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Adjuvant Chemotherapy for Patients with T2N0M0 NSCLC
Accepted Manuscript Adjuvant Chemotherapy for Patients with T2N0M0 Non-small-cell Lung Cancer (NSCLC) Daniel Morgensztern, Lingling Du, Saiama N. Waqar, Aalok Patel, Pamela Samson, Siddhartha Devarakonda, Feng Gao, Clifford Robinson, Jeffrey Bradley, Maria Baggstrom, Ashiq Masood, Ramaswamy Govindan, Varun Puri PII:
S1556-0864(16)30497-X
DOI:
10.1016/j.jtho.2016.05.022
Reference:
JTHO 217
To appear in:
Journal of Thoracic Oncology
Received Date: 9 March 2016 Revised Date:
10 May 2016
Accepted Date: 26 May 2016
Please cite this article as: Morgensztern D, Du L, Waqar SN, Patel A, Samson P, Devarakonda S, Gao F, Robinson C, Bradley J, Baggstrom M, Masood A, Govindan R, Puri V, Adjuvant Chemotherapy for Patients with T2N0M0 Non-small-cell Lung Cancer (NSCLC), Journal of Thoracic Oncology (2016), doi: 10.1016/j.jtho.2016.05.022. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Adjuvant Chemotherapy for Patients with T2N0M0 Non-small-cell Lung Cancer (NSCLC)
Daniel Morgensztern, Lingling Du, Saiama N Waqar, Aalok Patel, Pamela Samson, Siddhartha
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Devarakonda, Feng Gao, Clifford Robinson, Jeffrey Bradley, Maria Baggstrom, Ashiq Masood,
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Ramaswamy Govindan, Varun Puri
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Abstract Background: Adjuvant chemotherapy improves survival in patients with completely resected stage II and III non-small cell lung cancer (NSCLC). However, its role in patients with stage IB
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disease remains unclear. We evaluated the role of adjuvant chemotherapy in a large dataset of patients with completely resected T2N0M0 NSCLC. Methods: Patients with pathologic stage T2N0M0 NSCLC who underwent complete (R0) resection from 2004 to 2011 were identified
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from the National Cancer Database (NCDB) and classified into four groups based on tumor size: 3.1-3.9 cm, 4-4.9 cm, 5-5.9 cm and 6-7 cm. Patients who died within 1 month from surgery were
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excluded. Survival curves were estimated by the Kaplan-Meier product-limit method and compared by log-rank test. Results: Among the 25,267 patients that met inclusion criteria, there were 4,996 (19.7%) who received adjuvant chemotherapy. Adjuvant chemotherapy was associated with improved median and 5-year overall survival (OS) compared to observation for
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all tumor size groups. In patients with T2 tumors < 4 cm, adjuvant chemotherapy was associated with improved median and 5-year OS in univariate (101.6 vs 68.2 months, 67% vs 55%, hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.61-0.72; P < 0.0001) and multivariable analysis
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(HR 0.77, 95% CI 0.70-0.83; P < 0.0001) as well as propensity matched score (101.6 vs 78.9 months, 68% vs 60%, HR 0.75, 95% CI 0.70-0.86; P < 0.0001). Conclusions: In patients with
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completely resected T2N0M0, adjuvant chemotherapy is associated with improved survival in all tumor size groups. The benefit in patients with tumors < 4 cm strongly suggests a role for chemotherapy in this patient population and counters its current status as an exclusion criteria for adjuvant trials.
Key words: Non-small cell lung cancer, adjuvant chemotherapy, stage I.
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For patients with medically operable clinical early-stage non-small-cell lung cancer (NSCLC), complete resection is the treatment of choice, providing the highest probability of cure.1 However, despite surgical treatment, 5-year overall survival (OS) remains suboptimal, ranging
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from 73% in patients with pathologic stage IA to 24% in those with stage IIIA.2 Although several studies including patients with completely resected NSCLC have demonstrated improved OS from adjuvant chemotherapy compared to observation3-5, a large pooled analysis showed that
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this benefit was restricted to patients with stage II or IIIA, with no significant improvement in patients with stage IB (hazard ratio [HR] 0.93, 95% confidence interval [CI] 0.78-1.10) and a
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likely detrimental effect in patients with stage IA (HR 1.40, 95% CI 0.95-2.06).6 In the most recent Cochrane systematic review and meta-analysis, including 8,447 patients from 34 trials, the use of adjuvant chemotherapy was associated with an absolute 5-year OS improvement of 4% (60% to 64%) compared to observation (HR 0.86, 95% CI 0.81-0.92; P = 0.009).7 In the subset
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of patients with stage IB treated with platinum-based chemotherapy, adjuvant chemotherapy was associated with a 5-year OS improvement from 55% to 60%. The same absolute benefit of 5% was observed in patients with stage II (40% to 45%) and stage III (30% to 35%). In a meta-
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analysis including 4,556 patients with resected stage IB NSCLC from 16 trials, adjuvant chemotherapy was associated with a significant improvement in OS (HR 0.74, 95% CI 0.63-
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0.88).8 However, the benefit was observed mostly in patients treated with adjuvant uracil and tegafur whereas there was no benefit from four cycles of adjuvant platinum-based adjuvant chemotherapy (HR 0.97, 95% CI 0.85-1.11).
In the only randomized clinical trial conducted exclusively in patients with stage IB disease there was no benefit from adjuvant chemotherapy with carboplatin plus paclitaxel.9 Nevertheless, an
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exploratory analysis showed improved median OS for patients in the chemotherapy arm whose tumors were ≥ 4 cm (99 months vs 77 months, HR 0.69, 95% CI 0.48-0.99; P = 0.043). The updated results from the JBR.10 study included a subset analysis by tumor size and showed a
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possible trend towards improved 5-year OS for patients with stage IB ≥ 4 cm treated with chemotherapy (79% vs 59%, HR 0.66, 95% CI 0.39-1.14; P = 0.13).10 Since then, randomized
patients with stage IB ≥ 4 cm in the eligibility criteria.11,12
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trials of adjuvant chemotherapy such as the ECOG 1505 and the ALCHEMIST have included
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The purpose of our study is to further evaluate the role of chemotherapy in patients with stage T2N0M0, including those with tumors smaller than 4 cm, using the National Cancer Database (NCDB). This joint dataset from the American College of Surgeons Commission on Cancer and the American Cancer Society collects data from approximately 70% of all new cases of cancer
Methods
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Patients
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diagnosed in the United States.
Patients with pathologic stage T2N0M0 NSCLC, diagnosed from 2004 to 2011, and who underwent R0 resection were identified from the NCDB using the International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3). Pathologic staging was based on the American Joint Committee on Cancer (AJCC) 7th edition staging criteria.2 Patients who had less than lobar resection, positive margins or who died within 1 month from surgery were excluded.
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Statistical Analysis Patients were de-identified and categorized into two cohorts: those who received adjuvant
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chemotherapy and those who did not (observation). Both cohorts were further stratified into four groups based on tumor size: 3.1-3.9 cm (S3), 4-4.9 cm (S4), 5-5.9 cm (S5), and 6-7 cm (S6-7). Independent 2 sample t-test was used to compare the distribution of continuous variables such as
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age and tumor size in the chemotherapy versus no chemotherapy cohorts. Categorical variables evaluated included tumor size group, age, gender, ethnicity, insurance, histology, and type of
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surgical resection. The comorbidity score was accessed using the Deyo adaptation of the Charlson comorbidity index with scores ranging from 0 to 2.13 For categorical variables the differences between the chemotherapy and no chemotherapy groups were compared using the Chi-square test. Overall survival (OS) was defined as the time from the date of diagnosis to the
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date of death from any cause. Survivors were censored at the date of last contact. Survival curves by chemotherapy status were estimated using the Kaplan-Meier product-limit method and
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compared by the log-rank test.
Univariate Cox proportional hazard models were used to determine the statistical significance of
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associations between the clinical variables and the OS. The Multivariate Cox model was used to examine whether adjuvant chemotherapy was independently associated with survival, after adjustment for other clinical variables. Two-way interaction terms between adjuvant chemotherapy and other clinical variables included in the multivariate Cox model were also assessed. All analyses were two-sided and p-value of 0.05 was used for significance.
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Propensity score matching was performed on patients for each tumor size category by adjuvant therapy status, using age, gender, race, distance from treating facility, Charlson-Deyo comorbidity score, population type, income, insurance status, center type, level of surgical
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resection and histologic type. After calculation of the propensity score using logistic regression, patients were matched 1:1 using nearest neighbor matching with a caliper distance of 0.20 of the standard deviation of the logit of the propensity score. Post-matching diagnostics included
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analysis of standardized mean differences among both the matching variables and their possible
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interactions between the two groups.
Data analyses were performed in SPSS, Version 23.0 (IBM Corp, Armonk, NY) with the propensity matching using the R Propensity Matched Extension Package.
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Results
A total of 25,267 patients were included in the study, including 4,996 (19.7%) who received adjuvant chemotherapy and 20,271 (81.3%) who did not receive adjuvant chemotherapy and
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were assigned as the observation group (Table 1). Compared to the observation group, patients treated with adjuvant chemotherapy were younger (P < 0.001) and had larger tumor size (P <
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0.001). Fewer patients in the chemotherapy group underwent sub-lobar resection compared to the observation group (6.1% versus 8.6%, P < 0.001).
Use of adjuvant chemotherapy peaked for both S3 and tumors ≥ 4 cm in 2005, being used in 27% and 30% of patients respectively. Since then, the percentage of patients with resected T2N0
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tumors undergoing adjuvant chemotherapy decreased to 10% in S3 and 21% in patients with tumors ≥ 4 cm in 2011.
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In univariate analysis, the 5-year OS was inversely related to tumor size in patients who did not receive adjuvant chemotherapy, decreasing from 55% in S3 to 44% in S6-7. Among patients receiving adjuvant chemotherapy, the 5-year OS ranged from 64% in S6-7 to 67% in S3 (Figure
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1 and Table 2). In comparison with observation, the use of chemotherapy was associated with improved median OS (100.5 months vs 62.6 months, HR 0.61, 95% CI 0.58-0.64; P < 0.0001)
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and 5-year OS (66% vs 51%; P < 0.0001) for all patients combined. The improved survival for chemotherapy compared to observation was also significant in all tumor size groups, with the absolute improvement directly linked to the tumor size, ranging from 12% in S3 to 20% in S6-7.
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Factors associated with improved survival in multivariable analyses included tumor size, gender, age, histology, Charlson-Deyo comorbidity score, type of surgery and use of chemotherapy (Table 3). Adjuvant chemotherapy was associated with increased survival for all tumor size
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categories.
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Propensity matched analysis compared 1,508 patient pairs with S3 tumors, 1,514 pairs for S4,743 pairs for S5, and 490 patient pairs for S6-7. Adjuvant chemotherapy was associated with a significant improvement in median OS and 5-year OS for all tumor size groups, with the absolute benefit of 8%, 11%, 9% and 16% for S3, S4, S5 and S6-7 respectively (Table 4).
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Discussion
Tumor size has been shown to predict outcomes in multiple studies for patients treated with
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curative intent.14-16 In a Surveillance, Epidemiology and End Results study including 7,620 patients with stage I NSCLC treated with curative intent surgery, the 12-year OS was significantly decreased with each increase in tumor size category except for the comparison
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between 2.6-3.5 cm and 3.6-4.5 cm, ranging from 69% in those with tumors measuring 0.5-1.5 cm to 43% in those measuring more than 4.5 cm.17 The effect of tumor size is also noticed on
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non-surgically treated patients, with smaller tumors associated with improved median OS in stage I NSCLC treated with radiation therapy18 and stage III patients.19 The importance of tumor size in the outcomes of patients with early stage NSCLC led to further subdivisions of T1 and T2 tumors in the seventh edition of the TNM classification and changing the stage for tumors larger
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than 7 cm to T3.20 Further modifications have been proposed in the eight edition of the TNM classification, with tumors larger than 5 cm and 7 cm classified as T3 and T4 respectively.21
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As expected, our study showed significant differences in 5-year OS according to tumor size among patients in the observation group. However, the 5-year OS was very similar for patients
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undergoing adjuvant chemotherapy, highlighting the effects of chemotherapy in this patient population where the highest benefit was observed in the larger tumors.
In a smaller study using the same database and including patients with resected T1-2N0 NSCLC measuring less than 1 to 8.5 cm, diagnosed between 2003 and 2006, adjuvant chemotherapy was associated with improved 5-year OS, compared to observation, from 66.9% to 74.3% (HR 0.75;
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P < 0.001) in patients with tumors < 4 cm and from 49.8% to 64.8% (HR 0.6; P < 0.001) in tumors ≥ 4cm.22 Although the study included patients with stage IA tumor, for which adjuvant chemotherapy is considered to be detrimental and tumors > 7 cm, which are currently staged as
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T3 and will likely be re-classified as T4, the results are similar to our study with a proportional higher benefit in larger tumors.
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There are several limitations to our data including the retrospective nature of the study, with limited information on the reasons for the choice between chemotherapy and observation.
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Furthermore, there is no data on staging procedures prior to the surgical resection, type of chemotherapy regimens used and surgical mortality. Nevertheless, the mortality risk is low in this patient population. In a recent NCDB study including 119,146 patients with resected NSCLC between 2004 and 2009, the risk of death within 30 days in 66,283 patients with stage I
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NSCLC was 2.7%.21 This small effect from early mortality was addressed in our study with the exclusion of patients who died within 30 days from surgery.
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The large number of patients included in the NCDB allowed the evaluation of each tumor size among patient with T2N0M0 tumors. The absolute benefit from adjuvant chemotherapy in the
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median and 5-year OS compared to observation was observed for each of the tumor size subgroups. Although it is very likely that chemotherapy was offered to more motivated patients with better performance status, the same bias would be applicable to all stages evaluated and not only for S3. In addition, the benefit from adjuvant chemotherapy for all tumor size groups, including S3, was also observed in the propensity score matching.
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In summary, our data suggest that there is a benefit from adjuvant chemotherapy in patients with completely resected stage T2N0M0 NSCLC regardless of tumor size. Assuming similar biases for the use of chemotherapy in all tumor size subgroups, the elimination of patients with early
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surgical mortality and the confirmed benefit from adjuvant chemotherapy in propensity matched analysis, our study suggest that the postulated benefit from adjuvant chemotherapy in patients with stage T2N0M0 NSCLC may be extended to tumors measuring 3.1 to 3.9 cm. Therefore, if
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this hypothesis is either confirmed or not further evaluated in prospective trials, the current
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exclusion of stage IB tumors < 4 cm in the adjuvant NSCLC trials should be revisited.
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Table 1. Patient characteristics
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Table 2. Overall survival by univariate analysis (chemotherapy versus observation)
Table 3. Multivariable Cox proportional hazards model for survival.
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Table 4. Propensity score matching for chemotherapy versus observation according to tumor size
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Figure 1. Kaplan-Meier survival curves according to tumor size and use of chemotherapy. A. Tumor size 3.1-3.9 cm
B. Tumor size 4-4.9 cm
C. Tumor size 5-5.9 cm
D. Tumor size 6-7 cm
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Figure 2. Kaplan-Meier Analysis for propensity score matched NSCLC patients with tumor size
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3.1-3.9 cm by adjuvant chemotherapy status.
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References
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1. Howington JA, Blum MG, Chang AC, et al: Treatment of stage I and II non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 143:e278S-313S, 2013 2. Goldstraw P, Crowley J, Chansky K, et al: The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol 2:706-14, 2007 3. Arriagada R, Bergman B, Dunant A, et al: Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 350:351-60, 2004 4. Winton T, Livingston R, Johnson D, et al: Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 352:2589-97, 2005 5. Douillard JY, Rosell R, De Lena M, 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 7:719-27, 2006 6. Pignon JP, Tribodet H, Scagliotti GV, et al: Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 26:3552-9, 2008 7. Burdett S, Pignon JP, Tierney J, et al: Adjuvant chemotherapy for resected earlystage non-small cell lung cancer. Cochrane Database Syst Rev 3:CD011430, 2015 8. He J, Shen J, Yang C, et al: Adjuvant Chemotherapy for the Completely Resected Stage IB Nonsmall Cell Lung Cancer: A Systematic Review and Meta-Analysis. Medicine (Baltimore) 94:e903, 2015 9. Strauss GM, Herndon JE, 2nd, Maddaus MA, et al: Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol 26:5043-51, 2008 10. Butts CA, Ding K, Seymour L, et al: Randomized phase III trial of vinorelbine plus cisplatin compared with observation in completely resected stage IB and II non-small-cell lung cancer: updated survival analysis of JBR-10. J Clin Oncol 28:29-34, 2010 11. Wakelee HA, Dahlberg SE, Keller SM, et al: Interim report of on-study demographics and toxicity from E1505, a phase III randomized trial of adjuvant (adj) chemotherapy (chemo) with or without bevacizumab (B) for completely resected early-stage non-small cell lung cancer (NSCLC). ASCO Meeting Abstracts 29:7013, 2011 12. Govindan R, Mandrekar SJ, Gerber DE, et al: ALCHEMIST Trials: A Golden Opportunity to Transform Outcomes in Early-Stage Non-Small Cell Lung Cancer. Clin Cancer Res 21:5439-44, 2015 13. Deyo RA, Cherkin DC, Ciol MA: Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol 45:613-9, 1992 14. Harpole DH, Jr., Herndon JE, 2nd, Young WG, Jr., et al: Stage I nonsmall cell lung cancer. A multivariate analysis of treatment methods and patterns of recurrence. Cancer 76:787-96, 1995 15. Padilla J, Calvo V, Penalver JC, et al: Surgical results and prognostic factors in early non-small cell lung cancer. Ann Thorac Surg 63:324-6, 1997
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16. Carbone E, Asamura H, Takei H, et al: T2 tumors larger than five centimeters in diameter can be upgraded to T3 in non-small cell lung cancer. J Thorac Cardiovasc Surg 122:907-12, 2001 17. Wisnivesky JP, Yankelevitz D, Henschke CI: The effect of tumor size on curability of stage I non-small cell lung cancers. Chest 126:761-5, 2004 18. Kupelian PA, Komaki R, Allen P: Prognostic factors in the treatment of nodenegative nonsmall cell lung carcinoma with radiotherapy alone. Int J Radiat Oncol Biol Phys 36:607-13, 1996 19. Morgensztern D, Waqar S, Subramanian J, et al: Prognostic significance of tumor size in patients with stage III non-small-cell lung cancer: a surveillance, epidemiology, and end results (SEER) survey from 1998 to 2003. J Thorac Oncol 7:1479-84, 2012 20. Rami-Porta R, Ball D, Crowley J, et al: The IASLC Lung Cancer Staging Project: proposals for the revision of the T descriptors in the forthcoming (seventh) edition of the TNM classification for lung cancer. J Thorac Oncol 2:593-602, 2007 21. Goldstraw P, Chansky K, Crowley J, et al: The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer. J Thorac Oncol 11:39-51, 2016 22. Speicher PJ, Gu L, Wang X, et al: Adjuvant Chemotherapy After Lobectomy for T1-2N0 Non-Small Cell Lung Cancer: Are the Guidelines Supported? J Natl Compr Canc Netw 13:755-61, 2015
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Race
Insurance
Histology
Female
8822 (43.5%)
2349 (47.0%)
<0.001
Male
11449 (56.5%)
2647 (53.0%)
3-3.9 cm
8979 (44.3%)
1608 (32.2%)
4-4.9 cm
6583 (32.5%)
1739 (34.8%)
5-5.9 cm
2824 (13.9%)
949 (19.0%)
6-7 cm
1885 (9.3%)
700 (14.0%)
< 50
535 (2.6%)
391 (7.8%)
50-70
9249 (45.6%)
3375 (67.6%)
> 70
10487 (51.7%)
1230 (24.6%)
White
18115 (89.4%)
4440 (88.9%)
Black
1578 (7.8%)
416 (8.3%)
Other
578 (2.9%)
140 (2.8%)
Uninsured
346 (1.7%)
124 (2.5%)
Private
5039 (25.2%)
2115 (42.8%)
Government
14623 (73.1%)
2703 (54.7%)
Adenocarcinoma
8777 (43.3%)
2314 (46.3%)
Squamous
9068 (44.7%)
1960 (39.2%)
648 (3.2%)
194 (3.9%)
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Large cell
Adenosquamous
693 (3.4%)
180 (3.6%)
Other
1085 (5.4%)
348 (7.0%)
0
9938 (49.0%)
2757 (55.2%)
1
7362 (36.3%)
1699 (34.0%)
≥2
2971 (14.7%)
540 (10.8%)
Sub-lobar
1746 (8.6%)
306 (6.1%)
Lobectomy
17678 (87.2%)
4422 (88.5%)
Pneumonectomy
847 (4.2%)
268 (5.4%)
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Charlson-Deyo
Type of surgery
<0.001
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Age
P value
<0.001
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Tumor size
Chemotherapy (n=4,996)
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Gender
Observation (n=20,271)
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Characteristics
0.44
<0.001
<0.001
<0.001
<0.001
Median OS (months) 100.5 vs 62.6 101.6 vs 68.2 102.3 vs 61.1 103.6 vs 56.0 91.8 vs 50.1
5-year OS 66% vs 51% 67% vs 55% 66% vs 51% 64% vs 48% 64% vs 44%
HR (95% CI) 0.61 (0.58-0.64) 0.66 (0.61-0.72) 0.58 (0.53-0.63) 0.57 (0.51-0.64) 0.56 (0.50-0.64)
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Tumor size 3.1-7 cm 3.1-3.9 cm 4-4.9 cm 5-5.9 cm 6-7 cm
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P-value < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001
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Race
Histology
Charlson-Deyo
4-4.9 cm
1.12 (1.08-1.17)
<0.0001
5-5.9 cm
1.21 (1.14-1.27)
<0.0001
6-7 cm
1.29 (1.22-1.37)
<0.0001
Female
Reference
Male
1.28 (1.23-1.32)
< 50
Reference
50-70
1.16 (1.03-1.31)
0.012
> 70
1.58 (1.40-1.78)
<0.0001
White
Reference
Black
0.99 (0.93-1.06)
0.057
Other
0.87 (0.78-0.98)
0.02
Adenocarcinoma
Reference
Squamous
1.06 (1.02-1.11)
0.002
Large cell
1.14 (1.04-1.26)
0.007
Adenosquamous
1.19 (1.08-1.30)
<0.0001
Other
1.12 (1.04-1.21)
0.004
0 1
Type of surgery
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Reference
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2
<0.0001
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Age
Reference
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Gender
P-value
3-3.9 cm
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Tumor size
HR (95% CI)
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Parameter
1.15 (1.10-1.19)
<0.0001
1.36 (1.29-1.43)
<0.0001
Sub-lobar
Reference
Lobectomy
0.63 (0.59-0.66)
<0.0001
Pneumonectomy
0.76 (0.68-0.83)
<0.0001
Adjuvant
None
Reference
Therapy
All cases
0.69 (0.66-0.73)
< 0.0001
3.1-3.9 cm
0.77 (0.70-0.83)
<0.001
4.0-4.9 cm
0.67 (0.62-0.74)
<0.001
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0.66 (0.59-0.74)
<0.001
6.0-6.9 cm
0.63 (0.55-0.71)
<0.001
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EP
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SC
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5.0-5.9 cm
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Median OS (months)
5-year OS
HR (95% CI)
P-value
3.1-3.9 cm
101.6 vs 78.9
68% vs 60%
0.75 (0.70-0.86)
< 0.0001
4-4.9 cm
102.3 vs 69.1
67% vs 56%
0.69 (0.61-0.77)
< 0.0001
5-5.9 cm
101.6 vs 68.5
63% vs 54%
0.72 (0.62-0.83)
< 0.0001
6-7 cm
58.7 vs 91.8
65% vs 49%
0.64 (0.54-0.77)
< 0.0001
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SC
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Tumor size
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A. Tumor size 3-3.9 cm
B. Tumor size 4-4.9 cm
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Adjuvant chemotherapy Observation
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Figure 1. Kaplan-Meier survival curves according to tumor size and use of chemotherapy.
D. Tumor size 6-7 cm
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C. Tumor size 5-5.9 cm
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Figure 2. Kaplan-Meier Analysis for propensity score matched NSCLC patients with tumor size
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SC
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3.1-3.9 cm by adjuvant chemotherapy status.
S1556-0864(16)30497-X
DOI:
10.1016/j.jtho.2016.05.022
Reference:
JTHO 217
To appear in:
Journal of Thoracic Oncology
Received Date: 9 March 2016 Revised Date:
10 May 2016
Accepted Date: 26 May 2016
Please cite this article as: Morgensztern D, Du L, Waqar SN, Patel A, Samson P, Devarakonda S, Gao F, Robinson C, Bradley J, Baggstrom M, Masood A, Govindan R, Puri V, Adjuvant Chemotherapy for Patients with T2N0M0 Non-small-cell Lung Cancer (NSCLC), Journal of Thoracic Oncology (2016), doi: 10.1016/j.jtho.2016.05.022. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Adjuvant Chemotherapy for Patients with T2N0M0 Non-small-cell Lung Cancer (NSCLC)
Daniel Morgensztern, Lingling Du, Saiama N Waqar, Aalok Patel, Pamela Samson, Siddhartha
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Devarakonda, Feng Gao, Clifford Robinson, Jeffrey Bradley, Maria Baggstrom, Ashiq Masood,
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Ramaswamy Govindan, Varun Puri
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Abstract Background: Adjuvant chemotherapy improves survival in patients with completely resected stage II and III non-small cell lung cancer (NSCLC). However, its role in patients with stage IB
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disease remains unclear. We evaluated the role of adjuvant chemotherapy in a large dataset of patients with completely resected T2N0M0 NSCLC. Methods: Patients with pathologic stage T2N0M0 NSCLC who underwent complete (R0) resection from 2004 to 2011 were identified
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from the National Cancer Database (NCDB) and classified into four groups based on tumor size: 3.1-3.9 cm, 4-4.9 cm, 5-5.9 cm and 6-7 cm. Patients who died within 1 month from surgery were
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excluded. Survival curves were estimated by the Kaplan-Meier product-limit method and compared by log-rank test. Results: Among the 25,267 patients that met inclusion criteria, there were 4,996 (19.7%) who received adjuvant chemotherapy. Adjuvant chemotherapy was associated with improved median and 5-year overall survival (OS) compared to observation for
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all tumor size groups. In patients with T2 tumors < 4 cm, adjuvant chemotherapy was associated with improved median and 5-year OS in univariate (101.6 vs 68.2 months, 67% vs 55%, hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.61-0.72; P < 0.0001) and multivariable analysis
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(HR 0.77, 95% CI 0.70-0.83; P < 0.0001) as well as propensity matched score (101.6 vs 78.9 months, 68% vs 60%, HR 0.75, 95% CI 0.70-0.86; P < 0.0001). Conclusions: In patients with
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completely resected T2N0M0, adjuvant chemotherapy is associated with improved survival in all tumor size groups. The benefit in patients with tumors < 4 cm strongly suggests a role for chemotherapy in this patient population and counters its current status as an exclusion criteria for adjuvant trials.
Key words: Non-small cell lung cancer, adjuvant chemotherapy, stage I.
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For patients with medically operable clinical early-stage non-small-cell lung cancer (NSCLC), complete resection is the treatment of choice, providing the highest probability of cure.1 However, despite surgical treatment, 5-year overall survival (OS) remains suboptimal, ranging
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from 73% in patients with pathologic stage IA to 24% in those with stage IIIA.2 Although several studies including patients with completely resected NSCLC have demonstrated improved OS from adjuvant chemotherapy compared to observation3-5, a large pooled analysis showed that
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this benefit was restricted to patients with stage II or IIIA, with no significant improvement in patients with stage IB (hazard ratio [HR] 0.93, 95% confidence interval [CI] 0.78-1.10) and a
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likely detrimental effect in patients with stage IA (HR 1.40, 95% CI 0.95-2.06).6 In the most recent Cochrane systematic review and meta-analysis, including 8,447 patients from 34 trials, the use of adjuvant chemotherapy was associated with an absolute 5-year OS improvement of 4% (60% to 64%) compared to observation (HR 0.86, 95% CI 0.81-0.92; P = 0.009).7 In the subset
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of patients with stage IB treated with platinum-based chemotherapy, adjuvant chemotherapy was associated with a 5-year OS improvement from 55% to 60%. The same absolute benefit of 5% was observed in patients with stage II (40% to 45%) and stage III (30% to 35%). In a meta-
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analysis including 4,556 patients with resected stage IB NSCLC from 16 trials, adjuvant chemotherapy was associated with a significant improvement in OS (HR 0.74, 95% CI 0.63-
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0.88).8 However, the benefit was observed mostly in patients treated with adjuvant uracil and tegafur whereas there was no benefit from four cycles of adjuvant platinum-based adjuvant chemotherapy (HR 0.97, 95% CI 0.85-1.11).
In the only randomized clinical trial conducted exclusively in patients with stage IB disease there was no benefit from adjuvant chemotherapy with carboplatin plus paclitaxel.9 Nevertheless, an
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exploratory analysis showed improved median OS for patients in the chemotherapy arm whose tumors were ≥ 4 cm (99 months vs 77 months, HR 0.69, 95% CI 0.48-0.99; P = 0.043). The updated results from the JBR.10 study included a subset analysis by tumor size and showed a
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possible trend towards improved 5-year OS for patients with stage IB ≥ 4 cm treated with chemotherapy (79% vs 59%, HR 0.66, 95% CI 0.39-1.14; P = 0.13).10 Since then, randomized
patients with stage IB ≥ 4 cm in the eligibility criteria.11,12
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trials of adjuvant chemotherapy such as the ECOG 1505 and the ALCHEMIST have included
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The purpose of our study is to further evaluate the role of chemotherapy in patients with stage T2N0M0, including those with tumors smaller than 4 cm, using the National Cancer Database (NCDB). This joint dataset from the American College of Surgeons Commission on Cancer and the American Cancer Society collects data from approximately 70% of all new cases of cancer
Methods
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Patients
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diagnosed in the United States.
Patients with pathologic stage T2N0M0 NSCLC, diagnosed from 2004 to 2011, and who underwent R0 resection were identified from the NCDB using the International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3). Pathologic staging was based on the American Joint Committee on Cancer (AJCC) 7th edition staging criteria.2 Patients who had less than lobar resection, positive margins or who died within 1 month from surgery were excluded.
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Statistical Analysis Patients were de-identified and categorized into two cohorts: those who received adjuvant
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chemotherapy and those who did not (observation). Both cohorts were further stratified into four groups based on tumor size: 3.1-3.9 cm (S3), 4-4.9 cm (S4), 5-5.9 cm (S5), and 6-7 cm (S6-7). Independent 2 sample t-test was used to compare the distribution of continuous variables such as
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age and tumor size in the chemotherapy versus no chemotherapy cohorts. Categorical variables evaluated included tumor size group, age, gender, ethnicity, insurance, histology, and type of
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surgical resection. The comorbidity score was accessed using the Deyo adaptation of the Charlson comorbidity index with scores ranging from 0 to 2.13 For categorical variables the differences between the chemotherapy and no chemotherapy groups were compared using the Chi-square test. Overall survival (OS) was defined as the time from the date of diagnosis to the
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date of death from any cause. Survivors were censored at the date of last contact. Survival curves by chemotherapy status were estimated using the Kaplan-Meier product-limit method and
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compared by the log-rank test.
Univariate Cox proportional hazard models were used to determine the statistical significance of
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associations between the clinical variables and the OS. The Multivariate Cox model was used to examine whether adjuvant chemotherapy was independently associated with survival, after adjustment for other clinical variables. Two-way interaction terms between adjuvant chemotherapy and other clinical variables included in the multivariate Cox model were also assessed. All analyses were two-sided and p-value of 0.05 was used for significance.
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Propensity score matching was performed on patients for each tumor size category by adjuvant therapy status, using age, gender, race, distance from treating facility, Charlson-Deyo comorbidity score, population type, income, insurance status, center type, level of surgical
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resection and histologic type. After calculation of the propensity score using logistic regression, patients were matched 1:1 using nearest neighbor matching with a caliper distance of 0.20 of the standard deviation of the logit of the propensity score. Post-matching diagnostics included
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analysis of standardized mean differences among both the matching variables and their possible
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interactions between the two groups.
Data analyses were performed in SPSS, Version 23.0 (IBM Corp, Armonk, NY) with the propensity matching using the R Propensity Matched Extension Package.
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Results
A total of 25,267 patients were included in the study, including 4,996 (19.7%) who received adjuvant chemotherapy and 20,271 (81.3%) who did not receive adjuvant chemotherapy and
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were assigned as the observation group (Table 1). Compared to the observation group, patients treated with adjuvant chemotherapy were younger (P < 0.001) and had larger tumor size (P <
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0.001). Fewer patients in the chemotherapy group underwent sub-lobar resection compared to the observation group (6.1% versus 8.6%, P < 0.001).
Use of adjuvant chemotherapy peaked for both S3 and tumors ≥ 4 cm in 2005, being used in 27% and 30% of patients respectively. Since then, the percentage of patients with resected T2N0
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tumors undergoing adjuvant chemotherapy decreased to 10% in S3 and 21% in patients with tumors ≥ 4 cm in 2011.
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In univariate analysis, the 5-year OS was inversely related to tumor size in patients who did not receive adjuvant chemotherapy, decreasing from 55% in S3 to 44% in S6-7. Among patients receiving adjuvant chemotherapy, the 5-year OS ranged from 64% in S6-7 to 67% in S3 (Figure
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1 and Table 2). In comparison with observation, the use of chemotherapy was associated with improved median OS (100.5 months vs 62.6 months, HR 0.61, 95% CI 0.58-0.64; P < 0.0001)
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and 5-year OS (66% vs 51%; P < 0.0001) for all patients combined. The improved survival for chemotherapy compared to observation was also significant in all tumor size groups, with the absolute improvement directly linked to the tumor size, ranging from 12% in S3 to 20% in S6-7.
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Factors associated with improved survival in multivariable analyses included tumor size, gender, age, histology, Charlson-Deyo comorbidity score, type of surgery and use of chemotherapy (Table 3). Adjuvant chemotherapy was associated with increased survival for all tumor size
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categories.
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Propensity matched analysis compared 1,508 patient pairs with S3 tumors, 1,514 pairs for S4,743 pairs for S5, and 490 patient pairs for S6-7. Adjuvant chemotherapy was associated with a significant improvement in median OS and 5-year OS for all tumor size groups, with the absolute benefit of 8%, 11%, 9% and 16% for S3, S4, S5 and S6-7 respectively (Table 4).
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Discussion
Tumor size has been shown to predict outcomes in multiple studies for patients treated with
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curative intent.14-16 In a Surveillance, Epidemiology and End Results study including 7,620 patients with stage I NSCLC treated with curative intent surgery, the 12-year OS was significantly decreased with each increase in tumor size category except for the comparison
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between 2.6-3.5 cm and 3.6-4.5 cm, ranging from 69% in those with tumors measuring 0.5-1.5 cm to 43% in those measuring more than 4.5 cm.17 The effect of tumor size is also noticed on
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non-surgically treated patients, with smaller tumors associated with improved median OS in stage I NSCLC treated with radiation therapy18 and stage III patients.19 The importance of tumor size in the outcomes of patients with early stage NSCLC led to further subdivisions of T1 and T2 tumors in the seventh edition of the TNM classification and changing the stage for tumors larger
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than 7 cm to T3.20 Further modifications have been proposed in the eight edition of the TNM classification, with tumors larger than 5 cm and 7 cm classified as T3 and T4 respectively.21
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As expected, our study showed significant differences in 5-year OS according to tumor size among patients in the observation group. However, the 5-year OS was very similar for patients
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undergoing adjuvant chemotherapy, highlighting the effects of chemotherapy in this patient population where the highest benefit was observed in the larger tumors.
In a smaller study using the same database and including patients with resected T1-2N0 NSCLC measuring less than 1 to 8.5 cm, diagnosed between 2003 and 2006, adjuvant chemotherapy was associated with improved 5-year OS, compared to observation, from 66.9% to 74.3% (HR 0.75;
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P < 0.001) in patients with tumors < 4 cm and from 49.8% to 64.8% (HR 0.6; P < 0.001) in tumors ≥ 4cm.22 Although the study included patients with stage IA tumor, for which adjuvant chemotherapy is considered to be detrimental and tumors > 7 cm, which are currently staged as
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T3 and will likely be re-classified as T4, the results are similar to our study with a proportional higher benefit in larger tumors.
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There are several limitations to our data including the retrospective nature of the study, with limited information on the reasons for the choice between chemotherapy and observation.
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Furthermore, there is no data on staging procedures prior to the surgical resection, type of chemotherapy regimens used and surgical mortality. Nevertheless, the mortality risk is low in this patient population. In a recent NCDB study including 119,146 patients with resected NSCLC between 2004 and 2009, the risk of death within 30 days in 66,283 patients with stage I
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NSCLC was 2.7%.21 This small effect from early mortality was addressed in our study with the exclusion of patients who died within 30 days from surgery.
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The large number of patients included in the NCDB allowed the evaluation of each tumor size among patient with T2N0M0 tumors. The absolute benefit from adjuvant chemotherapy in the
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median and 5-year OS compared to observation was observed for each of the tumor size subgroups. Although it is very likely that chemotherapy was offered to more motivated patients with better performance status, the same bias would be applicable to all stages evaluated and not only for S3. In addition, the benefit from adjuvant chemotherapy for all tumor size groups, including S3, was also observed in the propensity score matching.
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In summary, our data suggest that there is a benefit from adjuvant chemotherapy in patients with completely resected stage T2N0M0 NSCLC regardless of tumor size. Assuming similar biases for the use of chemotherapy in all tumor size subgroups, the elimination of patients with early
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surgical mortality and the confirmed benefit from adjuvant chemotherapy in propensity matched analysis, our study suggest that the postulated benefit from adjuvant chemotherapy in patients with stage T2N0M0 NSCLC may be extended to tumors measuring 3.1 to 3.9 cm. Therefore, if
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this hypothesis is either confirmed or not further evaluated in prospective trials, the current
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exclusion of stage IB tumors < 4 cm in the adjuvant NSCLC trials should be revisited.
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Table 1. Patient characteristics
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Table 2. Overall survival by univariate analysis (chemotherapy versus observation)
Table 3. Multivariable Cox proportional hazards model for survival.
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Table 4. Propensity score matching for chemotherapy versus observation according to tumor size
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Figure 1. Kaplan-Meier survival curves according to tumor size and use of chemotherapy. A. Tumor size 3.1-3.9 cm
B. Tumor size 4-4.9 cm
C. Tumor size 5-5.9 cm
D. Tumor size 6-7 cm
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Figure 2. Kaplan-Meier Analysis for propensity score matched NSCLC patients with tumor size
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3.1-3.9 cm by adjuvant chemotherapy status.
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References
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1. Howington JA, Blum MG, Chang AC, et al: Treatment of stage I and II non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 143:e278S-313S, 2013 2. Goldstraw P, Crowley J, Chansky K, et al: The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol 2:706-14, 2007 3. Arriagada R, Bergman B, Dunant A, et al: Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 350:351-60, 2004 4. Winton T, Livingston R, Johnson D, et al: Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 352:2589-97, 2005 5. Douillard JY, Rosell R, De Lena M, 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 7:719-27, 2006 6. Pignon JP, Tribodet H, Scagliotti GV, et al: Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 26:3552-9, 2008 7. Burdett S, Pignon JP, Tierney J, et al: Adjuvant chemotherapy for resected earlystage non-small cell lung cancer. Cochrane Database Syst Rev 3:CD011430, 2015 8. He J, Shen J, Yang C, et al: Adjuvant Chemotherapy for the Completely Resected Stage IB Nonsmall Cell Lung Cancer: A Systematic Review and Meta-Analysis. Medicine (Baltimore) 94:e903, 2015 9. Strauss GM, Herndon JE, 2nd, Maddaus MA, et al: Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol 26:5043-51, 2008 10. Butts CA, Ding K, Seymour L, et al: Randomized phase III trial of vinorelbine plus cisplatin compared with observation in completely resected stage IB and II non-small-cell lung cancer: updated survival analysis of JBR-10. J Clin Oncol 28:29-34, 2010 11. Wakelee HA, Dahlberg SE, Keller SM, et al: Interim report of on-study demographics and toxicity from E1505, a phase III randomized trial of adjuvant (adj) chemotherapy (chemo) with or without bevacizumab (B) for completely resected early-stage non-small cell lung cancer (NSCLC). ASCO Meeting Abstracts 29:7013, 2011 12. Govindan R, Mandrekar SJ, Gerber DE, et al: ALCHEMIST Trials: A Golden Opportunity to Transform Outcomes in Early-Stage Non-Small Cell Lung Cancer. Clin Cancer Res 21:5439-44, 2015 13. Deyo RA, Cherkin DC, Ciol MA: Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol 45:613-9, 1992 14. Harpole DH, Jr., Herndon JE, 2nd, Young WG, Jr., et al: Stage I nonsmall cell lung cancer. A multivariate analysis of treatment methods and patterns of recurrence. Cancer 76:787-96, 1995 15. Padilla J, Calvo V, Penalver JC, et al: Surgical results and prognostic factors in early non-small cell lung cancer. Ann Thorac Surg 63:324-6, 1997
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16. Carbone E, Asamura H, Takei H, et al: T2 tumors larger than five centimeters in diameter can be upgraded to T3 in non-small cell lung cancer. J Thorac Cardiovasc Surg 122:907-12, 2001 17. Wisnivesky JP, Yankelevitz D, Henschke CI: The effect of tumor size on curability of stage I non-small cell lung cancers. Chest 126:761-5, 2004 18. Kupelian PA, Komaki R, Allen P: Prognostic factors in the treatment of nodenegative nonsmall cell lung carcinoma with radiotherapy alone. Int J Radiat Oncol Biol Phys 36:607-13, 1996 19. Morgensztern D, Waqar S, Subramanian J, et al: Prognostic significance of tumor size in patients with stage III non-small-cell lung cancer: a surveillance, epidemiology, and end results (SEER) survey from 1998 to 2003. J Thorac Oncol 7:1479-84, 2012 20. Rami-Porta R, Ball D, Crowley J, et al: The IASLC Lung Cancer Staging Project: proposals for the revision of the T descriptors in the forthcoming (seventh) edition of the TNM classification for lung cancer. J Thorac Oncol 2:593-602, 2007 21. Goldstraw P, Chansky K, Crowley J, et al: The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer. J Thorac Oncol 11:39-51, 2016 22. Speicher PJ, Gu L, Wang X, et al: Adjuvant Chemotherapy After Lobectomy for T1-2N0 Non-Small Cell Lung Cancer: Are the Guidelines Supported? J Natl Compr Canc Netw 13:755-61, 2015
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Race
Insurance
Histology
Female
8822 (43.5%)
2349 (47.0%)
<0.001
Male
11449 (56.5%)
2647 (53.0%)
3-3.9 cm
8979 (44.3%)
1608 (32.2%)
4-4.9 cm
6583 (32.5%)
1739 (34.8%)
5-5.9 cm
2824 (13.9%)
949 (19.0%)
6-7 cm
1885 (9.3%)
700 (14.0%)
< 50
535 (2.6%)
391 (7.8%)
50-70
9249 (45.6%)
3375 (67.6%)
> 70
10487 (51.7%)
1230 (24.6%)
White
18115 (89.4%)
4440 (88.9%)
Black
1578 (7.8%)
416 (8.3%)
Other
578 (2.9%)
140 (2.8%)
Uninsured
346 (1.7%)
124 (2.5%)
Private
5039 (25.2%)
2115 (42.8%)
Government
14623 (73.1%)
2703 (54.7%)
Adenocarcinoma
8777 (43.3%)
2314 (46.3%)
Squamous
9068 (44.7%)
1960 (39.2%)
648 (3.2%)
194 (3.9%)
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Large cell
Adenosquamous
693 (3.4%)
180 (3.6%)
Other
1085 (5.4%)
348 (7.0%)
0
9938 (49.0%)
2757 (55.2%)
1
7362 (36.3%)
1699 (34.0%)
≥2
2971 (14.7%)
540 (10.8%)
Sub-lobar
1746 (8.6%)
306 (6.1%)
Lobectomy
17678 (87.2%)
4422 (88.5%)
Pneumonectomy
847 (4.2%)
268 (5.4%)
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Charlson-Deyo
Type of surgery
<0.001
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Age
P value
<0.001
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Tumor size
Chemotherapy (n=4,996)
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Gender
Observation (n=20,271)
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Characteristics
0.44
<0.001
<0.001
<0.001
<0.001
Median OS (months) 100.5 vs 62.6 101.6 vs 68.2 102.3 vs 61.1 103.6 vs 56.0 91.8 vs 50.1
5-year OS 66% vs 51% 67% vs 55% 66% vs 51% 64% vs 48% 64% vs 44%
HR (95% CI) 0.61 (0.58-0.64) 0.66 (0.61-0.72) 0.58 (0.53-0.63) 0.57 (0.51-0.64) 0.56 (0.50-0.64)
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Tumor size 3.1-7 cm 3.1-3.9 cm 4-4.9 cm 5-5.9 cm 6-7 cm
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P-value < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001
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Race
Histology
Charlson-Deyo
4-4.9 cm
1.12 (1.08-1.17)
<0.0001
5-5.9 cm
1.21 (1.14-1.27)
<0.0001
6-7 cm
1.29 (1.22-1.37)
<0.0001
Female
Reference
Male
1.28 (1.23-1.32)
< 50
Reference
50-70
1.16 (1.03-1.31)
0.012
> 70
1.58 (1.40-1.78)
<0.0001
White
Reference
Black
0.99 (0.93-1.06)
0.057
Other
0.87 (0.78-0.98)
0.02
Adenocarcinoma
Reference
Squamous
1.06 (1.02-1.11)
0.002
Large cell
1.14 (1.04-1.26)
0.007
Adenosquamous
1.19 (1.08-1.30)
<0.0001
Other
1.12 (1.04-1.21)
0.004
0 1
Type of surgery
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Reference
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2
<0.0001
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Age
Reference
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Gender
P-value
3-3.9 cm
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Tumor size
HR (95% CI)
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Parameter
1.15 (1.10-1.19)
<0.0001
1.36 (1.29-1.43)
<0.0001
Sub-lobar
Reference
Lobectomy
0.63 (0.59-0.66)
<0.0001
Pneumonectomy
0.76 (0.68-0.83)
<0.0001
Adjuvant
None
Reference
Therapy
All cases
0.69 (0.66-0.73)
< 0.0001
3.1-3.9 cm
0.77 (0.70-0.83)
<0.001
4.0-4.9 cm
0.67 (0.62-0.74)
<0.001
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0.66 (0.59-0.74)
<0.001
6.0-6.9 cm
0.63 (0.55-0.71)
<0.001
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5.0-5.9 cm
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Median OS (months)
5-year OS
HR (95% CI)
P-value
3.1-3.9 cm
101.6 vs 78.9
68% vs 60%
0.75 (0.70-0.86)
< 0.0001
4-4.9 cm
102.3 vs 69.1
67% vs 56%
0.69 (0.61-0.77)
< 0.0001
5-5.9 cm
101.6 vs 68.5
63% vs 54%
0.72 (0.62-0.83)
< 0.0001
6-7 cm
58.7 vs 91.8
65% vs 49%
0.64 (0.54-0.77)
< 0.0001
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Tumor size
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A. Tumor size 3-3.9 cm
B. Tumor size 4-4.9 cm
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Adjuvant chemotherapy Observation
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Figure 1. Kaplan-Meier survival curves according to tumor size and use of chemotherapy.
D. Tumor size 6-7 cm
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C. Tumor size 5-5.9 cm
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Figure 2. Kaplan-Meier Analysis for propensity score matched NSCLC patients with tumor size
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3.1-3.9 cm by adjuvant chemotherapy status.