Resection of the primary lesion may provide effective local control because chemoradiation therapy often fails, with a locoregional failure rate of 31%–100% [18,19]. In addition, as minimally invasive surgery has been adopted and experience with lung cancer surgery has been accumulated, surgery-related morbidity and mortality have decreased [20,21], and hence, surgical resection of a parenchymal lung lesion can be safely performed without adding significant operative complications. In our study, it was evident that primary tumor resection was performed in patients with good physical status, clinical N0 stage, and minimal pleural seeding. However, Li et al. [17] reported that there were no differences in survival according to performance status, clinical stage, the presence of malignant pleural effusion, or the extent of pleural nodules in cases of adenocarcinoma. Notwithstanding, it is undeniable that when resection of the primary tumor can be safely performed, surgeons might decide to proceed to curative resection.

In several other reports, in which 57%–72% of patients received systemic treatment, chemotherapy was not found to improve survival [7,8,11]. Those conclusions are contradictory to ours. Most patients (85%) received systemic treatment in our series and demonstrated significantly better survival than those who did not, which may have resulted from selection bias. However, the fact that surgical resection of the lung lesion was only beneficial if the patient underwent systemic treatment was interesting. A possible explanation for our observations is that surgery decreased the tumor burden, while chemotherapy treated microscopic disease. In fact, we found that the best long-term survival was achieved when both the tumor size and nodal stage were low. Although our data do not provide direct evidence regarding this possibility, our observations suggest that primary tumor resection may play a more impactful role for tumors with actionable mutations that can be treated with molecular target agents. We analyzed the presence of an EGFR mutation as a factor that might affect patients’ outcome. Unfortunately, however, we did not routinely examine EGFR mutation status and we failed to prove that EGFR mutation status had a statistically significant relationship with survival, as was shown in a previous study [17]. Currently, we routinely evaluate EGFR mutation status and ALK gene rearrangement in all patients, and we hope to clarify the role of surgical resection of the primary tumor in patients who harbor a targetable mutation in the near future.

It has been suggested that tumor stage, sex, weight loss, and performance status are predictive factors of the success of systemic treatment. Performance status is an extremely powerful prognostic factor for survival and has been considered as the most important factor in selecting patients eligible for chemotherapy [22,23]. However, we did not include performance status in this study, because surgery was planned for all patients, meaning that their performance status was good.

We were not able to extract information regarding the number of pleural nodules. Dry pleural dissemination has been reported to have a better prognosis than wet pleural dissemination [8,9,16,24]. As all the patients were in the cM0 stage, the majority of our patients had dry pleural metastases. However, a multicenter survey reported that there was no significant difference in prognosis according to M1a descriptors (pleural effusion, pleural nodules, contralateral lung nodules) [3].

There are several limitations of this study. Surgical resection is not recommended for cases of extremely advanced lung cancer with overt pleural effusion or pleural nodules; hence, there was obvious selection bias in our study. Importantly, our conclusions should only be applied to patients in whom pleural seeding was unexpectedly diagnosed at the time of surgery. EGFR mutation data was available for only half of the patients. In addition, we did not analyze patients’ response to chemotherapy or disease progression. As a consequence, we were not able to perform an interaction analysis to eliminate the effect of tumor biology. However, our results suggest that resection of the primary tumor can lead to improved survival if patients can undergo systemic treatment for NSCLC with pleural dissemination that was unexpectedly encountered during surgery, especially in cases of adenocarcinoma without lymph node metastasis. Furthermore, in the era of precision medicine, surgical resection of the primary tumor may serve as an effective local treatment in conjunction with appropriate targeted therapy.

In conclusion, when pleural metastasis is encountered during surgical exploration, primary tumor resection can improve long-term survival in conjunction with systemic treatment, especially in selected patients with adenocarcinoma histology without lymph node metastasis.

No potential conflict of interest relevant to this article was reported.

The authors would like to express their appreciation for the statistical advice provided by the Medical Research Collaborating Center at Seoul National University Hospital and the Seoul National University College of Medicine.

This study was supported by the National Research Foun­dation: ID (http://dx.doi.org/10.13039/100011512); award no. (NRF-2014R1A2A2A05003665).

Go to Figures
Fig. 1.Kaplan-Meier plot of the overall survival rate of non-small cell lung cancer patients with pleural metastasis.
Fig. 2.Kaplan-Meier plots of survival rates according to primary tumor resection (solid line: primary tumor resection group; dotted line: biopsy group).
Fig. 3.Kaplan-Meier plots of survival rates according to systemic treatment (solid line: primary tumor resection group; dotted line: biopsy group). (A) Patients who received systemic treatment. (B) Patients who did not receive systemic treatment.

Clinicopathological characteristics of the patients

Characteristic Total (N=130) Primary tumor resection group (n=40) Biopsy group (n=90) p-value
Age (yr) 61.5±11.7 62.7±11.1 61.0±12.0 0.425
Female sex 55 (42.3) 16 (40.0) 39 (43.3) 0.723
Never-smoker 74 (56.9) 21 (52.5) 53 (58.9) 0.566
Forced expiratory volume in 1 second (predicted %) 98.1±21.4 102.6±21.7 95.7±21.0 0.117
Tumor size (cm) 3.2±1.4 3.3±1.7 3.1±1.2 0.428
Tumor location 0.670
Central 35 (26.9) 12 (30.0) 23 (25.6)
Periphery 95 (73.1) 28 (70.0) 67 (74.4)
Histology 130 40 90 0.287
Squamous cell carcinoma 12 (9.2) 6 (15.0) 6 (6.7)
Adenocarcinoma 109 (83.8) 32 (80.0) 77 (85.6)
Others 9 (6.9) 2 (5.0) 7 (7.8)
Systemic treatment (yes) 110 (84.6) 35 (87.5) 75 (83.3) 0.543
Cytotoxic chemotherapy (yes) 96 (73.8) 28 (70.0) 68 (75.6) 0.522
Tyrosine kinase inhibitor (yes) 72 (55.4) 21 (52.5) 51 (56.7) 0.705
T stage 0.503
1 38 (29.2) 14 (35.5) 24 (26.7)
2 61 (46.9) 18 (45.0) 43 (47.8)
3 22 (16.9) 7 (17.5) 15 (16.7)
4 9 (6.9) 1 (2.5) 8 (6.2)
N stage 0.168
0 86 (66.2) 26 (65.0) 60 (66.7)
1 21 (16.2) 10 (25.0) 11 (12.2)
2 21 (16.2) 4 (10.0) 17 (18.9)
3 2 (1.5) 0 2 (2.2)
Surgery 130 40 90
Pleural or lung biopsy - 90 (100.0)
Primary tumor resection 40 (100.0) -
Wedge resection 16 (40.0)
Lobectomy 21 (52.5)
Pneumonectomy 3 (7.5)
Length of hospital stay 8.0±7.9 9.9±11.7 7.1±5.2 0.153
Epidermal growth factor receptor mutation (yes) (n=65) 33/65 (50.5) 16/27 (59.3) 17/38 (44.7) 0.248

Values are presented as mean±standard deviation or number (%).


Univariate analysis of prognostic factors for long-term survival in non–small cell lung cancer

Variable Hazard ratio (95% confidence interval) p-value
Age (vs. ≥65 yr)
<65 yr 1.225 (0.815–1.840) 0.328
Sex (vs. male)
Female 0.990 (0.660–1.484) 0.961
Smoking (vs. ever-smoker)
Never-smoker 0.700 (0.468–1.045) 0.081
Epidermal growth factor receptor mutation (vs. wild-type)
Yes 0.621 (0.327–1.180) 0.146
Tumor size (vs. ≥3 cm)
<3 cm 0.951 (0.626–1.445) 0.815
Tumor location (vs. central)
Periphery 0.795 (0.511–1.236) 0.308
Clinical T stage (vs. ≥T2)
T1 0.883 (0.568–1.374) 0.581
Clinical N stage (vs. ≥N1)
N0 0.644 (0.419–0.990) 0.045
Systemic treatment (vs. no)
Yes 0.254 (0.149–0.431) <0.001
Resection (vs. biopsy only)
Primary tumor resection 0.557 (0.343–0.903) 0.018
Extent of resection (vs. wedge resection) (n=40)
≥ Lobectomy 0.842 (0.330–2.146) 0.719
Histology (vs. squamous cell carcinoma) 0.039
Adenocarcinoma 0.512 (0.263–0.997) 0.049
Others 0.981 (0.396–2.429) 0.966

Multivariate Cox regression analysis of prognostic factors for long-term survival in non–small cell lung cancer

Variable Hazard ratio (95% confidence interval) p-value
Clinical N stage (vs. ≥N1)
N0 0.566 (0.362–0.884) 0.012
Histology (vs. squamous cell carcinoma) 0.009
Adenocarcinoma 0.372 (0.186–0.742) 0.005
Others 0.637 (0.248–1.632) 0.347
Systemic treatment & resection 0.017
Primary tumor resection (vs. biopsy only)
Systemic treatment (yes) 0.464 (0.264–0.815) 0.008
Systemic treatment (no) 1.994 (0.693–5.736) 0.201
Systemic treatment (vs. no)
Primary tumor resection (yes) 0.069 (0.024–0.200) <0.001
Primary tumor resection (no) 0.296 (0.158–0.555) <0.001

  1. Ou SH, Zell JA. Validation study of the proposed IASLC staging revisions of the T4 and M non-small cell lung cancer descriptors using data from 23,583 patients in the California Cancer Registry. J Thorac Oncol 2008;3:216-27.
    Pubmed CrossRef
  2. Postmus PE, Brambilla E, Chansky K, et al. The IASLC Lung Cancer Staging Project: proposals for revision of the M descriptors in the forthcoming (seventh) edition of the TNM classification of lung cancer. J Thorac Oncol 2007;2:686-93.
    Pubmed CrossRef
  3. Eberhardt WE, Mitchell A, Crowley J, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the M descriptors in the forthcoming eighth edition of the TNM classification of lung cancer. J Thorac Oncol 2015;10:1515-22.
    Pubmed CrossRef
  4. Billing PS, Miller DL, Allen MS, Deschamps C, Trastek VF, Pairolero PC. Surgical treatment of primary lung cancer with synchronous brain metastases. J Thorac Cardiovasc Surg 2001;122:548-53.
    Pubmed CrossRef
  5. Mercier O, Fadel E, de Perrot M, et al. Surgical treatment of solitary adrenal metastasis from non-small cell lung cancer. J Thorac Cardiovasc Surg 2005;130:136-40.
    Pubmed CrossRef
  6. Ettinger DS, Wood DE, Akerley W, et al. NCCN guidelines insights: non-small cell lung cancer, version 4. J Natl Compr Canc Netw 2016 2016;14:255-64.
    Pubmed CrossRef
  7. Ichinose Y, Tsuchiya R, Koike T, et al. Prognosis of resected non-small cell lung cancer patients with carcinomatous pleuritis of minimal disease. Lung Cancer 2001;32:55-60.
    Pubmed CrossRef
  8. Iida T, Shiba M, Yoshino I, et al. Surgical intervention for non-small-cell lung cancer patients with pleural carcinomatosis: results from the Japanese Lung Cancer Registry in 2004. J Thorac Oncol 2015;10:1076-82.
    Pubmed CrossRef
  9. Fukuse T, Hirata T, Tanaka F, Wada H. The prognostic significance of malignant pleural effusion at the time of thoracotomy in patients with non-small cell lung cancer. Lung Cancer 2001;34:75-81.
    Pubmed CrossRef
  10. Go T, Misaki N, Matsuura N, Chang SS, Tarumi S, Yokomise H. Role of surgery in multi-modality treatment for carcinomatous pleuritis in patients with non-small cell lung cancer. Surg Today 2015;45:197-202.
    Pubmed CrossRef
  11. Mordant P, Arame A, Foucault C, Dujon A, Le Pimpec Barthes F, Riquet M. Surgery for metastatic pleural extension of non-small-cell lung cancer. Eur J Cardiothorac Surg 2011;40:1444-9.
    Pubmed CrossRef
  12. Sawabata N, Matsumura A, Motohiro A, et al. Malignant minor pleural effusion detected on thoracotomy for patients with non-small cell lung cancer: is tumor resection beneficial for prognosis? Ann Thorac Surg 2002;73:412-5.
    Pubmed CrossRef
  13. Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy and supportive care versus supportive care alone for advanced non-small cell lung cancer. Cochrane Database Syst Rev 2010;5:CD007309.
    Pubmed CrossRef
  14. Ashworth AB, Senan S, Palma DA, et al. An individual patient data metaanalysis of outcomes and prognostic factors after treatment of oligometastatic non-small-cell lung cancer. Clin Lung Cancer 2014;15:346-55.
    Pubmed CrossRef
  15. Yokoi K, Matsuguma H, Anraku M. Extrapleural pneumonectomy for lung cancer with carcinomatous pleuritis. J Thorac Cardiovasc Surg 2002;123:184-5.
    Pubmed CrossRef
  16. Okamoto T, Iwata T, Mizobuchi T, et al. Pulmonary resection for lung cancer with malignant pleural disease first detected at thoracotomy. Eur J Cardiothorac Surg 2012;41:25-30.
    Pubmed KoreaMed CrossRef
  17. Li C, Kuo SW, Hsu HH, Lin MW, Chen JS. Lung adenocarcinoma with intraoperatively diagnosed pleural seeding: is main tumor resection beneficial for prognosis? J Thorac Cardiovasc Surg 2018;155:1238-49.
    Pubmed CrossRef
  18. Ball D, Mitchell A, Giroux D, Rami-Porta R; IASLC Staging Committee and Participating Institutions. Effect of tumor size on prognosis in patients treated with radical radiotherapy or chemoradiotherapy for non-small cell lung cancer: an analysis of the staging project database of the International Association for the Study of Lung Cancer. J Thorac Oncol 2013;8:315-21.
    Pubmed CrossRef
  19. Nguyen NP, Bishop M, Borok TJ, et al. Pattern of failure following chemoradiation for locally advanced non-small cell lung cancer: potential role for stereotactic body radiotherapy. Anticancer Res 2010;30:953-61.
    Pubmed
  20. Pages PB, Cottenet J, Mariet AS, Bernard A, Quantin C. In-hospital mortality following lung cancer resection: nationwide administrative database. Eur Respir J 2016;47:1809-17.
    Pubmed CrossRef
  21. Paul S, Altorki NK, Sheng S, et al. Thoracoscopic lobectomy is associated with lower morbidity than open lobectomy: a propensity-matched analysis from the STS database. J Thorac Cardiovasc Surg 2010;139:366-78.
    Pubmed CrossRef
  22. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002;346:92-8.
    Pubmed CrossRef
  23. Masters GA, Temin S, Azzoli CG, et al. Systemic therapy for stage iv non-small-cell lung cancer: American Society of Clinical Oncology Clinical Practice Guideline update. J Clin Oncol 2015;33:3488-515.
    Pubmed KoreaMed CrossRef
  24. Kim YK, Lee HY, Lee KS, et al. Dry pleural dissemination in non-small cell lung cancer: prognostic and diagnostic implications. Radiology 2011;260:568-74.
    Pubmed CrossRef

Article

Clinical Research

Korean J Thorac Cardiovasc Surg 2020; 53(3): 114-120

Published online June 5, 2020 https://doi.org/10.5090/kjtcs.2020.53.3.114

Copyright © Journal of Chest Surgery.

The Role of Primary Tumor Resection in Patients with Pleural Metastasis Encountered at the Time of Surgery

Samina Park , M.D., Yongwoo Chung , M.D., Hyun Joo Lee , M.D., In Kyu Park , M.D., Chang Hyun Kang , M.D., Young Tae Kim , M.D.

Department of Thoracic and Cardiovascular Surgery, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea

Correspondence to:Young Tae Kim
Tel 82-2-2072-3161
Fax 82-2-764-3664
E-mail ytkim@snu.ac.kr
ORCID
https://orcid.org/0000-0001-9006-4881

Received: October 10, 2019; Revised: November 11, 2019; Accepted: November 22, 2019

This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properlycited.

Abstract

Background: Evidence is lacking on whether the resection of lung parenchymal cancer improves the survival of patients with unexpected pleural metastasis encountered during surgery. We conducted a single-center retrospective study to determine the role of lung resection in the long-term survival of these patients.
Methods: Among 4683 patients who underwent lung surgery between 1995 and 2014, 132 (2.8%) had pleural metastasis. After excluding 2 patients who had incomplete medical records, 130 patients’ data were collected. Only a diagnostic pleural and/or lung biopsy was performed in 90 patients, while the lung parenchymal mass was resected in 40 patients.
Results: The mean follow-up duration was 29.8 months. The 5-year survival rate of the resection group (34.7%±9.4%) was superior to that of the biopsy group (15.9%±4.3%, p=0.016). Multivariate Cox regression analysis demonstrated that primary tumor resection (p=0.041), systemic treatment (p<0.001), lower clinical N stage (p=0.018), and adenocarcinoma histology (p=0.009) were significant predictors of a favorable outcome. Interestingly, primary tumor resection only played a significant prognostic role in patients who received systemic treatment.
Conclusion: When pleural metastasis is unexpectedly encountered during surgical exploration, resection in conjunction with systemic treatment may improve long-term survival, especially in adenocarcinoma patients without lymph node metastasis.

Keywords: Lung neoplasms, Non-small-cell lung carcinoma, Pleural metastasis

Introduction

Approximately 40% of cases of non–small cell lung cancer (NSCLC) are metastatic at the time of diagnosis [1]. Pleural dissemination, which refers to malignant pleural effusion and/or pleural nodules, is identified in 1%–7.5% of NSCLCs and is a component of the M1a descriptor [1,2]. The median survival duration of patients with M1a disease is 8–11.5 months [2,3]. Owing to the poor prognosis of pleural dissemination, with a 2% 5-year survival rate, NSCLC with pleural dissemination was reclassified from T4 to M1a in the seventh edition of the tumor-node-metastasis (TNM) staging system [2].

NSCLC with a solitary metastasis may be treated by resecting both the primary and metastatic lesions, with a favorable survival rate [4,5]. Consequently, it was proposed for the eighth edition of the TNM staging system that metastasis at a single site or single organ should be distinguished from other distant metastatic lung cancer [3]. A contralateral lung nodule (the other M1a descriptor) may sometimes also be a surgical candidate. In contrast, NSCLC with pleural metastasis is not a candidate for surgical resection according to standard treatment guidelines, as pleural dissemination is not amenable to complete resection [6]; therefore, the M1a category was not revised for the eighth edition of the TNM staging system [3]. However, several studies have reported reasonable survival outcomes after surgical resection of the primary tumor in patients with pleural dissemination [7,-11]. Therefore, it remains unclear whether resection of the primary tumor can improve survival in patients with pleural metastasis encountered at the time of surgery [12].

We aimed to evaluate the role of primary tumor resection in patients with pleural dissemination of NSCLC and to identify other predictors of long-term survival.

Methods

Patients

Among 4,683 patients who underwent lung surgery between 1995 and 2014, 132 (2.8%) were identified as having clinical M0 stage disease and found to have unexpected pleural metastasis at the time of surgery. After excluding 2 patients whose medical records were not complete, 130 patients’ data were collected. Survival data were confirmed using medical records, telephone surveys, and the national insurance database. Data were analyzed to test the role of lung resection in long-term survival and to identify other predictors of patients’ prognosis. The primary tumor was not resected in 90 patients, in whom only a diagnostic pleural biopsy was performed, whereas the primary lung mass was resected in 40 patients. Systemic treatment (cytotoxic chemotherapy and/or tyrosine kinase inhibitors) was administered to 110 patients (84.6%). Several clinical variables were analyzed to identify factors that could have influenced the long-term survival of these 2 groups. This study was reviewed and approved by the Institutional Review Board at Seoul National University Hospital (IRB approval no., H-1602-050-739). The recommendations of the Declaration of Helsinki for biomedical research involving human subjects were followed. Informed consent was waived.

Statistical analysis

Categorical variables are presented as numbers and percentages. Continuous variables are presented as means and standard deviations. Statistical analysis was performed using IBM SPSS ver. 22.0 (IBM Corp., Armonk, NY, USA). In the univariate analysis, categorical variables were compared using the chi-square test and the Fisher exact test. Continuous variables were compared using the Student t-test. Survival curves were obtained using the Kaplan-Meier method and compared between the 2 groups using the log-rank test. Prognostic factors for survival were analyzed with a Cox proportional hazard ratio model fit with a backward selection method. The proportional hazards assumption, tested by a log minus log plot, was satisfied. Variables with p≤0.1 in the univariate analysis were included in the multivariate analysis. Interactions between any 2 variables in the multivariate models were tested. A p-value of ≤0.05 was considered to indicate statistical significance in both the univariate and multivariate analyses.

Results

Clinicopathologic characteristics

Patients’ characteristics are described in Table 1. The study population had a male predominance (total, 130; male-to-female ratio, 75:55) and most patients had adenocarcinoma (n=109, 83.8%). The mean age was 61.5 years. The mean follow-up duration was 29.8±23.7 months. There were no cases of surgery-related mortality. Of the 65 patients tested for epidermal growth factor receptor (EGFR) mutation status, 50.5% were positive. Clinical variables including age, sex, tumor size, tumor location, histologic cell type, systemic treatment, clinical T stage, clinical N stage, EGFR mutation status, and preoperative pulmonary function were similar between the 2 groups.

Survival

The overall 5-year survival rate was 20.1% (Fig. 1). The median survival time was estimated at 26.3 months. Patients who received systemic treatment survived longer than those who did not (5-year survival rate, 22.3% versus 6.2%; p<0.001). The 5-year survival rate of the resection group was superior to that of the biopsy group (5-year survival rate, 34.7% versus 15.9%; p=0.016) (Fig. 2). There was no significant difference in survival according to the extent of resection (p=0.719). When patients were stratified according to whether they received systemic treatment, the survival curves of the 2 groups showed different patterns. A protective role of primary tumor resection was only observed in patients who received systemic treatment (Fig. 3A). In the systemic treatment group, patients who underwent primary tumor resection showed better survival outcomes than those who underwent biopsy (5-year survival rate, 40.0% versus 17.2%; p=0.009). However, among patients who did not receive chemotherapy, the median survival time was extremely poor in both groups (resection group versus biopsy group: 11.8 months versus 8.3 months), indicating that resection failed to improve survival (p=0.775) (Fig. 3B).

Prognostic factors for long-term survival

In the univariate analysis, clinical N stage and adenocarcinoma histology were additional significant factors associated with favorable survival outcomes, whereas age, sex, and clinical T stage were not significant (Table 2). In the multivariate Cox regression analysis, primary tumor resection, systemic treatment, clinical N0 stage, and adenocarcinoma histology remained significant factors associated with favorable outcomes (Table 3).

Interaction analysis

A significant interaction was found between primary tumor resection and systemic treatment (p=0.017). This demonstrated a differential effect of systemic treatment on the impact of primary tumor resection. After adjusting for interaction between primary tumor resection and systemic treatment, clinical N0 stage (hazard ratio [HR], 1.811; 95% confidence interval [CI], 1.158–2.832; p=0.009) and adenocarcinoma histology (HR, 0.344; 95% CI, 0.172–0.689; p=0.003) remained significant predictors of favorable survival. We then estimated the HRs for mortality according to whether primary tumor resection was performed. The HR of systemic treatment decreased from 0.296 (95% CI, 0.158–0.555; p<0.001) to 0.069 (95% CI, 0.024–0.200; p<0.001), suggesting that resection of the primary tumor may significantly strengthen the effect of systemic treatment (Table 3).

Discussion

Although the mainstay of treatment in patients with advanced-stage cancer is systemic chemotherapy [13], our study showed that surgery can yield an additional survival benefit in carefully selected patients. Metastasis to a single organ, such as the adrenal gland or brain, can be treated with resection of the primary tumor and local management of the metastatic lesion, either with surgery or with a gamma knife. Therefore, the recent eighth edition of the TNM staging system for lung cancer proposed a subclassification of the M description based on the number of metastatic lesions and sites [3]. Oligometastasis in the brain, liver, bone, adrenal gland, skin, and distant lymph nodes, which can be managed with aggressive local treatment, has a survival rate similar to that of M1a disease and better than that of cases with multiple metastases to a single organ [3,14]. These outcomes contributed to the subclassification of the M stage, which was divided into M1a and M1b, corresponding to a distinction between stage IV and stage IVa, in the eighth edition [3].

Pleural dissemination, which accounts for 13%–14% of all cases of metastatic lung cancer, remained in the M1a category [2,3], and the role of primary tumor resection in cases of pleural dissemination has not been established. Unlike brain or adrenal metastases, complete resection is not possible in pleural dissemination, with the exception of extra-pleural pneumonectomy. Yokoi et al. [15] reported a 5-year survival rate as high as 54.5% after extra-pleural pneumonectomy in carefully selected patients. More recent studies have reported that surgical resection of the primary tumor in NSCLC with pleural dissemination was beneficial in selected patients, particularly in those with N0 status, T1-2 disease, and adenocarcinoma histology [7,-10,16,17]. Resection of the primary lesion may provide effective local control because chemoradiation therapy often fails, with a locoregional failure rate of 31%–100% [18,19]. In addition, as minimally invasive surgery has been adopted and experience with lung cancer surgery has been accumulated, surgery-related morbidity and mortality have decreased [20,21], and hence, surgical resection of a parenchymal lung lesion can be safely performed without adding significant operative complications. In our study, it was evident that primary tumor resection was performed in patients with good physical status, clinical N0 stage, and minimal pleural seeding. However, Li et al. [17] reported that there were no differences in survival according to performance status, clinical stage, the presence of malignant pleural effusion, or the extent of pleural nodules in cases of adenocarcinoma. Notwithstanding, it is undeniable that when resection of the primary tumor can be safely performed, surgeons might decide to proceed to curative resection.

In several other reports, in which 57%–72% of patients received systemic treatment, chemotherapy was not found to improve survival [7,8,11]. Those conclusions are contradictory to ours. Most patients (85%) received systemic treatment in our series and demonstrated significantly better survival than those who did not, which may have resulted from selection bias. However, the fact that surgical resection of the lung lesion was only beneficial if the patient underwent systemic treatment was interesting. A possible explanation for our observations is that surgery decreased the tumor burden, while chemotherapy treated microscopic disease. In fact, we found that the best long-term survival was achieved when both the tumor size and nodal stage were low. Although our data do not provide direct evidence regarding this possibility, our observations suggest that primary tumor resection may play a more impactful role for tumors with actionable mutations that can be treated with molecular target agents. We analyzed the presence of an EGFR mutation as a factor that might affect patients’ outcome. Unfortunately, however, we did not routinely examine EGFR mutation status and we failed to prove that EGFR mutation status had a statistically significant relationship with survival, as was shown in a previous study [17]. Currently, we routinely evaluate EGFR mutation status and ALK gene rearrangement in all patients, and we hope to clarify the role of surgical resection of the primary tumor in patients who harbor a targetable mutation in the near future.

It has been suggested that tumor stage, sex, weight loss, and performance status are predictive factors of the success of systemic treatment. Performance status is an extremely powerful prognostic factor for survival and has been considered as the most important factor in selecting patients eligible for chemotherapy [22,23]. However, we did not include performance status in this study, because surgery was planned for all patients, meaning that their performance status was good.

We were not able to extract information regarding the number of pleural nodules. Dry pleural dissemination has been reported to have a better prognosis than wet pleural dissemination [8,9,16,24]. As all the patients were in the cM0 stage, the majority of our patients had dry pleural metastases. However, a multicenter survey reported that there was no significant difference in prognosis according to M1a descriptors (pleural effusion, pleural nodules, contralateral lung nodules) [3].

There are several limitations of this study. Surgical resection is not recommended for cases of extremely advanced lung cancer with overt pleural effusion or pleural nodules; hence, there was obvious selection bias in our study. Importantly, our conclusions should only be applied to patients in whom pleural seeding was unexpectedly diagnosed at the time of surgery. EGFR mutation data was available for only half of the patients. In addition, we did not analyze patients’ response to chemotherapy or disease progression. As a consequence, we were not able to perform an interaction analysis to eliminate the effect of tumor biology. However, our results suggest that resection of the primary tumor can lead to improved survival if patients can undergo systemic treatment for NSCLC with pleural dissemination that was unexpectedly encountered during surgery, especially in cases of adenocarcinoma without lymph node metastasis. Furthermore, in the era of precision medicine, surgical resection of the primary tumor may serve as an effective local treatment in conjunction with appropriate targeted therapy.

In conclusion, when pleural metastasis is encountered during surgical exploration, primary tumor resection can improve long-term survival in conjunction with systemic treatment, especially in selected patients with adenocarcinoma histology without lymph node metastasis.

Conflict of interest

No potential conflict of interest relevant to this article was reported.

Acknowledgments

The authors would like to express their appreciation for the statistical advice provided by the Medical Research Collaborating Center at Seoul National University Hospital and the Seoul National University College of Medicine.

Funding

This study was supported by the National Research Foun­dation: ID (http://dx.doi.org/10.13039/100011512); award no. (NRF-2014R1A2A2A05003665).

Fig 1.

Figure 1.Kaplan-Meier plot of the overall survival rate of non-small cell lung cancer patients with pleural metastasis.
Journal of Chest Surgery 2020; 53: 114-120https://doi.org/10.5090/kjtcs.2020.53.3.114

Fig 2.

Figure 2.Kaplan-Meier plots of survival rates according to primary tumor resection (solid line: primary tumor resection group; dotted line: biopsy group).
Journal of Chest Surgery 2020; 53: 114-120https://doi.org/10.5090/kjtcs.2020.53.3.114

Fig 3.

Figure 3.Kaplan-Meier plots of survival rates according to systemic treatment (solid line: primary tumor resection group; dotted line: biopsy group). (A) Patients who received systemic treatment. (B) Patients who did not receive systemic treatment.
Journal of Chest Surgery 2020; 53: 114-120https://doi.org/10.5090/kjtcs.2020.53.3.114

Table 1 . Clinicopathological characteristics of the patients.

CharacteristicTotal (N=130)Primary tumor resection group (n=40)Biopsy group (n=90)p-value
Age (yr)61.5±11.762.7±11.161.0±12.00.425
Female sex55 (42.3)16 (40.0)39 (43.3)0.723
Never-smoker74 (56.9)21 (52.5)53 (58.9)0.566
Forced expiratory volume in 1 second (predicted %)98.1±21.4102.6±21.795.7±21.00.117
Tumor size (cm)3.2±1.43.3±1.73.1±1.20.428
Tumor location0.670
Central35 (26.9)12 (30.0)23 (25.6)
Periphery95 (73.1)28 (70.0)67 (74.4)
Histology13040900.287
Squamous cell carcinoma12 (9.2)6 (15.0)6 (6.7)
Adenocarcinoma109 (83.8)32 (80.0)77 (85.6)
Others9 (6.9)2 (5.0)7 (7.8)
Systemic treatment (yes)110 (84.6)35 (87.5)75 (83.3)0.543
Cytotoxic chemotherapy (yes)96 (73.8)28 (70.0)68 (75.6)0.522
Tyrosine kinase inhibitor (yes)72 (55.4)21 (52.5)51 (56.7)0.705
T stage0.503
138 (29.2)14 (35.5)24 (26.7)
261 (46.9)18 (45.0)43 (47.8)
322 (16.9)7 (17.5)15 (16.7)
49 (6.9)1 (2.5)8 (6.2)
N stage0.168
086 (66.2)26 (65.0)60 (66.7)
121 (16.2)10 (25.0)11 (12.2)
221 (16.2)4 (10.0)17 (18.9)
32 (1.5)02 (2.2)
Surgery1304090
Pleural or lung biopsy-90 (100.0)
Primary tumor resection40 (100.0)-
Wedge resection16 (40.0)
Lobectomy21 (52.5)
Pneumonectomy3 (7.5)
Length of hospital stay8.0±7.99.9±11.77.1±5.20.153
Epidermal growth factor receptor mutation (yes) (n=65)33/65 (50.5)16/27 (59.3)17/38 (44.7)0.248

Values are presented as mean±standard deviation or number (%)..


Table 2 . Univariate analysis of prognostic factors for long-term survival in non–small cell lung cancer.

VariableHazard ratio (95% confidence interval)p-value
Age (vs. ≥65 yr)
<65 yr1.225 (0.815–1.840)0.328
Sex (vs. male)
Female0.990 (0.660–1.484)0.961
Smoking (vs. ever-smoker)
Never-smoker0.700 (0.468–1.045)0.081
Epidermal growth factor receptor mutation (vs. wild-type)
Yes0.621 (0.327–1.180)0.146
Tumor size (vs. ≥3 cm)
<3 cm0.951 (0.626–1.445)0.815
Tumor location (vs. central)
Periphery0.795 (0.511–1.236)0.308
Clinical T stage (vs. ≥T2)
T10.883 (0.568–1.374)0.581
Clinical N stage (vs. ≥N1)
N00.644 (0.419–0.990)0.045
Systemic treatment (vs. no)
Yes0.254 (0.149–0.431)<0.001
Resection (vs. biopsy only)
Primary tumor resection0.557 (0.343–0.903)0.018
Extent of resection (vs. wedge resection) (n=40)
≥ Lobectomy0.842 (0.330–2.146)0.719
Histology (vs. squamous cell carcinoma)0.039
Adenocarcinoma0.512 (0.263–0.997)0.049
Others0.981 (0.396–2.429)0.966

Table 3 . Multivariate Cox regression analysis of prognostic factors for long-term survival in non–small cell lung cancer.

VariableHazard ratio (95% confidence interval)p-value
Clinical N stage (vs. ≥N1)
N00.566 (0.362–0.884)0.012
Histology (vs. squamous cell carcinoma)0.009
Adenocarcinoma0.372 (0.186–0.742)0.005
Others0.637 (0.248–1.632)0.347
Systemic treatment & resection0.017
Primary tumor resection (vs. biopsy only)
Systemic treatment (yes)0.464 (0.264–0.815)0.008
Systemic treatment (no)1.994 (0.693–5.736)0.201
Systemic treatment (vs. no)
Primary tumor resection (yes)0.069 (0.024–0.200)<0.001
Primary tumor resection (no)0.296 (0.158–0.555)<0.001

References

  1. Ou SH, Zell JA. Validation study of the proposed IASLC staging revisions of the T4 and M non-small cell lung cancer descriptors using data from 23,583 patients in the California Cancer Registry. J Thorac Oncol 2008;3:216-27.
    Pubmed CrossRef
  2. Postmus PE, Brambilla E, Chansky K, et al. The IASLC Lung Cancer Staging Project: proposals for revision of the M descriptors in the forthcoming (seventh) edition of the TNM classification of lung cancer. J Thorac Oncol 2007;2:686-93.
    Pubmed CrossRef
  3. Eberhardt WE, Mitchell A, Crowley J, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the M descriptors in the forthcoming eighth edition of the TNM classification of lung cancer. J Thorac Oncol 2015;10:1515-22.
    Pubmed CrossRef
  4. Billing PS, Miller DL, Allen MS, Deschamps C, Trastek VF, Pairolero PC. Surgical treatment of primary lung cancer with synchronous brain metastases. J Thorac Cardiovasc Surg 2001;122:548-53.
    Pubmed CrossRef
  5. Mercier O, Fadel E, de Perrot M, et al. Surgical treatment of solitary adrenal metastasis from non-small cell lung cancer. J Thorac Cardiovasc Surg 2005;130:136-40.
    Pubmed CrossRef
  6. Ettinger DS, Wood DE, Akerley W, et al. NCCN guidelines insights: non-small cell lung cancer, version 4. J Natl Compr Canc Netw 2016 2016;14:255-64.
    Pubmed CrossRef
  7. Ichinose Y, Tsuchiya R, Koike T, et al. Prognosis of resected non-small cell lung cancer patients with carcinomatous pleuritis of minimal disease. Lung Cancer 2001;32:55-60.
    Pubmed CrossRef
  8. Iida T, Shiba M, Yoshino I, et al. Surgical intervention for non-small-cell lung cancer patients with pleural carcinomatosis: results from the Japanese Lung Cancer Registry in 2004. J Thorac Oncol 2015;10:1076-82.
    Pubmed CrossRef
  9. Fukuse T, Hirata T, Tanaka F, Wada H. The prognostic significance of malignant pleural effusion at the time of thoracotomy in patients with non-small cell lung cancer. Lung Cancer 2001;34:75-81.
    Pubmed CrossRef
  10. Go T, Misaki N, Matsuura N, Chang SS, Tarumi S, Yokomise H. Role of surgery in multi-modality treatment for carcinomatous pleuritis in patients with non-small cell lung cancer. Surg Today 2015;45:197-202.
    Pubmed CrossRef
  11. Mordant P, Arame A, Foucault C, Dujon A, Le Pimpec Barthes F, Riquet M. Surgery for metastatic pleural extension of non-small-cell lung cancer. Eur J Cardiothorac Surg 2011;40:1444-9.
    Pubmed CrossRef
  12. Sawabata N, Matsumura A, Motohiro A, et al. Malignant minor pleural effusion detected on thoracotomy for patients with non-small cell lung cancer: is tumor resection beneficial for prognosis? Ann Thorac Surg 2002;73:412-5.
    Pubmed CrossRef
  13. Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy and supportive care versus supportive care alone for advanced non-small cell lung cancer. Cochrane Database Syst Rev 2010;5:CD007309.
    Pubmed CrossRef
  14. Ashworth AB, Senan S, Palma DA, et al. An individual patient data metaanalysis of outcomes and prognostic factors after treatment of oligometastatic non-small-cell lung cancer. Clin Lung Cancer 2014;15:346-55.
    Pubmed CrossRef
  15. Yokoi K, Matsuguma H, Anraku M. Extrapleural pneumonectomy for lung cancer with carcinomatous pleuritis. J Thorac Cardiovasc Surg 2002;123:184-5.
    Pubmed CrossRef
  16. Okamoto T, Iwata T, Mizobuchi T, et al. Pulmonary resection for lung cancer with malignant pleural disease first detected at thoracotomy. Eur J Cardiothorac Surg 2012;41:25-30.
    Pubmed KoreaMed CrossRef
  17. Li C, Kuo SW, Hsu HH, Lin MW, Chen JS. Lung adenocarcinoma with intraoperatively diagnosed pleural seeding: is main tumor resection beneficial for prognosis? J Thorac Cardiovasc Surg 2018;155:1238-49.
    Pubmed CrossRef
  18. Ball D, Mitchell A, Giroux D, Rami-Porta R; IASLC Staging Committee and Participating Institutions. Effect of tumor size on prognosis in patients treated with radical radiotherapy or chemoradiotherapy for non-small cell lung cancer: an analysis of the staging project database of the International Association for the Study of Lung Cancer. J Thorac Oncol 2013;8:315-21.
    Pubmed CrossRef
  19. Nguyen NP, Bishop M, Borok TJ, et al. Pattern of failure following chemoradiation for locally advanced non-small cell lung cancer: potential role for stereotactic body radiotherapy. Anticancer Res 2010;30:953-61.
    Pubmed
  20. Pages PB, Cottenet J, Mariet AS, Bernard A, Quantin C. In-hospital mortality following lung cancer resection: nationwide administrative database. Eur Respir J 2016;47:1809-17.
    Pubmed CrossRef
  21. Paul S, Altorki NK, Sheng S, et al. Thoracoscopic lobectomy is associated with lower morbidity than open lobectomy: a propensity-matched analysis from the STS database. J Thorac Cardiovasc Surg 2010;139:366-78.
    Pubmed CrossRef
  22. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002;346:92-8.
    Pubmed CrossRef
  23. Masters GA, Temin S, Azzoli CG, et al. Systemic therapy for stage iv non-small-cell lung cancer: American Society of Clinical Oncology Clinical Practice Guideline update. J Clin Oncol 2015;33:3488-515.
    Pubmed KoreaMed CrossRef
  24. Kim YK, Lee HY, Lee KS, et al. Dry pleural dissemination in non-small cell lung cancer: prognostic and diagnostic implications. Radiology 2011;260:568-74.
    Pubmed CrossRef

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