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Survival disparities following surgery among patients with different histological types of non-small cell lung cancer
Lung Cancer 140 (2020) 55–58
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Survival disparities following surgery among patients with different histological types of non-small cell lung cancer
T
Horiana B. Grosua,*, Andrea Manzanerab, Sudeep Shivakumarc, Simon Sund, Graciela Noguras Gonzaleze, David E. Osta a
Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States Advantagene, Inc., Auburndale, MA, United States c Department of Medicine, Dalhousie University, Halifax, Canada d Department of Thoracic Surgery, University of Ottawa, Ottawa, Canada e Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States b
A R T I C LE I N FO
A B S T R A C T
Keywords: Non–small cell lung cancer Lung cancer histology
Objectives: Clinical decisions for NSCLC patients are often based on TNM stage, which does not account for different histological subtype. Whether histological subtype affects survival still remains unclear. The main objective of this study was to determine the extent to which the survival outcomes of patients with early-stage NSCLC differ by histological subtype. Material and methods: Retrospective cohort study of SEER data base. Patients with stage IA and IB NSCLC that underwent surgery with lymph node dissection were included. The primary outcome was the time to death. Cox proportional hazards models were used to identify risk factors associated with overall survival (OS). The secondary outcome was the time to death from lung cancer. A Cox model and a Fine-Gray subdistribution hazards model in which death from causes other than lung cancer was considered a competing risk event were used to identify risk factors for death from lung cancer. Results: Analysis of the SEER database identified 28,584 NSCLC patients, of whom 19,750 (69 %) had adenocarcinoma and 8834 (31 %) had squamous cell carcinoma. In the multivariate for OS, older age (p < 0.001), male gender (p < 0.001), pneumonectomy (p < 0.001), larger tumor size (p < 0.001), squamous cell carcinoma (p < 0.001) not being Hispanic or Asian were associated with increased risk of death. In the competing risk model, older age (p < 0.001), male gender (p < 0.001), pneumonectomy (p < 0.001), larger tumor size (p < 0.001), and squamous cell carcinoma (p < 0.001) were was associated with an increased risk of death from lung cancer. Conclusion: This study suggests that among patients with stage I NSCLC, those with squamous histology have a higher risk of mortality than those with adenocarcinoma histology taking into account competing risks.
1. Introduction Patients with early-stage non-small cell lung cancer (NSCLC) who undergo surgical excision, have 5-year survival rates of only 30 %―75 % depending on disease stage [1]. Whether patients with stage IA or IB non–small cell lung cancer (NSCLC) should receive chemotherapy or if histology should play a role in therapeutic decision making remains controversial. Given the significant toxicity associated with chemotherapy, a better evaluation of risk incorporating the histological subtype of
NSCLC may improve clinical decision making and facilitate the design of future trials [2,3]. Also, new targeted and immunotherapeutic agents with improved safety profiles are emerging, raising the possibility that patients with early-stage disease could receive more aggressive treatment. Contemporary clinical decisions for NSCLC patients are often based on TNM stage, which does not account for different histological subtype. However, whether histological subtypes of NSCLC affects survival for stage I disease still remains unclear, and studies have yielded conflicting results [4].
Abbreviations: NSCLC, non–small cell lung cancer; SEER, Surveillance, Epidemiology, and End Results ⁎ Corresponding author at: Department of Pulmonary Medicine, Unit 1462, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, United States. E-mail address: [email protected] (H.B. Grosu). https://doi.org/10.1016/j.lungcan.2019.12.007 Received 25 September 2019; Received in revised form 27 November 2019; Accepted 16 December 2019 0169-5002/ © 2019 Elsevier B.V. All rights reserved.
Lung Cancer 140 (2020) 55–58
H.B. Grosu, et al.
The main objective of this study was to determine the extent to which the survival outcomes of patients with early-stage NSCLC differ by histological subtype. We hypothesized that after adjustment for disease stage, NSCLC patients with adenocarcinoma histology who undergo curative-intent surgery have a lower survival 5-year survival rate than do NSCLC patients with squamous cell histology who undergo curative-intent surgery. The 8th edition of the TNM staging was used in this study.
Table 1 Patients’ baseline characteristics by histological subtype (N = 28,584).
2. Materials and methods
Adenocarcinoma
Squamous cell carcinoma
Characteristic
N
N
Age N Mean (SD) Median (Min-Max)
19750 67.47 (9.59) 68.00 (24.00–96.00)
8834 69.73 (8.32) 70.00 (35.00–94.00)
8322 11428
42.14 57.86
5080 3754
57.51 42.49
19552 198
99.00 1.00
8587 247
97.20 2.80
15,777 1,558 57
79.88 7.89 0.29
7,619 632 44
86.25 7.15 0.50
1,457
7.38
252
2.85
901
4.56
287
3.25
1413 8413 6709 3215
7.15 42.60 33.97 16.28
512 3019 3115 2188
5.80 34.17 35.26 24.77
Gender Male Female Surgical treatment Lobectomy Pneumonectomy Race White Black American Indian/ Alaska Native Asian or Pacific Islander Hispanic Tumor size < 10 11-20 21-30 31-40
2.1. Patients In this retrospective cohort study, the Surveillance, Epidemiology, and End Results (SEER) database was used to identify patients who underwent surgery with lymph node dissection for early-stage NSCLC between January 2005 and December 2014. Patients with a tumor < 4 cm and N0 disease NSCLC, adenocarcinoma or squamous histology were included in the study. Patients T stage was determined using pathology data and was based on TNM 8th edition (T1a < 1 cm, T1b > 1 but < 2, T1c < 2 but > 3, T2a > 3 but < 4). Only patients who underwent lobectomy or pneumonectomy with lymph node dissection were included; patients that underwent wedge resections or segmentectomy were excluded due to lack of lymph node dissection in these patients. Disease stage was defined as the pathological stage after surgery. Patients with lung cancer of other histological types (e.g., small cell, neuroendocrine) or with stage II, III or IV disease were excluded. Patients with missing data (date of diagnosis, date of death, histology, or disease stage) were also excluded. Overall mortality is recorded in SEER and death due to lung cancer is recorded in the SEER database as a separate field. The primary outcome was time to death, defined as the time from the date of lung cancer diagnosis to the date of death. The secondary outcome was the time to death from lung cancer, defined as the time from the date of lung cancer diagnosis to the date of death from lung cancer.
%
%
p-value < 0.001
< 0.001
< 0.001
< 0.001
< 0.001
(p < 0.001), and squamous cell carcinoma (p < 0.001) was associated with an increased risk of death from lung cancer (Table 3). The adjusted cumulative incidence for lung cancer-specific mortality by histological subtype is shown in Fig. 2. At 5 years the unadjusted overall survival of patients with adenocarcinoma was 0.69, 95 % CI (0.68–0.70) while squamous cell carcinoma survival was 0.57, 95 % CI (0.55–0.58). 4. Discussion
2.2. Statistical analysis This study suggests that the histological subtype of stage I NSCLC is an important prognostic indicator for lung cancer death when competing risk is taken into account. Larger tumors, T1b,T1c and T2a in patients with squamous histology have a higher risk of mortality than those with adenocarcinoma histology in the competing risk model. Our results are similar to those of Nakamura et al. where the authors reviewed 537 post-surgical lung cancer patients and concluded that squamous cell histology has a poorer OS compared to adenocarcinoma histology [7]. One of the reasons postulated to account for this difference was the fact that that squamous cell cancers were associated with male gender, and male gender was associated with death. In addition the study demonstrated that patients with squamous cell histology were more likely to be smokers [7]. Smoking is associated with diseases such as emphysema, pneumonia, ischemic heart diseases, cerebrovascular disease, and other cancers outside of the respiratory system, all of which may worsen OS [7]. Similarly in a study using Japanese lung cancer registry data, an evaluation of 13,010 patients and authors concluded that adenocarcinoma was associated with a lower mortality than squamous cell [8]. The authors postulated that the reasons for this deference may be due to refinements in the evaluation of surgical candidates, advancements and improvement in treatment I those patients with adenocarcinoma [8]. Our results differ from those of other investigators that suggested that adenocarcinomas may be associated with lower survival. The authors of the ANITA (Adjuvant Navelbine International Trialist Association) trial looked at the survival of NSCLC patients with resected stage IB, II, or IIIA disease who were randomly assigned to vinorelbine plus cisplatin or to observation [10]. Median survival time was 37.3
Descriptive statistics and frequencies tables were used to summarize demographic and clinical characteristics.Cox proportional hazards models were used to identify risk factors associated with overall survival. For time to death from lung cancer, we used a Cox model to assess the cause specific hazard associated with risk factors for death from lung cancer. We then used a Fine-Gray subdistribution hazards model to account for competing risks [6]. In the Fine-Gray model, death from causes other than lung cancer was considered a competing risk event. A two-tailed p-value of < 0.05 was used to determine statistical significance in all analyses. Statistical analysis was performed using Stata/ SE version 16.0 statistical software (Stata Corp. LP, College Station, TX). 3. Results The medical records of 28,584 NSCLC patients, of whom 19,750 (69 %) had adenocarcinoma and 8834 (31 %) had squamous cell carcinoma. The baseline characteristics of the study population by histological subtype are given in Table 1. In multivariate models for OS, older age (p < 0.001), male gender (p < 0.001), pneumonectomy (p < 0.001), larger tumor size (p < 0.001), squamous cell carcinoma (p < 0.001), and not being Hispanic or Asian were associated with increased risk of death (Table 2). The Kaplan-Meyer curve for overall survival by histolgy type is shown in Fig. 1. In the competing risk model, older patients (p < 0.001), male gender (p < 0.001), pneumonectomy (p < 0.001), tumor size 56
Lung Cancer 140 (2020) 55–58
H.B. Grosu, et al.
Table 2 Cox Survival Analysis for Overall Survival. Univariate Analysis Characteristic
HR
95 % CI
Age Histology type Adenocarcinoma Squamous cell carcinoma Gender Male Female Race White Black American Indian/Alaska Native Asian or Pacific Islander Hispanic Surgical treatment Lobectomy Pneumonectomy Tumor size < 10 11-20 21-30 31-40
1.04
1.03
1.57
Multivariate Analysis p-value
HR
95 % CI
p-value
1.04
< 0.001
1.04
1.03
1.04
< 0.001
1.50
1.63
< 0.001
1.35
1.29
1.41
< 0.001
0.69
0.66
0.72
< 0.001
0.74
0.71
0.77
< 0.001
0.97 0.92 0.73 0.83
0.90 0.64 0.66 0.74
1.05 1.31 0.80 0.92
0.472 0.636 < 0.001 0.001
1.11 1.03 0.77 0.90
1.03 0.72 0.70 0.80
1.20 1.48 0.85 1.00
0.009 0.864 < 0.001 0.046
1.79
1.57
2.03
< 0.001
1.75
1.54
2.00
< 0.001
1.13 1.41 1.64
1.03 1.29 1.49
1.24 1.55 1.80
0.008 < 0.001 < 0.001
1.08 1.25 1.36
0.98 1.14 1.24
1.18 1.37 1.50
0.119 < 0.001 < 0.001
competing risk model to account for deaths from other causes. Some of the observed mortality differences between different histologic forms of cancer could be due to differences in smoking associated diseases that correlate with histologic type. Failure to adjust for competing risks would lead to over estimating of the incidence of lung cancer related death. Furthermore, because we used the SEER database, we had sufficient power to demonstrate the difference. Our competing risk model suggests that even after adjustment for competing risks, there is still a statistically and clinically significant difference in risk of death is higher in squamous cell histology patients compared to adenocarcinoma histology. The choice of the model used to analyze this type of data is important, because some models have inherent weaknesses that make them less suitable for clinical applications than for other applications. Compared with conventional Kaplan-Meier and Cox models, competing risk models offer better clinical prediction. When competing risks are present and occur with high frequency (such as with NSCLC), the Kaplan-Meier survival function consistently overestimates the crude incidence of an outcome of interest [13]. The magnitude of this error is proportional to the frequency of the competing risk. Because our analysis did not include data on smoking and smoking-related comorbidities, such as chronic obstructive pulmonary disease and cardiovascular diseases, we had to account for death from other causes. Our study has some potential limitations owing to our use of the SEER database as this database does not have information on how recurrences were treated. Data on the different histological subtypes (invasive vs non-invasive) was not available, nor data on imaging and on how many of these tumors were ground glass opacities vs solid tumors. In addition, the SEER database does not have information about adjuvant therapy (e.g., radiation, chemotherapy), smoking, or chronic obstructive pulmonary disease. The data could be impacted by these missing data as not adjusting for other confounding factors. However, based on previous literature regarding the standard of care for patients with early-stage NSCLC, it is unlikely that the patients in the present study received any additional treatments prior to surgery. While we cannot adjust for treatment of recurrence, it is unlikely that adjuvant treatments have confounded our result. This study suggests that the addition of histological subtype enhances traditional TNM classification to provide a more accurate risk assessment of patients with early-stage NSCLC is necessary. However for this study we used the 6th edition of the TNM staging and even
Fig. 1. Kaplan-Meier estimates for overall survival by histological subtype. Red line adenocarcinoma, blue line squamous cell carcinoma. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article).
months and 45.5 months for patients with adenocarcinoma and squamous cell, respectively, the authors concluded that adenocarcinoma histology appeared to be a poor prognostic factor in patients with resected NSCLC [11]. In a meta-analysis of 2003 patients in Japan with surgically resected early-stage adenocarcinoma and squamous cell carcinoma, Hamada et al. found that those patients in whom postoperative adjuvant chemotherapy was administered had improved 5and 7-year survival [12]. Similarly, Ost et al. demonstrated that histology, together with more precise size specifications, can be used to more accurately identify patients at risk for lung cancer―specific death after potentially curative-intent lung cancer surgery [4]. It is important to note that all the studies that showed no difference in survival for different histologic forms of NSCLC used data from patients treated prior to 2000. We believe that one plausible explanation for the differences observed in this study is that treatment for adenocarcinoma have significantly improved with the development of targeted therapy. This study adds to the existing body of evidence on the topic by adjusting for competing risks of death. This study is the first to use a 57
Lung Cancer 140 (2020) 55–58
H.B. Grosu, et al.
Table 3 Competing risk model analysis of 5-year lung cancer―specific mortality. Univariate
Age Histology type Adenocarcinoma Squamous cell carcinoma Gender Male Female Race White Black American Indian/Alaska Native Asian or Pacific Islander Hispanic Surgical treatment Lobectomy Pneumonectomy Tumor size ≤10 11-20 21-30 31-40
Multivariate
SHR
95 % CI
p-value
SHR
95 % CI
1.02
1.01
1.26
p-value
1.02
< 0.001
1.01
1.01
1.02
< 0.001
1.19
1.34
< 0.001
1.13
1.06
1.20
< 0.001
0.77
0.73
0.81
< 0.001
0.81
0.77
0.86
< 0.001
0.97 0.74 0.88 0.89
0.87 0.43 0.78 0.77
1.08 1.27 1.00 1.03
0.578 0.271 0.050 0.113
1.03 0.76 0.90 0.93
0.92 0.44 0.79 0.80
1.14 1.32 1.02 1.07
0.601 0.323 0.098 0.314
1.87
1.57
2.23
< 0.001
1.78
1.49
2.13
< 0.001
1.21 1.53 1.85
1.06 1.34 1.61
1.37 1.75 2.11
0.005 < 0.001 < 0.001
1.18 1.45 1.68
1.03 1.27 1.47
1.34 1.65 1.93
0.015 < 0.001 < 0.001
Declaration of Competing Interest The authors have no conflicts of interest to disclose. Acknowledgments None. References [1] P.A. Groome, V. Bolejack, J.J. Crowley, et al., The IASLC Lung Cancer Staging Project: Validation of the Proposals for Revision of the T, N, and M Descriptors and Consequent Stage Groupings in the Forthcoming (Seventh) Edition of the TNM Classification of Malignant Tumours, J. Thorac. Oncol. 2 (8) (2007) 694–705. [2] T. Winton, R. Livingston, D. Johnson, et al., Vinorelbine plus cisplatin vs. observation in resected non–small-cell lung cancer, N. Engl. J. Med. 352 (25) (2005) 2589–2597. [3] G.A. Woodard, S.X. Wang, J.R. Kratz, et al., Adjuvant chemotherapy guided by molecular profiling and improved outcomes in early stage, non-small-cell lung cancer, Clin. Lung Cancer 19 (1) (2018) 58–64. [4] D. Ost, J. Goldberg, L. Rolnitzky, W.N. Rom, Survival after surgery in stage IA and IB nonsmall cell lung cancer, Am. J. Respir. Crit. Care Med. 177 (5) (2008) 516–523. [6] B. Lau, S.R. Cole, S.J. Gange, Competing risk regression models for epidemiologic data, Am. J. Epidemiol. 170 (2) (2009) 244–256. [7] H. Nakamura, H. Sakai, H. Kimura, T. Miyazawa, H. Marushima, H. Saji, Difference in postsurgical prognostic factors between lung adenocarcinoma and squamous cell carcinoma, Ann. Thorac. Cardiovasc. Surg. 23 (6) (2017) 291–297. [8] N. Sawabata, E. Miyaoka, H. Asamura, et al., Japanese lung cancer registry study of 11,663 surgical cases in 2004: demographic and prognosis changes over decade, J. Thorac. Oncol. 6 (7) (2011) 1229–1235. [10] J.Y. Douillard, R. Rosell, M. De Lena, et al., Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial, Lancet Oncol. 7 (9) (2006) 719–727. [11] J. Bennouna, H. Senellart, S. Hiret, N. Vaissiere, J.Y. Douillard, Impact of histology on survival of resected non-small cell lung cancer (NSCLC) receiving adjuvant chemotherapy: subgroup analysis of the adjuvant vinorelbine (NVB) cisplatin (CDDP) versus observation in the ANITA trial, Lung Cancer (Amsterdam, Netherlands) 74 (1) (2011) 30–34. [12] C. Hamada, F. Tanaka, M. Ohta, et al., Meta-analysis of postoperative adjuvant chemotherapy with tegafur-uracil in non-small-cell lung cancer, J. Clin. Oncol. 23 (22) (2005) 4999–5006. [13] P.C. Austin, D.S. Lee, J.P. Fine, Introduction to the analysis of survival data in the presence of competing risks, Circulation 133 (6) (2016) 601–609. [14] J.G. Paez, P.A. Janne, J.C. Lee, et al., EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy, Science (New York, N.Y.) 304 (5676) (2004) 1497–1500. [15] E.L. Kwak, Y.J. Bang, D.R. Camidge, et al., Anaplastic lymphoma kinase inhibition in nonsmall-cell lung cancer, N. Engl. J. Med. 363 (18) (2010) 1693–1703. [16] J. El Masri, S. Ren, J. Zhang, Getting familiar with the forthcoming eighth edition of TNM classification of lung cancer: from the T to N and M descriptors, Ann. Transl. Med. 4 (4) (2016) 67-67.
Fig. 2. Adjusted Cumulative Incidence for lung cancer―specific mortality by histological subtype.
though the 8th included 23 non anatomical elements, and the combination of anatomic and non-anatomic elements in a combined prognostic index enhances the capacity to prognosticate beyond that of the TNM classification alone there are still significant limitations in terms of including mutations as of EGFR and ALK that would significantly impact treatment response and outcome [14–16]. In conclusion, our study shows that among patients with stage I NSCLC, those with adenocarcinoma histology have better survival than those with squamous cell histology taking into account competing risks. Funding/support None. Authors contributions DEO and HBG were principal investigators and were responsible for study design, analysis, management, writing, and editing. AM, SS, and SS were responsible for data study analysis and writing. All authors participated in reviewing and editing the manuscript.
58
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Survival disparities following surgery among patients with different histological types of non-small cell lung cancer
T
Horiana B. Grosua,*, Andrea Manzanerab, Sudeep Shivakumarc, Simon Sund, Graciela Noguras Gonzaleze, David E. Osta a
Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States Advantagene, Inc., Auburndale, MA, United States c Department of Medicine, Dalhousie University, Halifax, Canada d Department of Thoracic Surgery, University of Ottawa, Ottawa, Canada e Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States b
A R T I C LE I N FO
A B S T R A C T
Keywords: Non–small cell lung cancer Lung cancer histology
Objectives: Clinical decisions for NSCLC patients are often based on TNM stage, which does not account for different histological subtype. Whether histological subtype affects survival still remains unclear. The main objective of this study was to determine the extent to which the survival outcomes of patients with early-stage NSCLC differ by histological subtype. Material and methods: Retrospective cohort study of SEER data base. Patients with stage IA and IB NSCLC that underwent surgery with lymph node dissection were included. The primary outcome was the time to death. Cox proportional hazards models were used to identify risk factors associated with overall survival (OS). The secondary outcome was the time to death from lung cancer. A Cox model and a Fine-Gray subdistribution hazards model in which death from causes other than lung cancer was considered a competing risk event were used to identify risk factors for death from lung cancer. Results: Analysis of the SEER database identified 28,584 NSCLC patients, of whom 19,750 (69 %) had adenocarcinoma and 8834 (31 %) had squamous cell carcinoma. In the multivariate for OS, older age (p < 0.001), male gender (p < 0.001), pneumonectomy (p < 0.001), larger tumor size (p < 0.001), squamous cell carcinoma (p < 0.001) not being Hispanic or Asian were associated with increased risk of death. In the competing risk model, older age (p < 0.001), male gender (p < 0.001), pneumonectomy (p < 0.001), larger tumor size (p < 0.001), and squamous cell carcinoma (p < 0.001) were was associated with an increased risk of death from lung cancer. Conclusion: This study suggests that among patients with stage I NSCLC, those with squamous histology have a higher risk of mortality than those with adenocarcinoma histology taking into account competing risks.
1. Introduction Patients with early-stage non-small cell lung cancer (NSCLC) who undergo surgical excision, have 5-year survival rates of only 30 %―75 % depending on disease stage [1]. Whether patients with stage IA or IB non–small cell lung cancer (NSCLC) should receive chemotherapy or if histology should play a role in therapeutic decision making remains controversial. Given the significant toxicity associated with chemotherapy, a better evaluation of risk incorporating the histological subtype of
NSCLC may improve clinical decision making and facilitate the design of future trials [2,3]. Also, new targeted and immunotherapeutic agents with improved safety profiles are emerging, raising the possibility that patients with early-stage disease could receive more aggressive treatment. Contemporary clinical decisions for NSCLC patients are often based on TNM stage, which does not account for different histological subtype. However, whether histological subtypes of NSCLC affects survival for stage I disease still remains unclear, and studies have yielded conflicting results [4].
Abbreviations: NSCLC, non–small cell lung cancer; SEER, Surveillance, Epidemiology, and End Results ⁎ Corresponding author at: Department of Pulmonary Medicine, Unit 1462, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, United States. E-mail address: [email protected] (H.B. Grosu). https://doi.org/10.1016/j.lungcan.2019.12.007 Received 25 September 2019; Received in revised form 27 November 2019; Accepted 16 December 2019 0169-5002/ © 2019 Elsevier B.V. All rights reserved.
Lung Cancer 140 (2020) 55–58
H.B. Grosu, et al.
The main objective of this study was to determine the extent to which the survival outcomes of patients with early-stage NSCLC differ by histological subtype. We hypothesized that after adjustment for disease stage, NSCLC patients with adenocarcinoma histology who undergo curative-intent surgery have a lower survival 5-year survival rate than do NSCLC patients with squamous cell histology who undergo curative-intent surgery. The 8th edition of the TNM staging was used in this study.
Table 1 Patients’ baseline characteristics by histological subtype (N = 28,584).
2. Materials and methods
Adenocarcinoma
Squamous cell carcinoma
Characteristic
N
N
Age N Mean (SD) Median (Min-Max)
19750 67.47 (9.59) 68.00 (24.00–96.00)
8834 69.73 (8.32) 70.00 (35.00–94.00)
8322 11428
42.14 57.86
5080 3754
57.51 42.49
19552 198
99.00 1.00
8587 247
97.20 2.80
15,777 1,558 57
79.88 7.89 0.29
7,619 632 44
86.25 7.15 0.50
1,457
7.38
252
2.85
901
4.56
287
3.25
1413 8413 6709 3215
7.15 42.60 33.97 16.28
512 3019 3115 2188
5.80 34.17 35.26 24.77
Gender Male Female Surgical treatment Lobectomy Pneumonectomy Race White Black American Indian/ Alaska Native Asian or Pacific Islander Hispanic Tumor size < 10 11-20 21-30 31-40
2.1. Patients In this retrospective cohort study, the Surveillance, Epidemiology, and End Results (SEER) database was used to identify patients who underwent surgery with lymph node dissection for early-stage NSCLC between January 2005 and December 2014. Patients with a tumor < 4 cm and N0 disease NSCLC, adenocarcinoma or squamous histology were included in the study. Patients T stage was determined using pathology data and was based on TNM 8th edition (T1a < 1 cm, T1b > 1 but < 2, T1c < 2 but > 3, T2a > 3 but < 4). Only patients who underwent lobectomy or pneumonectomy with lymph node dissection were included; patients that underwent wedge resections or segmentectomy were excluded due to lack of lymph node dissection in these patients. Disease stage was defined as the pathological stage after surgery. Patients with lung cancer of other histological types (e.g., small cell, neuroendocrine) or with stage II, III or IV disease were excluded. Patients with missing data (date of diagnosis, date of death, histology, or disease stage) were also excluded. Overall mortality is recorded in SEER and death due to lung cancer is recorded in the SEER database as a separate field. The primary outcome was time to death, defined as the time from the date of lung cancer diagnosis to the date of death. The secondary outcome was the time to death from lung cancer, defined as the time from the date of lung cancer diagnosis to the date of death from lung cancer.
%
%
p-value < 0.001
< 0.001
< 0.001
< 0.001
< 0.001
(p < 0.001), and squamous cell carcinoma (p < 0.001) was associated with an increased risk of death from lung cancer (Table 3). The adjusted cumulative incidence for lung cancer-specific mortality by histological subtype is shown in Fig. 2. At 5 years the unadjusted overall survival of patients with adenocarcinoma was 0.69, 95 % CI (0.68–0.70) while squamous cell carcinoma survival was 0.57, 95 % CI (0.55–0.58). 4. Discussion
2.2. Statistical analysis This study suggests that the histological subtype of stage I NSCLC is an important prognostic indicator for lung cancer death when competing risk is taken into account. Larger tumors, T1b,T1c and T2a in patients with squamous histology have a higher risk of mortality than those with adenocarcinoma histology in the competing risk model. Our results are similar to those of Nakamura et al. where the authors reviewed 537 post-surgical lung cancer patients and concluded that squamous cell histology has a poorer OS compared to adenocarcinoma histology [7]. One of the reasons postulated to account for this difference was the fact that that squamous cell cancers were associated with male gender, and male gender was associated with death. In addition the study demonstrated that patients with squamous cell histology were more likely to be smokers [7]. Smoking is associated with diseases such as emphysema, pneumonia, ischemic heart diseases, cerebrovascular disease, and other cancers outside of the respiratory system, all of which may worsen OS [7]. Similarly in a study using Japanese lung cancer registry data, an evaluation of 13,010 patients and authors concluded that adenocarcinoma was associated with a lower mortality than squamous cell [8]. The authors postulated that the reasons for this deference may be due to refinements in the evaluation of surgical candidates, advancements and improvement in treatment I those patients with adenocarcinoma [8]. Our results differ from those of other investigators that suggested that adenocarcinomas may be associated with lower survival. The authors of the ANITA (Adjuvant Navelbine International Trialist Association) trial looked at the survival of NSCLC patients with resected stage IB, II, or IIIA disease who were randomly assigned to vinorelbine plus cisplatin or to observation [10]. Median survival time was 37.3
Descriptive statistics and frequencies tables were used to summarize demographic and clinical characteristics.Cox proportional hazards models were used to identify risk factors associated with overall survival. For time to death from lung cancer, we used a Cox model to assess the cause specific hazard associated with risk factors for death from lung cancer. We then used a Fine-Gray subdistribution hazards model to account for competing risks [6]. In the Fine-Gray model, death from causes other than lung cancer was considered a competing risk event. A two-tailed p-value of < 0.05 was used to determine statistical significance in all analyses. Statistical analysis was performed using Stata/ SE version 16.0 statistical software (Stata Corp. LP, College Station, TX). 3. Results The medical records of 28,584 NSCLC patients, of whom 19,750 (69 %) had adenocarcinoma and 8834 (31 %) had squamous cell carcinoma. The baseline characteristics of the study population by histological subtype are given in Table 1. In multivariate models for OS, older age (p < 0.001), male gender (p < 0.001), pneumonectomy (p < 0.001), larger tumor size (p < 0.001), squamous cell carcinoma (p < 0.001), and not being Hispanic or Asian were associated with increased risk of death (Table 2). The Kaplan-Meyer curve for overall survival by histolgy type is shown in Fig. 1. In the competing risk model, older patients (p < 0.001), male gender (p < 0.001), pneumonectomy (p < 0.001), tumor size 56
Lung Cancer 140 (2020) 55–58
H.B. Grosu, et al.
Table 2 Cox Survival Analysis for Overall Survival. Univariate Analysis Characteristic
HR
95 % CI
Age Histology type Adenocarcinoma Squamous cell carcinoma Gender Male Female Race White Black American Indian/Alaska Native Asian or Pacific Islander Hispanic Surgical treatment Lobectomy Pneumonectomy Tumor size < 10 11-20 21-30 31-40
1.04
1.03
1.57
Multivariate Analysis p-value
HR
95 % CI
p-value
1.04
< 0.001
1.04
1.03
1.04
< 0.001
1.50
1.63
< 0.001
1.35
1.29
1.41
< 0.001
0.69
0.66
0.72
< 0.001
0.74
0.71
0.77
< 0.001
0.97 0.92 0.73 0.83
0.90 0.64 0.66 0.74
1.05 1.31 0.80 0.92
0.472 0.636 < 0.001 0.001
1.11 1.03 0.77 0.90
1.03 0.72 0.70 0.80
1.20 1.48 0.85 1.00
0.009 0.864 < 0.001 0.046
1.79
1.57
2.03
< 0.001
1.75
1.54
2.00
< 0.001
1.13 1.41 1.64
1.03 1.29 1.49
1.24 1.55 1.80
0.008 < 0.001 < 0.001
1.08 1.25 1.36
0.98 1.14 1.24
1.18 1.37 1.50
0.119 < 0.001 < 0.001
competing risk model to account for deaths from other causes. Some of the observed mortality differences between different histologic forms of cancer could be due to differences in smoking associated diseases that correlate with histologic type. Failure to adjust for competing risks would lead to over estimating of the incidence of lung cancer related death. Furthermore, because we used the SEER database, we had sufficient power to demonstrate the difference. Our competing risk model suggests that even after adjustment for competing risks, there is still a statistically and clinically significant difference in risk of death is higher in squamous cell histology patients compared to adenocarcinoma histology. The choice of the model used to analyze this type of data is important, because some models have inherent weaknesses that make them less suitable for clinical applications than for other applications. Compared with conventional Kaplan-Meier and Cox models, competing risk models offer better clinical prediction. When competing risks are present and occur with high frequency (such as with NSCLC), the Kaplan-Meier survival function consistently overestimates the crude incidence of an outcome of interest [13]. The magnitude of this error is proportional to the frequency of the competing risk. Because our analysis did not include data on smoking and smoking-related comorbidities, such as chronic obstructive pulmonary disease and cardiovascular diseases, we had to account for death from other causes. Our study has some potential limitations owing to our use of the SEER database as this database does not have information on how recurrences were treated. Data on the different histological subtypes (invasive vs non-invasive) was not available, nor data on imaging and on how many of these tumors were ground glass opacities vs solid tumors. In addition, the SEER database does not have information about adjuvant therapy (e.g., radiation, chemotherapy), smoking, or chronic obstructive pulmonary disease. The data could be impacted by these missing data as not adjusting for other confounding factors. However, based on previous literature regarding the standard of care for patients with early-stage NSCLC, it is unlikely that the patients in the present study received any additional treatments prior to surgery. While we cannot adjust for treatment of recurrence, it is unlikely that adjuvant treatments have confounded our result. This study suggests that the addition of histological subtype enhances traditional TNM classification to provide a more accurate risk assessment of patients with early-stage NSCLC is necessary. However for this study we used the 6th edition of the TNM staging and even
Fig. 1. Kaplan-Meier estimates for overall survival by histological subtype. Red line adenocarcinoma, blue line squamous cell carcinoma. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article).
months and 45.5 months for patients with adenocarcinoma and squamous cell, respectively, the authors concluded that adenocarcinoma histology appeared to be a poor prognostic factor in patients with resected NSCLC [11]. In a meta-analysis of 2003 patients in Japan with surgically resected early-stage adenocarcinoma and squamous cell carcinoma, Hamada et al. found that those patients in whom postoperative adjuvant chemotherapy was administered had improved 5and 7-year survival [12]. Similarly, Ost et al. demonstrated that histology, together with more precise size specifications, can be used to more accurately identify patients at risk for lung cancer―specific death after potentially curative-intent lung cancer surgery [4]. It is important to note that all the studies that showed no difference in survival for different histologic forms of NSCLC used data from patients treated prior to 2000. We believe that one plausible explanation for the differences observed in this study is that treatment for adenocarcinoma have significantly improved with the development of targeted therapy. This study adds to the existing body of evidence on the topic by adjusting for competing risks of death. This study is the first to use a 57
Lung Cancer 140 (2020) 55–58
H.B. Grosu, et al.
Table 3 Competing risk model analysis of 5-year lung cancer―specific mortality. Univariate
Age Histology type Adenocarcinoma Squamous cell carcinoma Gender Male Female Race White Black American Indian/Alaska Native Asian or Pacific Islander Hispanic Surgical treatment Lobectomy Pneumonectomy Tumor size ≤10 11-20 21-30 31-40
Multivariate
SHR
95 % CI
p-value
SHR
95 % CI
1.02
1.01
1.26
p-value
1.02
< 0.001
1.01
1.01
1.02
< 0.001
1.19
1.34
< 0.001
1.13
1.06
1.20
< 0.001
0.77
0.73
0.81
< 0.001
0.81
0.77
0.86
< 0.001
0.97 0.74 0.88 0.89
0.87 0.43 0.78 0.77
1.08 1.27 1.00 1.03
0.578 0.271 0.050 0.113
1.03 0.76 0.90 0.93
0.92 0.44 0.79 0.80
1.14 1.32 1.02 1.07
0.601 0.323 0.098 0.314
1.87
1.57
2.23
< 0.001
1.78
1.49
2.13
< 0.001
1.21 1.53 1.85
1.06 1.34 1.61
1.37 1.75 2.11
0.005 < 0.001 < 0.001
1.18 1.45 1.68
1.03 1.27 1.47
1.34 1.65 1.93
0.015 < 0.001 < 0.001
Declaration of Competing Interest The authors have no conflicts of interest to disclose. Acknowledgments None. References [1] P.A. Groome, V. Bolejack, J.J. Crowley, et al., The IASLC Lung Cancer Staging Project: Validation of the Proposals for Revision of the T, N, and M Descriptors and Consequent Stage Groupings in the Forthcoming (Seventh) Edition of the TNM Classification of Malignant Tumours, J. Thorac. Oncol. 2 (8) (2007) 694–705. [2] T. Winton, R. Livingston, D. Johnson, et al., Vinorelbine plus cisplatin vs. observation in resected non–small-cell lung cancer, N. Engl. J. Med. 352 (25) (2005) 2589–2597. [3] G.A. Woodard, S.X. Wang, J.R. Kratz, et al., Adjuvant chemotherapy guided by molecular profiling and improved outcomes in early stage, non-small-cell lung cancer, Clin. Lung Cancer 19 (1) (2018) 58–64. [4] D. Ost, J. Goldberg, L. Rolnitzky, W.N. Rom, Survival after surgery in stage IA and IB nonsmall cell lung cancer, Am. J. Respir. Crit. Care Med. 177 (5) (2008) 516–523. [6] B. Lau, S.R. Cole, S.J. Gange, Competing risk regression models for epidemiologic data, Am. J. Epidemiol. 170 (2) (2009) 244–256. [7] H. Nakamura, H. Sakai, H. Kimura, T. Miyazawa, H. Marushima, H. Saji, Difference in postsurgical prognostic factors between lung adenocarcinoma and squamous cell carcinoma, Ann. Thorac. Cardiovasc. Surg. 23 (6) (2017) 291–297. [8] N. Sawabata, E. Miyaoka, H. Asamura, et al., Japanese lung cancer registry study of 11,663 surgical cases in 2004: demographic and prognosis changes over decade, J. Thorac. Oncol. 6 (7) (2011) 1229–1235. [10] J.Y. Douillard, R. Rosell, M. De Lena, et al., Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial, Lancet Oncol. 7 (9) (2006) 719–727. [11] J. Bennouna, H. Senellart, S. Hiret, N. Vaissiere, J.Y. Douillard, Impact of histology on survival of resected non-small cell lung cancer (NSCLC) receiving adjuvant chemotherapy: subgroup analysis of the adjuvant vinorelbine (NVB) cisplatin (CDDP) versus observation in the ANITA trial, Lung Cancer (Amsterdam, Netherlands) 74 (1) (2011) 30–34. [12] C. Hamada, F. Tanaka, M. Ohta, et al., Meta-analysis of postoperative adjuvant chemotherapy with tegafur-uracil in non-small-cell lung cancer, J. Clin. Oncol. 23 (22) (2005) 4999–5006. [13] P.C. Austin, D.S. Lee, J.P. Fine, Introduction to the analysis of survival data in the presence of competing risks, Circulation 133 (6) (2016) 601–609. [14] J.G. Paez, P.A. Janne, J.C. Lee, et al., EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy, Science (New York, N.Y.) 304 (5676) (2004) 1497–1500. [15] E.L. Kwak, Y.J. Bang, D.R. Camidge, et al., Anaplastic lymphoma kinase inhibition in nonsmall-cell lung cancer, N. Engl. J. Med. 363 (18) (2010) 1693–1703. [16] J. El Masri, S. Ren, J. Zhang, Getting familiar with the forthcoming eighth edition of TNM classification of lung cancer: from the T to N and M descriptors, Ann. Transl. Med. 4 (4) (2016) 67-67.
Fig. 2. Adjusted Cumulative Incidence for lung cancer―specific mortality by histological subtype.
though the 8th included 23 non anatomical elements, and the combination of anatomic and non-anatomic elements in a combined prognostic index enhances the capacity to prognosticate beyond that of the TNM classification alone there are still significant limitations in terms of including mutations as of EGFR and ALK that would significantly impact treatment response and outcome [14–16]. In conclusion, our study shows that among patients with stage I NSCLC, those with adenocarcinoma histology have better survival than those with squamous cell histology taking into account competing risks. Funding/support None. Authors contributions DEO and HBG were principal investigators and were responsible for study design, analysis, management, writing, and editing. AM, SS, and SS were responsible for data study analysis and writing. All authors participated in reviewing and editing the manuscript.
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