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J Thorac Oncol. Author manuscript; available in PMC 2017 October 01. Published in final edited form as: J Thorac Oncol. 2016 October ; 11(10): 1729–1735. doi:10.1016/j.jtho.2016.05.022.
Adjuvant Chemotherapy for Patients with T2N0M0 NSCLC Daniel Morgensztern, MDa,*, Lingling Du, MDa, Saiama N. Waqar, MDa, Aalok Patel, MDb, Pamela Samson, MDb, Siddhartha Devarakonda, MDa, Feng Gao, PhDc, Cliff G. Robinson, MDd, Jeffrey Bradley, MDd, Maria Baggstrom, MDa, Ashiq Masood, MDa, Ramaswamy Govindan, MDa, and Varun Puri, MD, MSCIb aDepartment
Author Manuscript
of Medicine, Division of Medical Oncology, Washington University School of Medicine, St. Louis, Missouri
bDepartment
of Surgery, Washington University School of Medicine, St. Louis, Missouri
cDivision
of Biostatistics, Washington University School of Medicine, St. Louis, Missouri
dDivision
of Radiation Therapy, Washington University School of Medicine, St. Louis, Missouri
Abstract Background—Adjuvant chemotherapy improves survival in patients with completely resected stage II and III NSCLC. However, its role in patients with stage IB NSCLC disease remains unclear. We evaluated the role of adjuvant chemotherapy in a large data set of patients with completely resected T2N0M0 NSCLC.
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Methods—Patients with pathologic stage T2N0M0 NSCLC who underwent complete (R0) resection between 2004 and 2011 were identified from the National Cancer Data Base and classified into four groups based on tumor size: 3.1 to 3.9 cm, 4 to 4.9 cm, 5 to 5.9 cm, and 6 to 7 cm. Patients who died within 1 month after their operation were excluded. Survival curves were estimated by the Kaplan-Meier product-limit method and compared by log-rank test. Results—Among the 25,267 patients who met the inclusion criteria, there were 4996 (19.7%) who received adjuvant chemotherapy. Adjuvant chemotherapy was associated with improved median and 5-year overall survival compared with observation for all tumor size groups. In patients with T2 tumors smaller than 4 cm, adjuvant chemotherapy was associated with improved median and 5-year overall survival in univariate (101.6 versus 68.2 months [67% versus 55%], hazard ratio [HR] = 0.66, 95% confidence interval [CI]: 0.61–0.72, p < 0.0001) and multivariable
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*
Address for correspondence: Daniel Morgensztern, MD, Department of Medicine, Division of Medical Oncology, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8056, St. Louis, MO 63110. [email protected]. Disclosure: Dr. Morgensztern reports personal fees from Celgene, Genentech, Bristol-Myers Squibb, Heat Biologics, and Boehringer Ingelheim outside the submitted work. Dr. Waqar reports a grant from the National Institutes of Health (1 UM1 CA186704-01) outside the submitted work. Dr. Bradley reports an ownership interest in and research funding from ViewRay, personal fees from Varian Proton, and institutional research funding from Mevion Medical Systems outside the submitted work. Dr. Govindan reports personal fees from Boehringer Ingelheim, Pfizer, Merck, Clovis, Helsinn Healthcare, Glaxo Smith Kline, Celgene, Bayer, and Roche and compensation for travel, accommodation, and expenses from StemCentrx outside the submitted work. Dr. Robinson reports personal fees and an ownership interest and advisory role in Radialogica, personal fees from Variant, grants from Elekta and Varian Medical Systems outside the submitted work. Dr. Baggstrom reports being the site principal investigator of a clinical trial at Novartis, Merck, Wyeth, Imclone, Boehringer Ingelheim, Eli Lilly, Bristol-Myers Squibb, Endocyte, Astex, Onyx, CtyRx, Millenium Pharmaceuticals, Genentech, Academic and Community Cancer Research United, AstraZeneca, MedImmune, and GlaxoSmithKline outside the submitted work. The remaining authors declare no conflict of interest.
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analysis (HR = 0.77, 95% CI: 0.70–0.83, p < 0.001) as well as propensity-matched score (101.6 versus 78.9 months [68% versus 60%], HR = 0.75, 95% CI: 0.70–0.86; p < 0.0001). Conclusions—In patients with completely resected T2N0M0, adjuvant chemotherapy is associated with improved survival in all tumor size groups. The benefit in patients with tumors smaller than 4 cm strongly suggests a role for chemotherapy in this patient population and counters its current status as an exclusion criteria for adjuvant trials. Keywords NSCLC; Adjuvant chemotherapy; Stage I; National Cancer Data Base
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For patients with medically operable clinical early-stage 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 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 with observation,3–5 a large pooled analysis showed that this benefit was restricted to patients with stage II or IIIA disease, with no significant improvement in patients with stage IB (hazard ratio [HR] = 0.93, 95% confidence interval [CI]: 0.78–1.10) and a 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, which included 8447 patients from 34 trials, the use of adjuvant chemotherapy was associated with an absolute improvement in 5-year OS of 4% (from 60% to 64%) compared with observation (HR = 0.86, 95% CI: 0.81–0.92; p = 0.009).7 In the subset of patients with stage IB NSCLC treated with platinum-based chemotherapy, adjuvant chemotherapy was associated with a 5-year improvement in OS from 55% to 60%. The same absolute benefit of 5% was observed in patients with stage II (from 40% to 45%) and stage III disease (from 30% to 35%). In a meta-analysis including 4556 patients with resected stage IB NSCLC from 16 trials, adjuvant chemotherapy was associated with a significant improvement in OS (HR = 0.74, 95% CI: 0.63–0.88).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).
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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 exploratory analysis showed improved median OS for patients in the chemotherapy arm whose tumors were 4 cm or larger (99 months versus 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 numerically higher 5-year OS for patients with stage IB tumors 4 cm or larger treated with chemotherapy (79% versus 59%, HR = 0.66, 95% CI: 0.39–1.14, p = 0.13).10 Since then, randomized trials of adjuvant chemotherapy such as the ECOG 1505 and the ALCHEMIST trials have included patients with stage IB tumors 4 cm or larger in the eligibility criteria.11,12 The purpose of our study was to further evaluate the role of chemotherapy in patients with stage T2N0M0, including those with tumors smaller than 4 cm, by using the National
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Cancer Data Base (NCDB). This joint data set 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 diagnosed in the United States.
Methods Patients
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Patients in whom pathologic stage T2N0M0 NSCLC was diagnosed in 2004–2011 and who underwent R0 resection were identified from the NCDB using the International Classification of Diseases for Oncology, Third Edition. Pathologic staging was based on the American Joint Committee on Cancer seventh edition staging criteria.2 Patients who had positive margins or who died within 1 month after their operation were excluded. Only patients who received chemotherapy starting within 120 days from surgical resection were included. Statistical Analysis
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Patients were de-identified and categorized into two cohorts: those who received adjuvant chemotherapy and those who did not (observation). Both cohorts were further stratified into four groups based on tumor size: 3.1 to 3.9 cm (S3), 4 to 4.9 cm (S4), 5 to 5.9 cm (S5), and 6 to 7 cm (S6–7). Independent two-sample t test was used to compare the distribution of continuous variables such as age and tumor size in the chemotherapy versus nochemotherapy cohorts. Categorical variables evaluated included tumor size group, age, sex, ethnicity, insurance, histologic type, and type of 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. OS was defined as the time from the date of diagnosis to the 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 compared by the log-rank test. Univariate Cox proportional hazard models were used to determine the statistical significance of 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 a 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, sex, race, distance from treating facility, Charlson-Deyo comorbidity score, population type, income, insurance status, center type, level of surgical 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. Postmatching
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diagnostics included analysis of standardized mean differences among both the matching variables and their possible interactions between the two groups. Statistical analyses were performed with the Statistical Package for Social Sciences, version 23.0 (IBM SPSS Statistics, Chicago, IL, USA), with R propensity matching extension (R, version 2.15.0, R Foundation for Statistical Computing, Vienna, Austria).
Results
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A total of 25,267 patients were included in the study, including 4996 (19.7%) who received adjuvant chemotherapy and 20,271 (81.3%) who did not receive adjuvant chemotherapy and were assigned as the observation group (Table 1). Compared with the observation group, patients treated with adjuvant chemotherapy were younger (p < 0.001) and had larger tumors (p < 0.001). Fewer patients in the chemotherapy group underwent sublobar resection than in the observation group (6.1% versus 8.6%, p < 0.001). Use of adjuvant chemotherapy peaked for both S3 tumors and tumors 4 cm or larger in 2005, being used in 27% and 30% of patients, respectively. Since then, the percentage of patients with resected T2N0 tumors undergoing adjuvant chemotherapy decreased to 10% in S3 tumors and 21% in patients with tumors 4 cm or larger 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 tumors to 44% in S6–7 tumors. Among patients receiving adjuvant chemotherapy, the 5-year OS ranged from 64% in S6–7 tumors to 67% in S3 tumors (Fig. 1 and Table 2). Compared with observation, chemotherapy was associated with improved median OS (100.5 months versus 62.6 months, HR = 0.61, 95% CI: 0.58–0.64, p < 0.0001) and 5-year OS (66% versus 51%, p < 0.0001) for all patients combined. The improved survival for chemotherapy compared with observation was also significant in all tumor size groups, with the absolute 5-year OS improvement directly linked to the tumor size, ranging from 12% in S3 tumors to 20% in S6–7 tumors. Factors associated with improved survival in multi-variable analyses included tumor size, sex, age, histologic type, Charlson-Deyo comorbidity score, type of operation, and use of chemotherapy (Table 3). Adjuvant chemotherapy was associated with increased survival for all tumor size categories.
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Propensity-matched analysis compared 1508 patient pairs with S3 tumors, 1514 pairs with S4 tumors, 743 pairs with S5 tumors, and 490 patient pairs with S6–7 tumors. 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 tumors, respectively (Table 4). In patients with S3, the median and 5-year OS improved from 78.9 months and 60% respectively in the observation group to 101.6 months and 68% respectively in the adjuvant chemotherapy group (Fig. 2).
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Discussion
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Tumor size has been shown to predict outcomes in multiple studies for patients treated with curative intent.14–16 In a Surveillance, Epidemiology and End Results study including 7620 patients with stage I NSCLC treated with a curative-intent operation, the 12-year OS was significantly decreased with each increase in tumor size category except for the comparison between tumors measuring 2.6 to 3.5 cm and 3.6 to 4.5 cm, ranging from 69% in those with tumors measuring 0.5 to 1.5 cm to 43% in those measuring more than 4.5 cm.17 The effect of tumor size on nonsurgically treated patients is also noticed, with smaller tumors associated with improved median OS in stage I NSCLC treated with radiation therapy18 and patients with stage III disease.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 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 larger than 7 cm classified as T3 and T4, respectively.21 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 undergoing adjuvant chemotherapy, highlighting the effects of chemotherapy in this patient population in which the highest benefit was observed in the larger tumors.
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In a smaller study using the same database and including patients with resected T1N0 and T2N0 NSCLC measuring less than 1 to 8.5 cm diagnosed between 2003 and 2006, adjuvant chemotherapy was associated with improved 5-year OS compared with observation, improving from 66.9% to 74.3% (HR = 0.75, p < 0.001) in patients with tumors smaller than 4 cm and from 49.8% to 64.8% (HR = 0.6, p < 0.001) in tumors 4 cm or larger.22 Although the study included patients with stage IA tumor (for which adjuvant chemotherapy is considered detrimental) and tumors larger than 7 cm (which are currently staged as T3 and will likely be reclassified as T4), the results are similar to those of our study, with a proportionally 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. Furthermore, there are no data on staging procedures before the surgical resection, type of chemotherapy regimens used, and surgical mortality. Nevertheless, the surgical mortality risk is low in this patient population. In a recent NCDB study including 119,146 patients with NSCLC resected between 2004 and 2009, the risk for death within 30 days in 66,283 patients with stage I NSCLC was 2.7%.23 This small effect from early mortality was addressed in our study through the exclusion of patients who died within 30 days after their operation. The large number of patients included in the NCDB allowed the evaluation of each tumor size among patients with T2N0M0 tumors. The absolute benefit from adjuvant chemotherapy in terms of the median and 5-year OS compared with observation was observed for each of the tumor size subgroups. Although it is very likely that chemotherapy
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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 and in view of the elimination of patients with early surgical mortality and the confirmed benefit from adjuvant chemotherapy in propensity matched analysis, our study suggests 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 this hypothesis is either confirmed or not further evaluated in prospective trials, the current exclusion of stage IB tumors smaller than 4 cm in the adjuvant NSCLC trials should be revisited.
Acknowledgments This work was partially funded by a grant from the National Institute of Health (K12 CA167540 [to Dr. Waqar]).
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 evidencebased clinical practice guidelines. Chest. 2013; 43:e278S–e313S. 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. 2007; 2:706–714. [PubMed: 17762336] 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. 2004; 350:351–360. [PubMed: 14736927] 4. Winton T, Livingston R, Johnson D, et al. Vinorelbine plus cisplatin vs. observation in resected nonsmall-cell lung cancer. N Engl J Med. 2005; 352:2589–2597. [PubMed: 15972865] 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. 2006; 7:719–727. [PubMed: 16945766] 6. Pignon JP, Tribodet H, Scagliotti GV, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol. 2008; 26:3552–3559. [PubMed: 18506026] 7. Burdett S, Pignon JP, Tierney J, et al. Adjuvant chemotherapy for resected early-stage non-small cell lung cancer. Cochrane Database Syst Rev. 2015; 3:CD011430. 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). 2015; 94:e903. [PubMed: 26039122] 9. Strauss GM, Herndon JE 2nd, Maddaus MA, et al. Adju-vant 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. 2008; 26:5043–5051. [PubMed: 18809614] 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. 2010; 28:29–34. [PubMed: 19933915]
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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) [abstract]. J Clin Oncol. 2011; 29(suppl):7013. 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. 2015; 21:5439– 5444. [PubMed: 26672084] 13. Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol. 1992; 45:613–619. [PubMed: 1607900] 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. 1995; 76:787–796. [PubMed: 8625181] 15. Padilla J, Calvo V, Penalver JC, et al. Surgical results and prognostic factors in early non-small cell lung cancer. Ann Thorac Surg. 1997; 63:324–326. [PubMed: 9033294] 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. 2001; 122:907–912. [PubMed: 11689795] 17. Wisnivesky JP, Yankelevitz D, Henschke CI. The effect of tumor size on curability of stage I nonsmall cell lung cancers. Chest. 2004; 126:761–765. [PubMed: 15364754] 18. Kupelian PA, Komaki R, Allen P. Prognostic factors in the treatment of node-negative nonsmall cell lung carcinoma with radiotherapy alone. Int J Radiat Oncol Biol Phys. 1996; 36:607–613. [PubMed: 8948345] 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. 2012; 7:1479–1484. [PubMed: 22982648] 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. 2007; 2:593–602. [PubMed: 17607114] 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. 2016; 11:39–51. [PubMed: 26762738] 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. 2015; 13:755–761. [PubMed: 26085391] 23. Rosen JE, Hancock JG, Kim AW, et al. Predictorsof mortality after surgical management of lung cancer in the national cancer database. Ann Thorac Surg. 2014; 98:1953–1960. [PubMed: 25443003]
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Figure 1.
Kaplan-Meier survival curves according to tumor size and use of chemotherapy: (A) tumor size 3.1 to 3.9 cm, (B) tumor size 4 to 4.9 cm, (C) tumor size 5 to 5.9 cm, and (D) tumor size 6 to 7 cm.
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Kaplan-Meier analysis for propensity score–matched patients with NSCLC with a tumor size of 3.1 to 3.9 cm by adjuvant chemotherapy status.
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Table 1
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Patient Characteristics Characteristic
Observation (n = 20,271)
Chemotherapy (n = 4996)
Female
8822 (43.5%)
2349 (47.0%)
Male
11,449 (56.5%)
2647 (53.0%)
Sex
p Value
J Thorac Oncol. Author manuscript; available in PMC 2017 October 01. Published in final edited form as: J Thorac Oncol. 2016 October ; 11(10): 1729–1735. doi:10.1016/j.jtho.2016.05.022.
Adjuvant Chemotherapy for Patients with T2N0M0 NSCLC Daniel Morgensztern, MDa,*, Lingling Du, MDa, Saiama N. Waqar, MDa, Aalok Patel, MDb, Pamela Samson, MDb, Siddhartha Devarakonda, MDa, Feng Gao, PhDc, Cliff G. Robinson, MDd, Jeffrey Bradley, MDd, Maria Baggstrom, MDa, Ashiq Masood, MDa, Ramaswamy Govindan, MDa, and Varun Puri, MD, MSCIb aDepartment
Author Manuscript
of Medicine, Division of Medical Oncology, Washington University School of Medicine, St. Louis, Missouri
bDepartment
of Surgery, Washington University School of Medicine, St. Louis, Missouri
cDivision
of Biostatistics, Washington University School of Medicine, St. Louis, Missouri
dDivision
of Radiation Therapy, Washington University School of Medicine, St. Louis, Missouri
Abstract Background—Adjuvant chemotherapy improves survival in patients with completely resected stage II and III NSCLC. However, its role in patients with stage IB NSCLC disease remains unclear. We evaluated the role of adjuvant chemotherapy in a large data set of patients with completely resected T2N0M0 NSCLC.
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Methods—Patients with pathologic stage T2N0M0 NSCLC who underwent complete (R0) resection between 2004 and 2011 were identified from the National Cancer Data Base and classified into four groups based on tumor size: 3.1 to 3.9 cm, 4 to 4.9 cm, 5 to 5.9 cm, and 6 to 7 cm. Patients who died within 1 month after their operation were excluded. Survival curves were estimated by the Kaplan-Meier product-limit method and compared by log-rank test. Results—Among the 25,267 patients who met the inclusion criteria, there were 4996 (19.7%) who received adjuvant chemotherapy. Adjuvant chemotherapy was associated with improved median and 5-year overall survival compared with observation for all tumor size groups. In patients with T2 tumors smaller than 4 cm, adjuvant chemotherapy was associated with improved median and 5-year overall survival in univariate (101.6 versus 68.2 months [67% versus 55%], hazard ratio [HR] = 0.66, 95% confidence interval [CI]: 0.61–0.72, p < 0.0001) and multivariable
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*
Address for correspondence: Daniel Morgensztern, MD, Department of Medicine, Division of Medical Oncology, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8056, St. Louis, MO 63110. [email protected]. Disclosure: Dr. Morgensztern reports personal fees from Celgene, Genentech, Bristol-Myers Squibb, Heat Biologics, and Boehringer Ingelheim outside the submitted work. Dr. Waqar reports a grant from the National Institutes of Health (1 UM1 CA186704-01) outside the submitted work. Dr. Bradley reports an ownership interest in and research funding from ViewRay, personal fees from Varian Proton, and institutional research funding from Mevion Medical Systems outside the submitted work. Dr. Govindan reports personal fees from Boehringer Ingelheim, Pfizer, Merck, Clovis, Helsinn Healthcare, Glaxo Smith Kline, Celgene, Bayer, and Roche and compensation for travel, accommodation, and expenses from StemCentrx outside the submitted work. Dr. Robinson reports personal fees and an ownership interest and advisory role in Radialogica, personal fees from Variant, grants from Elekta and Varian Medical Systems outside the submitted work. Dr. Baggstrom reports being the site principal investigator of a clinical trial at Novartis, Merck, Wyeth, Imclone, Boehringer Ingelheim, Eli Lilly, Bristol-Myers Squibb, Endocyte, Astex, Onyx, CtyRx, Millenium Pharmaceuticals, Genentech, Academic and Community Cancer Research United, AstraZeneca, MedImmune, and GlaxoSmithKline outside the submitted work. The remaining authors declare no conflict of interest.
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analysis (HR = 0.77, 95% CI: 0.70–0.83, p < 0.001) as well as propensity-matched score (101.6 versus 78.9 months [68% versus 60%], HR = 0.75, 95% CI: 0.70–0.86; p < 0.0001). Conclusions—In patients with completely resected T2N0M0, adjuvant chemotherapy is associated with improved survival in all tumor size groups. The benefit in patients with tumors smaller than 4 cm strongly suggests a role for chemotherapy in this patient population and counters its current status as an exclusion criteria for adjuvant trials. Keywords NSCLC; Adjuvant chemotherapy; Stage I; National Cancer Data Base
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For patients with medically operable clinical early-stage 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 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 with observation,3–5 a large pooled analysis showed that this benefit was restricted to patients with stage II or IIIA disease, with no significant improvement in patients with stage IB (hazard ratio [HR] = 0.93, 95% confidence interval [CI]: 0.78–1.10) and a 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, which included 8447 patients from 34 trials, the use of adjuvant chemotherapy was associated with an absolute improvement in 5-year OS of 4% (from 60% to 64%) compared with observation (HR = 0.86, 95% CI: 0.81–0.92; p = 0.009).7 In the subset of patients with stage IB NSCLC treated with platinum-based chemotherapy, adjuvant chemotherapy was associated with a 5-year improvement in OS from 55% to 60%. The same absolute benefit of 5% was observed in patients with stage II (from 40% to 45%) and stage III disease (from 30% to 35%). In a meta-analysis including 4556 patients with resected stage IB NSCLC from 16 trials, adjuvant chemotherapy was associated with a significant improvement in OS (HR = 0.74, 95% CI: 0.63–0.88).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).
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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 exploratory analysis showed improved median OS for patients in the chemotherapy arm whose tumors were 4 cm or larger (99 months versus 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 numerically higher 5-year OS for patients with stage IB tumors 4 cm or larger treated with chemotherapy (79% versus 59%, HR = 0.66, 95% CI: 0.39–1.14, p = 0.13).10 Since then, randomized trials of adjuvant chemotherapy such as the ECOG 1505 and the ALCHEMIST trials have included patients with stage IB tumors 4 cm or larger in the eligibility criteria.11,12 The purpose of our study was to further evaluate the role of chemotherapy in patients with stage T2N0M0, including those with tumors smaller than 4 cm, by using the National
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Cancer Data Base (NCDB). This joint data set 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 diagnosed in the United States.
Methods Patients
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Patients in whom pathologic stage T2N0M0 NSCLC was diagnosed in 2004–2011 and who underwent R0 resection were identified from the NCDB using the International Classification of Diseases for Oncology, Third Edition. Pathologic staging was based on the American Joint Committee on Cancer seventh edition staging criteria.2 Patients who had positive margins or who died within 1 month after their operation were excluded. Only patients who received chemotherapy starting within 120 days from surgical resection were included. Statistical Analysis
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Patients were de-identified and categorized into two cohorts: those who received adjuvant chemotherapy and those who did not (observation). Both cohorts were further stratified into four groups based on tumor size: 3.1 to 3.9 cm (S3), 4 to 4.9 cm (S4), 5 to 5.9 cm (S5), and 6 to 7 cm (S6–7). Independent two-sample t test was used to compare the distribution of continuous variables such as age and tumor size in the chemotherapy versus nochemotherapy cohorts. Categorical variables evaluated included tumor size group, age, sex, ethnicity, insurance, histologic type, and type of 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. OS was defined as the time from the date of diagnosis to the 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 compared by the log-rank test. Univariate Cox proportional hazard models were used to determine the statistical significance of 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 a 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, sex, race, distance from treating facility, Charlson-Deyo comorbidity score, population type, income, insurance status, center type, level of surgical 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. Postmatching
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diagnostics included analysis of standardized mean differences among both the matching variables and their possible interactions between the two groups. Statistical analyses were performed with the Statistical Package for Social Sciences, version 23.0 (IBM SPSS Statistics, Chicago, IL, USA), with R propensity matching extension (R, version 2.15.0, R Foundation for Statistical Computing, Vienna, Austria).
Results
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A total of 25,267 patients were included in the study, including 4996 (19.7%) who received adjuvant chemotherapy and 20,271 (81.3%) who did not receive adjuvant chemotherapy and were assigned as the observation group (Table 1). Compared with the observation group, patients treated with adjuvant chemotherapy were younger (p < 0.001) and had larger tumors (p < 0.001). Fewer patients in the chemotherapy group underwent sublobar resection than in the observation group (6.1% versus 8.6%, p < 0.001). Use of adjuvant chemotherapy peaked for both S3 tumors and tumors 4 cm or larger in 2005, being used in 27% and 30% of patients, respectively. Since then, the percentage of patients with resected T2N0 tumors undergoing adjuvant chemotherapy decreased to 10% in S3 tumors and 21% in patients with tumors 4 cm or larger 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 tumors to 44% in S6–7 tumors. Among patients receiving adjuvant chemotherapy, the 5-year OS ranged from 64% in S6–7 tumors to 67% in S3 tumors (Fig. 1 and Table 2). Compared with observation, chemotherapy was associated with improved median OS (100.5 months versus 62.6 months, HR = 0.61, 95% CI: 0.58–0.64, p < 0.0001) and 5-year OS (66% versus 51%, p < 0.0001) for all patients combined. The improved survival for chemotherapy compared with observation was also significant in all tumor size groups, with the absolute 5-year OS improvement directly linked to the tumor size, ranging from 12% in S3 tumors to 20% in S6–7 tumors. Factors associated with improved survival in multi-variable analyses included tumor size, sex, age, histologic type, Charlson-Deyo comorbidity score, type of operation, and use of chemotherapy (Table 3). Adjuvant chemotherapy was associated with increased survival for all tumor size categories.
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Propensity-matched analysis compared 1508 patient pairs with S3 tumors, 1514 pairs with S4 tumors, 743 pairs with S5 tumors, and 490 patient pairs with S6–7 tumors. 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 tumors, respectively (Table 4). In patients with S3, the median and 5-year OS improved from 78.9 months and 60% respectively in the observation group to 101.6 months and 68% respectively in the adjuvant chemotherapy group (Fig. 2).
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Discussion
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Tumor size has been shown to predict outcomes in multiple studies for patients treated with curative intent.14–16 In a Surveillance, Epidemiology and End Results study including 7620 patients with stage I NSCLC treated with a curative-intent operation, the 12-year OS was significantly decreased with each increase in tumor size category except for the comparison between tumors measuring 2.6 to 3.5 cm and 3.6 to 4.5 cm, ranging from 69% in those with tumors measuring 0.5 to 1.5 cm to 43% in those measuring more than 4.5 cm.17 The effect of tumor size on nonsurgically treated patients is also noticed, with smaller tumors associated with improved median OS in stage I NSCLC treated with radiation therapy18 and patients with stage III disease.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 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 larger than 7 cm classified as T3 and T4, respectively.21 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 undergoing adjuvant chemotherapy, highlighting the effects of chemotherapy in this patient population in which the highest benefit was observed in the larger tumors.
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In a smaller study using the same database and including patients with resected T1N0 and T2N0 NSCLC measuring less than 1 to 8.5 cm diagnosed between 2003 and 2006, adjuvant chemotherapy was associated with improved 5-year OS compared with observation, improving from 66.9% to 74.3% (HR = 0.75, p < 0.001) in patients with tumors smaller than 4 cm and from 49.8% to 64.8% (HR = 0.6, p < 0.001) in tumors 4 cm or larger.22 Although the study included patients with stage IA tumor (for which adjuvant chemotherapy is considered detrimental) and tumors larger than 7 cm (which are currently staged as T3 and will likely be reclassified as T4), the results are similar to those of our study, with a proportionally 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. Furthermore, there are no data on staging procedures before the surgical resection, type of chemotherapy regimens used, and surgical mortality. Nevertheless, the surgical mortality risk is low in this patient population. In a recent NCDB study including 119,146 patients with NSCLC resected between 2004 and 2009, the risk for death within 30 days in 66,283 patients with stage I NSCLC was 2.7%.23 This small effect from early mortality was addressed in our study through the exclusion of patients who died within 30 days after their operation. The large number of patients included in the NCDB allowed the evaluation of each tumor size among patients with T2N0M0 tumors. The absolute benefit from adjuvant chemotherapy in terms of the median and 5-year OS compared with observation was observed for each of the tumor size subgroups. Although it is very likely that chemotherapy
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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 and in view of the elimination of patients with early surgical mortality and the confirmed benefit from adjuvant chemotherapy in propensity matched analysis, our study suggests 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 this hypothesis is either confirmed or not further evaluated in prospective trials, the current exclusion of stage IB tumors smaller than 4 cm in the adjuvant NSCLC trials should be revisited.
Acknowledgments This work was partially funded by a grant from the National Institute of Health (K12 CA167540 [to Dr. Waqar]).
References
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Figure 1.
Kaplan-Meier survival curves according to tumor size and use of chemotherapy: (A) tumor size 3.1 to 3.9 cm, (B) tumor size 4 to 4.9 cm, (C) tumor size 5 to 5.9 cm, and (D) tumor size 6 to 7 cm.
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Kaplan-Meier analysis for propensity score–matched patients with NSCLC with a tumor size of 3.1 to 3.9 cm by adjuvant chemotherapy status.
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Table 1
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Patient Characteristics Characteristic
Observation (n = 20,271)
Chemotherapy (n = 4996)
Female
8822 (43.5%)
2349 (47.0%)
Male
11,449 (56.5%)
2647 (53.0%)
Sex
p Value
