Original Thoracic
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Central Lung Cancer Management: Impact of Bronchial Resection Margin Length Dohun Kim1
Hong Kwan Kim2
Yong Soo Choi2
1 Department of Thoracic and Cardiovascular Surgery, Chungbuk
National University Hospital, Cheongju, Republic of Korea 2 Department of Thoracic and Cardiovascular Surgery, Samsung Medical Center, Seoul, Republic of Korea 3 Department of Thoracic and Cardiovascular Surgery, Seoul National University Bundang Hospital, Bundang, Republic of Korea
Kwhanmien Kim3
Jhingook Kim2
Young Mog Shim2
Address for correspondence Young Mog Shim, MD, PhD, Department of Thoracic and Cardiovascular Surgery, Samsung Medical Center, Irwon-Dong 50, Kangnam-Gu, Seoul 135-710, Republic of Korea (e-mail: [email protected]).
Abstract
Keywords
► lung cancer treatment ► surgery ► outcomes
Purpose The purpose of this study was to analyze the clinical impact of bronchial resection margin length in centrally located, non-small cell lung cancer. Materials and Methods A total of 1,854 pulmonary resections were performed between January 1994 and December 2005. Central lung cancer was defined as a tumor that was confirmed by bronchoscopy or a malignancy proven by bronchoscopic washing. Cases with neoadjuvant treatment that could alter the malignancy on the margin and those without documentation of margin length were excluded. To divide the study group into two groups, the cutoff value for the margin length was calculated by the minimum p-value approach. Clinical variables were then compared between the two groups and prognostic factors for survival were analyzed. Results A total of 573 patients were included. The patients were divided into two groups based on margin length, short (< 19 mm) and long ( 19 mm). Overall survival and disease-free survival were superior in the short length group by univariate analysis (p ¼ 0.03, 0.02). With multivariate analysis, advanced age (p < 0.00, 0.00), pneumonectomy (p < 0.00, 0.00), advanced pathologic stage (p < 0.00, 0.00), and no adjuvant chemotherapy (p < 0.00, 0.01) were poor prognostic factors for survival; however, bronchial resection margin length was not a statistically significant factor (p ¼ 0.90, 0.96). Conclusion A long bronchial resection margin length may not guarantee better oncologic outcomes in central lung cancer patients. Rather, avoiding pneumonectomy and the application of adjuvant chemotherapy should be considered to survival.
Introduction Although complete surgical resection (R0 resection) provides the best curative chance for non-small cell lung cancer, it is unclear whether the outcome of R0 resection is affected by bronchial resection margin length, which is defined as the length from the tumor to the bronchial resection margin. Kara et al reported that a bronchial resection margin of 1.5 cm in
received January 16, 2014 accepted after revision April 28, 2014 published online July 17, 2014
length from the macroscopic tumor provides clear margins in 93% of non-small cell lung cancer cases.1 Despite this apparent need for a safety margin in lung cancer, a recent study found that the extent of the bronchial margin had no clinically relevant impact on survival.2 Several factors need to be considered in the case of central lung cancer. If the tumor is located near the bronchus bifurcation, a lesser extent of resection is desired, but a sufficient
© 2015 Georg Thieme Verlag KG Stuttgart · New York
DOI http://dx.doi.org/ 10.1055/s-0034-1383813. ISSN 0171-6425.
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The Clinical Impact of Bronchial Resection Margin Length
Kim et al.
safety margin needs to be maintained.3 For a tumor located very close to the resection margin by pathologic report, selecting the appropriate adjuvant treatment may also be problematic.4,5 Moreover, it is uncertain whether local recurrence, including stump recurrence, results in poor survival.6 The purpose of this study was therefore to analyze the clinical impact of bronchial resection margin length in centrally located, non-small cell lung cancer.
curative intent surgery with R0 resections; (3) pathologic report documenting bronchial resection margin length; and (4) bronchoscopy-proven malignancy. The exclusion criteria were as follows: (1) a history of neoadjuvant therapy that could change the pathology of the resection margin; (2) R1, R2 resection in the bronchial resection margin or in an area other than the bronchus; and (3) multiple pulmonary malignancies. This study was reviewed and approved by the Institutional Review Board of Samsung Medical Center.
Materials and Methods Patients
Documentation of Central Lung Cancer, Bronchial Resection Margin Length, and Recurrence
A total of 1,854 consecutive pulmonary resections were performed between January 1994 and December 2005 at a university-based tertiary medical center. The study inclusion criteria were as follows: (1) presence of non-small cell lung cancer; (2)
Central lung cancer was defined as a tumor that was confirmed by bronchoscopy or a malignancy proven by bronchoscopic washing or biopsy. Bronchial resection margin length was defined as the shortest length between the tumor mass and
Table 1 Patient characteristics at baseline Characteristics
Overall
Short length
Long length
Number of patients
573
307 (54)
266 (46)
Margin length
19.9 15.4
8.4 4.9
33.2 12.4
Age at operation
60 9.6
60 9.8
61 9.2
Sex
p-Value
0.02 0.08
M
523 (91)
286 (93)
237 (89)
F
50 (9)
21 (7)
29 (11)
Type of cells
0.03
SQC
411 (72)
233 (76)
178 (67)
ADC
99 (17)
42 (14)
57 (21)
Othera
63 (11)
32 (10)
31 (12)
Lobectomy
284 (50)
189 (62)
95 (36)
Bilobectomy
101 (18)
66 (22)
35 (13)
Pneumonectomy
188 (33)
52 (16)
136 (51)
1
193 (34)
110 (36)
83 (31)
2
207 (36)
124 (40)
83 (31)
3
166 (29)
70 (23)
96 (36)
4
7 (1)
3 (1)
4 (2)
25 12.4
21 9.1
29 13.9
Positive LN
1.3 2.5
1.1 2.0
1.6 2.9
0.01
Dissected LN station
5.4 1.9
5.2 1.9
5.6 1.9
< 0.00
Positive LN station
0.6 0.8
0.5 0.8
0.7 0.9
0.09
63 (11)
36 (12)
27 (10)
0.54
136 (24)
87 (28)
49 (18)
< 0.00
< 0.00
Type of operations
< 0.00
Pathologic stages
Lymph nodes Dissected LN
< 0.00
Adjuvant chemotherapy Performed Adjuvant radiotherapy Performed
Abbreviations: ADC, adenocarcinoma; LN, lymph node; SQC, squamous cell carcinoma. Note: Short length was defined as bronchial resection margin < 19 mm. Long length was defined as bronchial resection margin 19 mm. a Malignancy excluding squamous cell carcinoma or adenocarcinoma. Thoracic and Cardiovascular Surgeon
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the bronchial resection margin, which was documented by a pathologist. Peripheral lung tumors that were located away from the airway were excluded from this study because most pathologic reports did not comment on a specific bronchial margin length. Recurrence was defined as follows: (1) stump recurrence—recurrence at the bronchial stump, around the stump, or in an ipsilateral airway near the stump; (2) local recurrence—tumor recurrence at the ipsilateral hilum and/or mediastinum; and (3) distant metastasis—all other sites of recurrence/metastasis except local/stump recurrence.
Study Design and Statistics The primary outcome was overall survival (OS) and diseasefree survival (DFS). Bronchial resection margin length was divided into two categories: short length and long length. To achieve a cutoff value, margin length was analyzed according to the OS by the minimum p-value approach with correction by Bonferroni method.7,8 Either the specific length or the cutoff value which showed the smallest p-value could be selected. Descriptive statistics were used to describe patient characteristics and outcomes. Categorical data were expressed as numbers and proportions. Continuous data were expressed as means with standard deviations. Chi-square or Fisher exact tests were used to compare categorical data, and t-tests were used for continuous variables. Logistic regression was used to evaluate the relationship between recurrence and lymph node. Kaplan–Meyer graphs and log-rank tests were used to compare OS and DFS. Cox proportional hazard regression models were used to analyze prognostic factors. A p-value of less than 0.05 was considered significant. Statistical analysis was performed using SAS version 9.1.3 (SAS Institute, Cary, North Carolina, United States) and R 2.13.2 (Vienna, Austria; http://www.R-project.org/).
Kim et al.
and 651 cases without central lesions were excluded. A further 28 patients with R1 resections were excluded, with a final total of 573 patients included in the study. Patient information is provided in ►Table 1. The mean age of patients was 60 years old and men were more common. About 70% of patients had squamous cell carcinoma and 17% had adenocarcinoma. Large cell carcinoma, atypical carcinoid, or mixed type malignancy were included in the “Others” category. Our surgical policy was complete anatomical resection and mediastinal lymph node dissection. Lobectomy was the most common procedure (n ¼ 284, 50%) and pneumonectomy was the second most common (n ¼ 188, 33%). Average 25 lymph nodes and 5 lymph node stations were dissected. Positive lymph node and station were 1.3 and 0.6 (►Table 1). Especially pathological N1 was in 173 (30%) and N2 (mediastinal lymph node positive) was in 93(16%) patients. Bronchial resection margin length for each group was as follows: 8 mm in short length and 33 mm in long length (►Table 1). In addition, they were as follows: 16.4 41.1 mm in lobectomy, 17.1 16.0 mm in bilobectomy, and 26.6 14.8 mm in pneumonectomy. There was no significant difference for the margin length (p ¼ 0.29). The pathologic stage was evenly distributed. For adjuvant treatment, 11% underwent chemotherapy and 24% underwent radiotherapy. The cutoff value dividing short length and long length was 19 mm by the minimum p-value approach. Therefore, margin length of less than 19 mm was defined as the short length, and the others were long length. There were 307 (51%) patients in the short length group, and 266 (44%) in the long length group. The long length group was older, but pathologic stages 1 and 2 were more prevalent in the short length group. Pneumonectomy and adjuvant radiotherapy were performed more often in the long length group.
Survival and Recurrence
Results Demographics and Grouping During the study period, 1,854 consecutive curative lung resections were performed at a single medical center. Neoadjuvant chemoradiation was performed in 201 patients with clinical N2 disease demonstrated by mediastinoscopic lymph node biopsy, and they were excluded from this study. An additional 401 patients whose bronchial resection margin length information was not provided in the pathologic report
All patients underwent follow-up until the last hospital visit or officially confirmed death. Chest computed tomography (CT) or positron-emission tomography-CT was used for follow-up. The period was 3 months in first visit, 6 months in second and third visits. After then annual follow-up was performed till postoperative 5 years. The average study period was 58 months. During the period, 352 (61%) patients died and overall recurrence was seen in 226 (39%) patients. Stump and local recurrences were more common in the long
Table 2 Surgical outcomes between short and long length groups Overall
Short length
Long length
Number of patients
573
307 (54)
266 (46)
Mortality
352
178 (58)
174 (65)
p-Value 0.06
Recurrence
226 (39)
117 (38)
109 (41)
0.48
Stump
24 (4)
10 (3)
14 (5)
0.23
Local
60 (10)
26 (8)
34 (13)
0.09
Distant
181 (32)
98 (32)
83 (31)
0.85
Note: Short length was defined as bronchial resection margin < 19 mm. Long length was defined as bronchial resection margin 19 mm. Thoracic and Cardiovascular Surgeon
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The Clinical Impact of Bronchial Resection Margin Length
The Clinical Impact of Bronchial Resection Margin Length
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length group (5 and 13%, respectively), but distant metastases were observed at the same frequency. Detailed information is provided in ►Table 2. Recurrence and distant recurrence were related with positive lymph node (p ¼ 0.01, < 0.00) and station (p ¼ 0.01, < 0.00). OS and DFS were significantly different between the groups (p ¼ 0.03 and 0.02, respectively). The short length group showed better survival than the long length group (►Fig. 1A, B).
Cox Proportional Hazards Model for Overall and Disease-Free Survival Age, type of operation, pathologic stage, positive lymph node and station, adjuvant chemotherapy, adjuvant radiotherapy (except in DFS), and bronchial resection margin length were significantly different in the univariate analysis. After adjusting for other factors by multivariate analysis, age (p < 0.00, 0.00; respectively), type of operation (p < 0.00, 0.01), pathologic stage (p < 0.00, 0.00), and adjuvant chemotherapy (p < 0.00, 0.01) were prognostic factors in OS and DFS. However, bronchial resection margin length was not a prognostic factor for survival (p ¼ 0.90 in overall and 0.96 in disease-free). According to the type of operation, the difference was significant only between lobectomy and pneumonectomy. Detailed information is provided in ►Tables 3 and 4.
Discussion This study is unique in providing clinical outcomes based on bronchial resection margin length. Although an adequate safety distance seems to be required in the lung parenchyma,9–11 the necessity of a safety margin in the bronchial tree has not been clearly established.2 Margin length was not a significant prognostic factor for survival in this study.
Fig. 1 (A) Overall and (B) disease-free survival according to bronchial resection margin length.
Table 3 Univariate and multivariate analyses for overall survival Characteristics
Univariate analysis
Multivariate analysis
HR
95% CI
p-Value
Age
1.04
1.03–1.06
< 0.00
Sex
0.77
0.52–1.14
0.19
Type of cell
0.93
0.79–1.09
0.38
Type of operation
1.36
1.21–1.53
< 0.00
HR
95% CI
p-Value
1.04
1.03–1.06
< 0.00
Operation 1a
1.38
1.02–1.85
0.03
b
1.57
1.21–2.04
< 0.00
1.37
1.18–1.59
< 0.00
Subgroup
Operation 2 Pathologic stage
1.44
1.27–1.64
< 0.00
Adjuvant chemotherapy
0.62
0.43–0.90
0.01
0.58
0.39–0.85
< 0.00
Adjuvant radiotherapy
1.28
1.02–1.63
0.03
1.06
0.82–1.38
0.61
Bronchial margin length
1.01
1.00–1.02
0.03
0.99
0.99–1.01
0.90
0.97
0.91–1.04
0.48
1.18
0.96–1.44
0.11
Dissected LN
1.00
0.99–1.01
0.65
Positive LN
1.04
1.01–1.08
0.01
Dissected LN station
0.97
0.92–1.03
0.44
Positive LN station
1.22
1.11–1.35
< 0.00
Abbreviations: HR, hazard ratio; 95% CI, 95% confidence interval. a Operation 1, lobectomy (reference) versus bilobectomy. b Operation 2, lobectomy (reference) versus pneumonectomy. Thoracic and Cardiovascular Surgeon
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Table 4 Univariate and multivariate analyses for disease-free survival Univariate analysis
Multivariate analysis
HR
95% CI
p-Value
Age
1.03
1.02–1.05
< 0.00
Sex
0.92
0.64–1.33
0.67
Type of cell
1.04
0.89–1.21
0.59
Type of operation
1.30
1.17–1.46
< 0.00
HR
95% CI
p-Value
1.03
1.02–1.05
< 0.00
Operation 1a
1.21
0.90–1.61
0.21
b
1.39
1.08–1.78
0.01
Subgroup
Operation 2 Pathologic stage
1.41
1.28–1.64
< 0.00
1.37
1.18–1.58
< 0.00
Adjuvant chemotherapy
0.67
0.47–0.95
0.02
0.61
0.42–0.89
0.01
Adjuvant radiotherapy
1.24
0.99–1.57
0.06
Bronchial margin length
1.01
1.00–1.02
0.02
0.99
0.98–1.01
0.96
1.00
0.93–1.07
0.99
1.13
0.93–1.37
0.19
Dissected LN
1.00
0.99–1.00
0.86
Positive LN
1.06
1.02–1.09
< 0.00
Dissected LN station
0.97
0.92–1.03
0.43
Positive LN station
1.25
1.14–1.37
< 0.00
Abbreviations: HR, hazard ratio; 95% CI, 95% confidence interval. a Operation 1, lobectomy (reference) versus bilobectomy. b Operation 2, lobectomy (reference) versus pneumonectomy.
Although the long length group had an adequate safety margin length, they showed poorer survival than the short length group by univariate analysis. This may have been because more pneumonectomies which could be fatal were included in the long length group.12,13 Therefore, the results changed after adjusting for multiple clinical factors including type of operation. Adjuvant chemotherapy14,15 and type of operation12,13 have been viewed as prognostic factors in lung cancer. Adjuvant chemotherapy has been recommended to improve survival,14,15 as was confirmed in this study group. According to the type of operation, pneumonectomy was proven to be a negative prognostic factor for survival, like previously reported.12,13 Considering these findings, avoiding pneumonectomy and undergoing adjuvant chemotherapy are recommended in these central lung cancer patients. We note that our study had some limitations. First, this was a retrospective study and therefore some selection bias may have occurred. Although recurrence was defined using standard criteria, the diagnostic modality of recurrence was different. Some cases were proven by biopsy, but others were proven by imaging alone. However, all records for recurrence were written by an oncologic specialist. Second, the method of adjuvant treatment varied because of the long study period and hospital variability. However, most of the patients were treated at our hospital. Third, the detailed pattern and dose of radiotherapy were not analyzed in this study, so the results regarding radiotherapy may have limitations. Despite these limitations, this study provides important clues for selecting the proper operative technique and adjuvant treatment in centrally located, non-small cell lung cancer with confident long-term follow-up in a large, unified cohort of patients.
In conclusion, a long bronchial resection margin length may not guarantee better oncologic outcomes in central lung cancer patients. Rather, avoiding pneumonectomy and the application of adjuvant chemotherapy should be considered to improve survival.
References 1 Kara M, Sak SD, Orhan D, Yavuzer S. Changing patterns of lung
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cancer; (3/4 in.) 1.9 cm; still a safe length for bronchial resection margin? Lung Cancer 2000;30(3):161–168 Tomaszek SC, Kim Y, Cassivi SD, et al. Bronchial resection margin length and clinical outcome in non-small cell lung cancer. Eur J Cardiothorac Surg 2011;40(5):1151–1156 Berthet JP, Paradela M, Jimenez MJ, Molins L, Gómez-Caro A. Extended sleeve lobectomy: one more step toward avoiding pneumonectomy in centrally located lung cancer. Ann Thorac Surg 2013;96(6):1988–1997 Wind J, Smit EJ, Senan S, Eerenberg JP. Residual disease at the bronchial stump after curative resection for lung cancer. Eur J Cardiothorac Surg 2007;32(1):29–34 Rineer J, Schreiber D, Katsoulakis E, et al. Survival following sublobar resection for early-stage non-small cell lung cancer with or without adjuvant external beam radiation therapy: a population-based study. Chest 2010;137(2):362–368 Lequaglie C, Conti B, Brega Massone PP, Giudice G. Unsuspected residual disease at the resection margin after surgery for lung cancer: fate of patients after long-term follow-up. Eur J Cardiothorac Surg 2003;23(2):229–232 Brent A, Williams M, Jayawant N, et al. Finding Optimal Cutpoints for Continuous Covariates with Binary and Time-to-Event Outcomes. Mayo Foundation Technical Report Series, no. 79. Rochester, MN: Department of Health Sciences Research, Mayo Clinic; 2006; Available at: http://ndc.mayo.edu/mayo/research/ biostat/upload/79.pdf
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using “optimal” cutpoints in the evaluation of prognostic factors. J Natl Cancer Inst 1994;86(11):829–835 Whitson BA, Groth SS, Andrade RS, Maddaus MA, Habermann EB, D’Cunha J. Survival after lobectomy versus segmentectomy for stage I non-small cell lung cancer: a population-based analysis. Ann Thorac Surg 2011;92(6):1943–1950 Ginsberg RJ, Rubinstein LV; Lung Cancer Study Group. Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Ann Thorac Surg 1995;60(3):615–622, discussion 622–623 Kelsey CR, Marks LB, Hollis D, et al. Local recurrence after surgery for early stage lung cancer: an 11-year experience with 975 patients. Cancer 2009;115(22):5218–5227 Kozower BD, Sheng S, O’Brien SM, et al. STS database risk models: predictors of mortality and major morbidity for lung cancer
Kim et al. resection. Ann Thorac Surg 2010;90(3):875–881, discussion 881–883 13 Shi W, Zhang W, Sun H, Shao Y. Sleeve lobectomy versus pneumonectomy for non-small cell lung cancer: a meta-analysis. World J Surg Oncol 2012;10:265 14 Arriagada R, Auperin A, Burdett S, et al; NSCLC Meta-analyses Collaborative Group. Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: two meta-analyses of individual patient data. Lancet 2010; 375(9722):1267–1277 15 Pisters KM, Evans WK, Azzoli CG, et al; Cancer Care Ontario American Society of Clinical Oncology. Cancer Care Ontario and American Society of Clinical Oncology adjuvant chemotherapy and adjuvant radiation therapy for stages I-IIIA resectable non small-cell lung cancer guideline. J Clin Oncol 2007;25(34): 5506–5518
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Thoracic and Cardiovascular Surgeon
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Central Lung Cancer Management: Impact of Bronchial Resection Margin Length Dohun Kim1
Hong Kwan Kim2
Yong Soo Choi2
1 Department of Thoracic and Cardiovascular Surgery, Chungbuk
National University Hospital, Cheongju, Republic of Korea 2 Department of Thoracic and Cardiovascular Surgery, Samsung Medical Center, Seoul, Republic of Korea 3 Department of Thoracic and Cardiovascular Surgery, Seoul National University Bundang Hospital, Bundang, Republic of Korea
Kwhanmien Kim3
Jhingook Kim2
Young Mog Shim2
Address for correspondence Young Mog Shim, MD, PhD, Department of Thoracic and Cardiovascular Surgery, Samsung Medical Center, Irwon-Dong 50, Kangnam-Gu, Seoul 135-710, Republic of Korea (e-mail: [email protected]).
Abstract
Keywords
► lung cancer treatment ► surgery ► outcomes
Purpose The purpose of this study was to analyze the clinical impact of bronchial resection margin length in centrally located, non-small cell lung cancer. Materials and Methods A total of 1,854 pulmonary resections were performed between January 1994 and December 2005. Central lung cancer was defined as a tumor that was confirmed by bronchoscopy or a malignancy proven by bronchoscopic washing. Cases with neoadjuvant treatment that could alter the malignancy on the margin and those without documentation of margin length were excluded. To divide the study group into two groups, the cutoff value for the margin length was calculated by the minimum p-value approach. Clinical variables were then compared between the two groups and prognostic factors for survival were analyzed. Results A total of 573 patients were included. The patients were divided into two groups based on margin length, short (< 19 mm) and long ( 19 mm). Overall survival and disease-free survival were superior in the short length group by univariate analysis (p ¼ 0.03, 0.02). With multivariate analysis, advanced age (p < 0.00, 0.00), pneumonectomy (p < 0.00, 0.00), advanced pathologic stage (p < 0.00, 0.00), and no adjuvant chemotherapy (p < 0.00, 0.01) were poor prognostic factors for survival; however, bronchial resection margin length was not a statistically significant factor (p ¼ 0.90, 0.96). Conclusion A long bronchial resection margin length may not guarantee better oncologic outcomes in central lung cancer patients. Rather, avoiding pneumonectomy and the application of adjuvant chemotherapy should be considered to survival.
Introduction Although complete surgical resection (R0 resection) provides the best curative chance for non-small cell lung cancer, it is unclear whether the outcome of R0 resection is affected by bronchial resection margin length, which is defined as the length from the tumor to the bronchial resection margin. Kara et al reported that a bronchial resection margin of 1.5 cm in
received January 16, 2014 accepted after revision April 28, 2014 published online July 17, 2014
length from the macroscopic tumor provides clear margins in 93% of non-small cell lung cancer cases.1 Despite this apparent need for a safety margin in lung cancer, a recent study found that the extent of the bronchial margin had no clinically relevant impact on survival.2 Several factors need to be considered in the case of central lung cancer. If the tumor is located near the bronchus bifurcation, a lesser extent of resection is desired, but a sufficient
© 2015 Georg Thieme Verlag KG Stuttgart · New York
DOI http://dx.doi.org/ 10.1055/s-0034-1383813. ISSN 0171-6425.
Downloaded by: University of Iowa Libraries. Copyrighted material.
Thorac Cardiovasc Surg 2015;63:583–588.
The Clinical Impact of Bronchial Resection Margin Length
Kim et al.
safety margin needs to be maintained.3 For a tumor located very close to the resection margin by pathologic report, selecting the appropriate adjuvant treatment may also be problematic.4,5 Moreover, it is uncertain whether local recurrence, including stump recurrence, results in poor survival.6 The purpose of this study was therefore to analyze the clinical impact of bronchial resection margin length in centrally located, non-small cell lung cancer.
curative intent surgery with R0 resections; (3) pathologic report documenting bronchial resection margin length; and (4) bronchoscopy-proven malignancy. The exclusion criteria were as follows: (1) a history of neoadjuvant therapy that could change the pathology of the resection margin; (2) R1, R2 resection in the bronchial resection margin or in an area other than the bronchus; and (3) multiple pulmonary malignancies. This study was reviewed and approved by the Institutional Review Board of Samsung Medical Center.
Materials and Methods Patients
Documentation of Central Lung Cancer, Bronchial Resection Margin Length, and Recurrence
A total of 1,854 consecutive pulmonary resections were performed between January 1994 and December 2005 at a university-based tertiary medical center. The study inclusion criteria were as follows: (1) presence of non-small cell lung cancer; (2)
Central lung cancer was defined as a tumor that was confirmed by bronchoscopy or a malignancy proven by bronchoscopic washing or biopsy. Bronchial resection margin length was defined as the shortest length between the tumor mass and
Table 1 Patient characteristics at baseline Characteristics
Overall
Short length
Long length
Number of patients
573
307 (54)
266 (46)
Margin length
19.9 15.4
8.4 4.9
33.2 12.4
Age at operation
60 9.6
60 9.8
61 9.2
Sex
p-Value
0.02 0.08
M
523 (91)
286 (93)
237 (89)
F
50 (9)
21 (7)
29 (11)
Type of cells
0.03
SQC
411 (72)
233 (76)
178 (67)
ADC
99 (17)
42 (14)
57 (21)
Othera
63 (11)
32 (10)
31 (12)
Lobectomy
284 (50)
189 (62)
95 (36)
Bilobectomy
101 (18)
66 (22)
35 (13)
Pneumonectomy
188 (33)
52 (16)
136 (51)
1
193 (34)
110 (36)
83 (31)
2
207 (36)
124 (40)
83 (31)
3
166 (29)
70 (23)
96 (36)
4
7 (1)
3 (1)
4 (2)
25 12.4
21 9.1
29 13.9
Positive LN
1.3 2.5
1.1 2.0
1.6 2.9
0.01
Dissected LN station
5.4 1.9
5.2 1.9
5.6 1.9
< 0.00
Positive LN station
0.6 0.8
0.5 0.8
0.7 0.9
0.09
63 (11)
36 (12)
27 (10)
0.54
136 (24)
87 (28)
49 (18)
< 0.00
< 0.00
Type of operations
< 0.00
Pathologic stages
Lymph nodes Dissected LN
< 0.00
Adjuvant chemotherapy Performed Adjuvant radiotherapy Performed
Abbreviations: ADC, adenocarcinoma; LN, lymph node; SQC, squamous cell carcinoma. Note: Short length was defined as bronchial resection margin < 19 mm. Long length was defined as bronchial resection margin 19 mm. a Malignancy excluding squamous cell carcinoma or adenocarcinoma. Thoracic and Cardiovascular Surgeon
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the bronchial resection margin, which was documented by a pathologist. Peripheral lung tumors that were located away from the airway were excluded from this study because most pathologic reports did not comment on a specific bronchial margin length. Recurrence was defined as follows: (1) stump recurrence—recurrence at the bronchial stump, around the stump, or in an ipsilateral airway near the stump; (2) local recurrence—tumor recurrence at the ipsilateral hilum and/or mediastinum; and (3) distant metastasis—all other sites of recurrence/metastasis except local/stump recurrence.
Study Design and Statistics The primary outcome was overall survival (OS) and diseasefree survival (DFS). Bronchial resection margin length was divided into two categories: short length and long length. To achieve a cutoff value, margin length was analyzed according to the OS by the minimum p-value approach with correction by Bonferroni method.7,8 Either the specific length or the cutoff value which showed the smallest p-value could be selected. Descriptive statistics were used to describe patient characteristics and outcomes. Categorical data were expressed as numbers and proportions. Continuous data were expressed as means with standard deviations. Chi-square or Fisher exact tests were used to compare categorical data, and t-tests were used for continuous variables. Logistic regression was used to evaluate the relationship between recurrence and lymph node. Kaplan–Meyer graphs and log-rank tests were used to compare OS and DFS. Cox proportional hazard regression models were used to analyze prognostic factors. A p-value of less than 0.05 was considered significant. Statistical analysis was performed using SAS version 9.1.3 (SAS Institute, Cary, North Carolina, United States) and R 2.13.2 (Vienna, Austria; http://www.R-project.org/).
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and 651 cases without central lesions were excluded. A further 28 patients with R1 resections were excluded, with a final total of 573 patients included in the study. Patient information is provided in ►Table 1. The mean age of patients was 60 years old and men were more common. About 70% of patients had squamous cell carcinoma and 17% had adenocarcinoma. Large cell carcinoma, atypical carcinoid, or mixed type malignancy were included in the “Others” category. Our surgical policy was complete anatomical resection and mediastinal lymph node dissection. Lobectomy was the most common procedure (n ¼ 284, 50%) and pneumonectomy was the second most common (n ¼ 188, 33%). Average 25 lymph nodes and 5 lymph node stations were dissected. Positive lymph node and station were 1.3 and 0.6 (►Table 1). Especially pathological N1 was in 173 (30%) and N2 (mediastinal lymph node positive) was in 93(16%) patients. Bronchial resection margin length for each group was as follows: 8 mm in short length and 33 mm in long length (►Table 1). In addition, they were as follows: 16.4 41.1 mm in lobectomy, 17.1 16.0 mm in bilobectomy, and 26.6 14.8 mm in pneumonectomy. There was no significant difference for the margin length (p ¼ 0.29). The pathologic stage was evenly distributed. For adjuvant treatment, 11% underwent chemotherapy and 24% underwent radiotherapy. The cutoff value dividing short length and long length was 19 mm by the minimum p-value approach. Therefore, margin length of less than 19 mm was defined as the short length, and the others were long length. There were 307 (51%) patients in the short length group, and 266 (44%) in the long length group. The long length group was older, but pathologic stages 1 and 2 were more prevalent in the short length group. Pneumonectomy and adjuvant radiotherapy were performed more often in the long length group.
Survival and Recurrence
Results Demographics and Grouping During the study period, 1,854 consecutive curative lung resections were performed at a single medical center. Neoadjuvant chemoradiation was performed in 201 patients with clinical N2 disease demonstrated by mediastinoscopic lymph node biopsy, and they were excluded from this study. An additional 401 patients whose bronchial resection margin length information was not provided in the pathologic report
All patients underwent follow-up until the last hospital visit or officially confirmed death. Chest computed tomography (CT) or positron-emission tomography-CT was used for follow-up. The period was 3 months in first visit, 6 months in second and third visits. After then annual follow-up was performed till postoperative 5 years. The average study period was 58 months. During the period, 352 (61%) patients died and overall recurrence was seen in 226 (39%) patients. Stump and local recurrences were more common in the long
Table 2 Surgical outcomes between short and long length groups Overall
Short length
Long length
Number of patients
573
307 (54)
266 (46)
Mortality
352
178 (58)
174 (65)
p-Value 0.06
Recurrence
226 (39)
117 (38)
109 (41)
0.48
Stump
24 (4)
10 (3)
14 (5)
0.23
Local
60 (10)
26 (8)
34 (13)
0.09
Distant
181 (32)
98 (32)
83 (31)
0.85
Note: Short length was defined as bronchial resection margin < 19 mm. Long length was defined as bronchial resection margin 19 mm. Thoracic and Cardiovascular Surgeon
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The Clinical Impact of Bronchial Resection Margin Length
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length group (5 and 13%, respectively), but distant metastases were observed at the same frequency. Detailed information is provided in ►Table 2. Recurrence and distant recurrence were related with positive lymph node (p ¼ 0.01, < 0.00) and station (p ¼ 0.01, < 0.00). OS and DFS were significantly different between the groups (p ¼ 0.03 and 0.02, respectively). The short length group showed better survival than the long length group (►Fig. 1A, B).
Cox Proportional Hazards Model for Overall and Disease-Free Survival Age, type of operation, pathologic stage, positive lymph node and station, adjuvant chemotherapy, adjuvant radiotherapy (except in DFS), and bronchial resection margin length were significantly different in the univariate analysis. After adjusting for other factors by multivariate analysis, age (p < 0.00, 0.00; respectively), type of operation (p < 0.00, 0.01), pathologic stage (p < 0.00, 0.00), and adjuvant chemotherapy (p < 0.00, 0.01) were prognostic factors in OS and DFS. However, bronchial resection margin length was not a prognostic factor for survival (p ¼ 0.90 in overall and 0.96 in disease-free). According to the type of operation, the difference was significant only between lobectomy and pneumonectomy. Detailed information is provided in ►Tables 3 and 4.
Discussion This study is unique in providing clinical outcomes based on bronchial resection margin length. Although an adequate safety distance seems to be required in the lung parenchyma,9–11 the necessity of a safety margin in the bronchial tree has not been clearly established.2 Margin length was not a significant prognostic factor for survival in this study.
Fig. 1 (A) Overall and (B) disease-free survival according to bronchial resection margin length.
Table 3 Univariate and multivariate analyses for overall survival Characteristics
Univariate analysis
Multivariate analysis
HR
95% CI
p-Value
Age
1.04
1.03–1.06
< 0.00
Sex
0.77
0.52–1.14
0.19
Type of cell
0.93
0.79–1.09
0.38
Type of operation
1.36
1.21–1.53
< 0.00
HR
95% CI
p-Value
1.04
1.03–1.06
< 0.00
Operation 1a
1.38
1.02–1.85
0.03
b
1.57
1.21–2.04
< 0.00
1.37
1.18–1.59
< 0.00
Subgroup
Operation 2 Pathologic stage
1.44
1.27–1.64
< 0.00
Adjuvant chemotherapy
0.62
0.43–0.90
0.01
0.58
0.39–0.85
< 0.00
Adjuvant radiotherapy
1.28
1.02–1.63
0.03
1.06
0.82–1.38
0.61
Bronchial margin length
1.01
1.00–1.02
0.03
0.99
0.99–1.01
0.90
0.97
0.91–1.04
0.48
1.18
0.96–1.44
0.11
Dissected LN
1.00
0.99–1.01
0.65
Positive LN
1.04
1.01–1.08
0.01
Dissected LN station
0.97
0.92–1.03
0.44
Positive LN station
1.22
1.11–1.35
< 0.00
Abbreviations: HR, hazard ratio; 95% CI, 95% confidence interval. a Operation 1, lobectomy (reference) versus bilobectomy. b Operation 2, lobectomy (reference) versus pneumonectomy. Thoracic and Cardiovascular Surgeon
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Table 4 Univariate and multivariate analyses for disease-free survival Univariate analysis
Multivariate analysis
HR
95% CI
p-Value
Age
1.03
1.02–1.05
< 0.00
Sex
0.92
0.64–1.33
0.67
Type of cell
1.04
0.89–1.21
0.59
Type of operation
1.30
1.17–1.46
< 0.00
HR
95% CI
p-Value
1.03
1.02–1.05
< 0.00
Operation 1a
1.21
0.90–1.61
0.21
b
1.39
1.08–1.78
0.01
Subgroup
Operation 2 Pathologic stage
1.41
1.28–1.64
< 0.00
1.37
1.18–1.58
< 0.00
Adjuvant chemotherapy
0.67
0.47–0.95
0.02
0.61
0.42–0.89
0.01
Adjuvant radiotherapy
1.24
0.99–1.57
0.06
Bronchial margin length
1.01
1.00–1.02
0.02
0.99
0.98–1.01
0.96
1.00
0.93–1.07
0.99
1.13
0.93–1.37
0.19
Dissected LN
1.00
0.99–1.00
0.86
Positive LN
1.06
1.02–1.09
< 0.00
Dissected LN station
0.97
0.92–1.03
0.43
Positive LN station
1.25
1.14–1.37
< 0.00
Abbreviations: HR, hazard ratio; 95% CI, 95% confidence interval. a Operation 1, lobectomy (reference) versus bilobectomy. b Operation 2, lobectomy (reference) versus pneumonectomy.
Although the long length group had an adequate safety margin length, they showed poorer survival than the short length group by univariate analysis. This may have been because more pneumonectomies which could be fatal were included in the long length group.12,13 Therefore, the results changed after adjusting for multiple clinical factors including type of operation. Adjuvant chemotherapy14,15 and type of operation12,13 have been viewed as prognostic factors in lung cancer. Adjuvant chemotherapy has been recommended to improve survival,14,15 as was confirmed in this study group. According to the type of operation, pneumonectomy was proven to be a negative prognostic factor for survival, like previously reported.12,13 Considering these findings, avoiding pneumonectomy and undergoing adjuvant chemotherapy are recommended in these central lung cancer patients. We note that our study had some limitations. First, this was a retrospective study and therefore some selection bias may have occurred. Although recurrence was defined using standard criteria, the diagnostic modality of recurrence was different. Some cases were proven by biopsy, but others were proven by imaging alone. However, all records for recurrence were written by an oncologic specialist. Second, the method of adjuvant treatment varied because of the long study period and hospital variability. However, most of the patients were treated at our hospital. Third, the detailed pattern and dose of radiotherapy were not analyzed in this study, so the results regarding radiotherapy may have limitations. Despite these limitations, this study provides important clues for selecting the proper operative technique and adjuvant treatment in centrally located, non-small cell lung cancer with confident long-term follow-up in a large, unified cohort of patients.
In conclusion, a long bronchial resection margin length may not guarantee better oncologic outcomes in central lung cancer patients. Rather, avoiding pneumonectomy and the application of adjuvant chemotherapy should be considered to improve survival.
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