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1 JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T Sequencing of Postoperative Radiotherapy and Chemotherapy for Locally Advanced or Incompletely Resected Non Small-Cell Lung Cancer Samual Francis, Andrew Orton, Greg Stoddard, Randa Tao, Ying J. Hitchcock, Wallace Akerley, and Kristine E. Kokeny Author affiliations and support information (if applicable) appear at the end of this article. Published at jco.org on December 13, 217. Corresponding author: Kristine E. Kokeny, MD, University of Utah Huntsman Cancer Institute, Department of Radiation Oncology, 195 Circle of Hope, Room 157, Salt Lake City, UT 84112; kristine.kokeny@hci.utah.edu. 217 by American Society of Clinical Oncology X/17/3599-1/$2. A B S T R A C T Purpose Although several feasibility studies have demonstrated the safety of adjuvant concurrent chemoradiotherapy () for locally advanced or incompletely resected non small-cell lung cancer (NSCLC), it remains uncertain whether this approach is superior to sequential chemotherapy followed by postoperative radiotherapy (C PORT). We sought to determine the most effective treatment sequence. Patients and Methods Using the National Cancer Database, we selected two cohorts of patients with nonmetastatic NSCLC who had received at least a lobectomy followed by multiagent chemotherapy and radiotherapy; cohort one included patients with R resection and pn2 disease, whereas cohort two included patients with R1-2 resection regardless of nodal status. Overall survival (OS) was examined using a propensity score matched analysis with a shared frailty Cox regression. Results A total of 747 patients in cohort one and 277 patients in cohort two were included, with a median followup of 32.8 and 27.9 months, respectively. The median OS was 58.8 months for patients who received C PORT versus 4.4 months for patients who received in cohort one (log-rank P,.1). For cohort two, the median OS was 42.6 months for patients who received C PORT versus 38.5 months for patients who received (log-rank P =.42). After propensity score matching, C PORT remained associated with improved OS compared with in cohort one (hazard ratio, 1.35; P =.19), and there was no statistical difference in OS between the sequencing groups for cohort two (hazard ratio, 1.35; P =.19). Conclusion Patients with NSCLC who undergo R resection and are found to have pn2 disease have improved outcomes when adjuvant chemotherapy is administered before, rather than concurrently with, radiotherapy. For patients with positive margins after surgery, there is not a clear association between treatment sequencing and survival. J Clin Oncol by American Society of Clinical Oncology ASSOCIATED CONTENT Appendix DOI: DOI: INTRODUCTION In patients with resected locally advanced non small-cell lung cancer (NSCLC), adjuvant chemotherapy has led to improved overall survival (OS) 1,2 and is considered standard of care. The benefit of postoperative radiotherapy (PORT) has been controversial. In a meta-analysis of multiple older clinical trials, PORTwas associated with worse outcomes in patients with early-stage disease. 3 However, several studies have indicated patients with pn2 disease 3-7 or incomplete resection may benefit fromport. 8 Current guidelines state indications for PORT include positive surgical margins or pn2 disease. 9,1 The ongoing phase III European Organisation for Research and Treatment of Cancer trial EORTC , Radiation Therapy in Treating Patients With Non Small-Cell Lung Cancer That Has Been Completely Removed by Surgery (LUNG ART) seeks to determine if PORT using modern treatment techniques is beneficial in pn2 disease. 11 Several randomized studies have shown benefit for more aggressive therapy for patients with unresectable cn2 locally advanced NSCLC identified on initial staging studies. Sequential chemotherapy with 5 weeks of platinum-based 217 by American Society of Clinical Oncology 1

2 Francis et al chemotherapy followed by RT is superior to RT alone. 12,13 Other trials have shown that concurrent chemoradiotherapy () offers a survival advantage over sequential regimens in the unresectable setting, making the standard of care in patients with unresectable disease with adequate performance status and minimal weight loss. 14,15 Although retrospective data suggest adding chemotherapy to PORT improves outcomes, 16 the preferred sequencing of chemotherapy and PORT in the adjuvant setting is controversial. Current guidelines advise sequential chemotherapy followed by PORT for patients with pn2 disease with negative margins (R) and suggest for patients with positive margins. 9,1 However, given the lack of randomized data and proven benefit of in the definitive treatment setting, we sought to determine the most effective treatment sequence. Diagnosed with lung cancer between 26 and 212 according to NCDB (N = 1,163,39) Patients with nonmetastatic disease (n = 691,885) Lobectomy or pneumonectomy (n = 247,941) Invasive SCC or adenocarcinoma (n = 191,643) PATIENTS AND METHODS Patient Population We used National Cancer Database (NCDB) registry data for patients with NSCLC diagnosed between 26 and 212 (most recent dataset available at time of study). The NCDB is a nationwide oncology outcomes database that captures 7% of all newly diagnosed cancer cases in the United States and provides access to data subsets to Commission on Cancer accredited programs via an online application process. From this dataset, we selected a cohort of patients with nonmetastatic disease who had undergone at least a lobectomy. The study cohort was limited to patients with adenocarcinoma or squamous cell carcinoma who had received adjuvant multiagent chemotherapy and external-beam RT to the lung, chest, or lymph nodes. Those without follow-up information or who had died within 3 months of diagnosis were excluded. Appendix Table A1 (online only) lists NCDB data codes used. We created two cohorts of patients based on National Comprehensive Cancer Network (NCCN) guidelines on indications for adjuvant chemotherapy and PORT. 1 Cohort one included patients with R resectionandpt1-t3andpn2diseasewhohadreceivedtotalradiation doses of 45, 5, 5.4, or 54 Gy in standard 1.8- or 2.-Gy fractionation. 6,1 Cohort two included patients with microscopic (R1) or grossly (R2) positive margins with pt1-t3 and pn-n2 disease who received total radiation doses of 45, 5, 5.4, 54, 59.4, 6, 66, 66.6, or 7 Gy in standard 1.8- or 2.-Gy fractionation (Fig 1). A higher dose range was used for cohort two based on recommendation for dose escalation for positive margins. 8,1 Patients were classified as having received sequential chemotherapy followed by radiation (C PORT group) if they received the first cycle of chemotherapy within 9 days after surgery and a minimum of 6 weeks before RT, based on NCCN recommendation of at least two cycles of adjuvant chemotherapy. 1 Patients were also included in the C PORT group if they had received the first cycle of chemotherapy within 9 days after surgery and up to a maximum of 18 weeks prior to starting RT; this was based on 4 cycles of adjuvant chemotherapy and allowing up to 6 weeks after chemotherapy before PORT as permitted in the ongoing LUNG ART trial. 11 Patients were classified as having received if they started RT within 9 days after surgery and received the first cycle of chemotherapy within 14 days before or after starting RT (Fig 2). Patients who completed RT before receiving their first cycle of chemotherapy were excluded. Patient characteristics for analysis included age, sex, race, treatment facility type, Charlson comorbidity score (CCS), tumor grade, histology, tumor size, pathologic T stage, pathologic N stage, surgical margin status, surgery type, and total radiation dose. Smoking information is not available in the NCDB. The primary end point was OS based on time of diagnosis until date of death. Cohort one R surgical margins (n = 2,377) Pathologic N2 disease (n = 1,458) Standard-fraction RT (45 to 54 Gy) (n = 747) Pathologic T1-3 disease (n = 159,834) Adjuvant multiagent chemotherapy (n = 26,274) Adjuvant irradiation of thorax (n = 5,53) Complete follow-up data available (n = 4,742) Alive > 3 months postdiagnosis (n = 4,734) Adjuvant sequencing: C PORT or (n = 3,247) Cohort two R1-2 surgical margins (n = 59) Pathologic N-2 disease (n = 52) pt1n disease excluded (n = 493) Standard-fraction RT (45 to 7 Gy) (n = 277) Fig 1. Patient CONSORT diagram detailing selection of cohort one (negative margins [R] and pn2 disease) and cohort two (positive margins [R1 or R2). C PORT, chemotherapy followed by postoperative radiotherapy;, chemoradiotherapy; NCDB, National Cancer Database; RT, radiotherapy; SCC, squamous cell carcinoma by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

3 Postoperative Radiotherapy and Chemotherapy Sequencing in NSCLC A Frequency (No. of patients) B Frequency (No. of patients) 1,5 1, 5 1,5 1, 5 C PORT RT start 5 Start of First Cycle of Chemotherapy Relative to Start of RT (days) C PORT Statistical Analysis x 2 analysis was used to compare categorical demographic and tumor characteristics between groups. t test was used to compare continuous variables between groups. Univariable (UVA) and multivariable analysis (MVA) logistic regression modeling were used to identify predictors for treatment sequence group, reported as odds ratios (ORs). UVA and MVA Cox proportional hazard modeling were used to identify factors associated with OS, reported as hazard ratios (HRs). The respective MVA models were created by including all covariates and then removing each covariate with a P value..2, starting with the covariate with the largest P value, in a reverse stepwise fashion. Categorical covariates were included in the final model if one of the covariate levels in comparison with the reference level had a P value,.2. 17,18 Propensity score (PS) analysis was used to account for differences in baseline patient characteristics between the C PORT and groups. Matching was performed based on patient characteristics and disease factors that included age, sex, CCS, tumor size, histology, grade, pathologic T stage, pathologic N stage, margin status, surgery type, treatment facility RT start 2 Start of First Cycle of Chemotherapy Relative to Start of RT (days) Fig 2. Treatment sequencing selection. (A) Entire patient cohort before exclusion. (B) Patient cohort after excluding those not meeting criteria for adjuvant sequencing groups (ie, chemotherapy followed by postoperative radiotherapy [C PORT] or chemoradiotherapy []). RT, radiotherapy. type, and radiation dose according to the method previously described by Rosenbaum and Rubin (Appendix, online only) After matching, a shared-frailty or matched-sample UVA Cox regression model was applied to the matched groups to estimate the effect of treatment sequence (C PORT v ) on survival. Forest plots were generated after PS matching using UVA Cox regression to analyze subgroup interactions. All analyses were performed using the STATA 14.2 statistical package (STATA, College Station, TX). RESULTS Cohort One A total of 747 patients with R resection and pn2 disease were included in the analysis. Patient characteristics are listed in Table 1. Fifty-nine percent of patients in cohort one received C PORT. The mean age of patients in cohort one was 63.5 years. Patients in the group had more medical comorbidities (ie, CCS. ) than those in the C PORT group ( group, 46% v C PORT group, 31%; P,.1). Most patients had moderate (46%) or poorly differentiated (47%) tumors, and slightly more patients in the group had poorly differentiated tumors compared with those in the C PORT group (51% v 44%, respectively; P =.1). The most common histology was adenocarcinoma, although more patients in the group had squamous cell histology compared with those in the C PORT group (, 27% v C PORT, 17%; P,.1). On average, tumors in the C PORT group were smaller than those in the group (37.2 v 46.2 mm, respectively; P =.7). Most patients had pt2 tumors (59%) and had undergone lobectomy (91%). There was no difference in radiation dose between those in the C PORT and groups, and the overall median dose was 5.4 Gy (interquartile range [IQR], Gy). Patients with more medical comorbidities (ie, CCS $ 1) were more likely to receive than C PORT (OR, 1.7; P,.1; Table 2). Additionally, increasing tumor size was predictive for receipt of over C PORT (OR, 1.1; P =.2). In contrast, race other than white, black, or Hispanic (OR,.3; P =.5), pt3 tumors (OR,.5; P =.4), and adenocarcinoma histology (OR,.6; P =.2) were predictive for receipt of C PORT. On Cox MVA (Appendix Table A2, online only), CCS $ 1 (HR, 1.25; P =.5), pt2 (HR, 1.46; P,.1), pt3 (HR, 1.16; P =.1), and (HR, 1.45; P,.1) were associated with increased risk of death. Women had improved OS (HR,.79; P =.4).Totestfor CCS interaction, we performed a Cox MVA for patients with CCS of and found to be associated with increased mortality (HR, 1.6; P =.1). When limited to patients with CCS $ 1, the effect of on survival lost statistical significance (HR, 1.25; P =.19). The use of for patients with negative margins and pn2 disease declined between 26 and 212, whereas the use of C PORT increased (Fig 3A). In 26, 53% of patients received C PORT and 47% received. In 212, 63% of patients received C PORT compared with 37% who received. In cohort one, the C PORT group had a median follow-up of 33.5 months and a median OS of 58.8 months (95% CI, 53.7 to 69.4 months), compared with the group, which had a median follow-up of 32.5 months and a median OS of 4.4 months (95% CI, 35.8 to 49.4 months; log-rank P,.1; Fig 4A). At last follow-up, 178 patients had died and 263 were alive in the jco.org 217 by American Society of Clinical Oncology 3

4 Francis et al Table 1. Baseline Patient Demographic and Clinical Characteristics Cohort One (R resection and pn2 disease) C PORT Total Cohort Two (R1-2 resection and any pn status) C PORT Total Characteristic No. % No. % No. % P No. % No. % No. % P Mean age, years (6 SD) 63.5 (6 9.7) 63.5 (6 9.3) 63.6 (6 9.6) (6 7.8) 63.2 (6 9.4) 63.6 (6 9.).24 Sex Male Female Total Race White Black Hispanic Other Total CCS Total Grade differentiation.1.3 Well Moderate Poor Undifferentiated Total Histology..1 Squamous Adenocarcinoma Total Mean tumor size, mm (6 SD) 37.2 (6 49.9) 46.2 (6 84.1) 4.9 (6 66.2) (6 19.9) 51.4 (6 71.5) 49. (6 62.9).28 Pathologic T stage.86.2 pt pt pt Total Pathologic N stage NA.2 pn NA pn1 NA pn Total Margin status NA.24 R NA R1 NA R2 NA Total Type of surgery performed Lobectomy Pneumonectomy Total Total dose, Gy.28.1 Median IQR Abbreviations: C PORT, chemotherapy followed by postoperative radiotherapy; CCS, Charlson comorbidity score;, concurrent chemoradiotherapy; IQR, interquartile range; NA, not applicable; SD, standard deviation. C PORTgroup,and172haddiedand134werealiveinthe group. After PS matching, 51 patients were available for analysis. The C PORT and groups were well balanced for demographic and cancer characteristics (Table 3). For the C PORT group, the median follow-up was 31.5 months and median OS was 56.9 months (95% CI, 49.6 to 69.4 months), compared with a median follow-up of 32.9 months and median OS of 41.5 months (95% CI, 36.7 to 5.4 months) for the group, which remained statistically significant (Fig 4B). The group had an increased risk of death compared with the C PORT group (HR, 1.35; 95% CI, 1.5 to 1.73; P =.19). After PS matching, at last follow-up, 11 patients had died and 145 were alive in the C PORT group, whereas 144 patients had died and 111 were alive in the group. On subgroup analysis (Appendix Fig A1, online only), no subgroup had a significant improvement with, whereas outcomes for CCS of, poorly differentiated tumors, pt2 disease, lobectomy, and doses of 45 or 54 Gy favored C PORT by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

5 Postoperative Radiotherapy and Chemotherapy Sequencing in NSCLC Table 2. Predictors for Sequencing of Adjuvant Treatment Cohort One (R resection and pn2 disease) Cohort Two (R1-2 resection and any pn status) Logistic UVA Logistic MVA Logistic UVA Logistic MVA Predictor OR 95% CI P OR 95% CI P OR 95% CI P OR 95% CI P Age at diagnosis, years to to to Race White 1. Reference 1. Reference 1. Reference 1. Reference Black.9.6 to to to to Hispanic.8.3 to to to to Other.3.1 to to to to CCS 1. Reference 1. Reference 1. Reference to to to Facility type Community cancer program 1. Reference 1. Reference 1. Reference Comprehensive community cancer program to to to Academic or research program.6.4 to to to Integrated.7.3 to to to Tumor size, per 1-mm increase to to to Type of surgery Lobectomy 1. Reference 1. Reference Pneumonectomy to to Pathologic T stage pt1 1. Reference 1. Reference 1. Reference pt to to to pt3.9.5 to to to Pathologic N stage pn 1. Reference 1. Reference pn1.6.3 to to pn2.4.2 to to.9.3 Histology Squamous 1. Reference 1. Reference 1. Reference 1. Reference Adenocarcinoma.5.4 to to to to.9.2 Grade differentiation Well 1. Reference NA Moderate.9.5 to Reference Poor to to Undifferentiated NA to Sex Male 1. Reference 1. Reference Female.8.6 to to Margin status R1 1. Reference 1. Reference R to to NOTE. OR, 1 favors C PORT; OR. 1 favors. Abbreviations: C PORT, chemotherapy followed by postoperative radiotherapy; CCS, Charlson comorbidity score;, concurrent chemoradiotherapy;mva, multivariable analysis; NA, not available; OR, odds ratio; UVA, univariable analysis. jco.org 217 by American Society of Clinical Oncology 5

6 Francis et al A 8 C PORT B 1 C PORT 8 Use (%) 6 4 Use (%) 6 4 Fig 3. Use of adjuvant treatment over time. (A) Cohort one: R pn2 group. (B) Cohort two: positive margins (R1-2) group Year of Diagnosis Year of Diagnosis Cohort Two A total of 277 patients with R1-2 margins and pn-n2 disease were included for analysis. Patient demographic and clinical characteristics are listed in Table 1. In cohort two, 25% of patients received C PORT, and 75% received. The average patient age was 63.6 years. Most patients had moderate (45%) or poorly differentiated (5%) tumors; the most common histology overall was adenocarcinoma (57%). More patients in the group had squamous cell histology (48%) compared with those in the C PORT group (28%; P =.1). Overall, the average tumor size was 49. mm. The most common T stage was pt2; however, more patients in the group had pt3 tumors (45%) compared with those in the C PORT group (26%; P =.2). More patients in the C PORT group had pn2 disease (42%) compared with those in the group (26%; P =.2). A vast majority of patients had R1 resection (94%), and although not statistically significant, more patients in the group had R2 resection (7%) compared with those in the C PORT group (3%; P =.24). Lobectomy (86%) was the most common surgery. Patients in the C PORT group had a lower total radiation dose than those in the group (C PORT, median was 59.4 Gy; IQR, Gy v, median was 59.4 Gy; IQR, 54-6 Gy; P =.1). On UVA, predictive factors for receipt of C PORT included pn2 disease (OR,.4; P =.1) and adenocarcinoma histology (OR,.5; P =.1; Table 2). These factors remained predictive on MVA. On Cox MVA (Appendix Table A3, online only), increasing age (HR, 1.2 per year; P =.2) and undifferentiated histology (HR, 6.87; P =.1) were associated with worse OS. The use of for this cohort increased from 26 to 212, whereas the use of C PORT decreased (Fig 3B), coincident with changes to NCCN guidelines. In 26, 33% of patients received C PORT compared with 19% in 212, in contrast to the 67% receiving in 26 compared with 81% in 212. For cohort two, the C PORT group had median follow-up time of 32.9 months and median OS of 42.6 months (95% CI, 32.4 to 59.5 months), compared with the group, which had a median follow-up of 27. months and median OS of 38.5 months (95% CI, 31.1 to 46.9 months; log-rank P =.42; Fig 4C). At last follow-up, 4 patients had died and 29 were alive in the C PORT group, whereas 119 had died and 89 were alive in the group. After PS matching, 128 patients were available for analysis. Groups C PORT and were well balanced on demographic and cancer characteristics (Table 3). The C PORT group had a median follow-up of 31.5 months and median OS of 38.3 months (95% CI, 27.2 to 59.5 months), compared with a median follow-up of 24.2 months and median OS of 33.8 months (95% CI, 18.8 to 47.9 months) for the group (Fig 4D). There remained no statistical difference in OS between the and C PORT groups (HR, 1.35; 95% CI,.86 to 2.13; P =.19). After PS matching, at last follow-up, 37 patients had died and 27 were alive in the C PORT group, whereas 41 had died and 23 were alive in the group. On subgroup analysis (Appendix Fig A2, online only), no factors were significantly associated with better survival based on treatment sequence. DISCUSSION For patients with pn2 disease and negative margins, sequential C PORT was associated with superior survival compared with. For patients with positive margins, there was no statistical difference in survival between treatment sequencing options. These findings remained consistent after PS-matched analysis. In the current American Society for Radiation Oncology evidence-based clinical practice guideline, Rodrigues et al 9 state that given the demonstrated overall survival associated with CT (chemotherapy) and lack of overall survival benefit with radiation therapy (for R N2 disease), adjuvant radiation therapy should be delivered sequentially after CT in order not to interfere with CT delivery because of a risk of combined chemoradiation side effects that can lead to potential treatment breaks or deintensification. 9(p152) More recently, an NCDB analysis by Robinson et al 7 found that modern PORT in addition to adjuvant chemotherapy was associated with improved OS in R pn2 disease, suggesting chemotherapy alone is not sufficient for these patients. In the definitive setting, was shown to be superior to sequential chemotherapy followed by thoracic radiotherapy (C TRT) in the Radiation Therapy Oncology Group phase III trial, Sequential Versus Concurrent Chemoradiation for Stage III Non Small-Cell Lung Cancer (RTOG 941), with a 6% improvement in by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

7 Postoperative Radiotherapy and Chemotherapy Sequencing in NSCLC A Overall Survival (proportion) P <.1 C PORT C Overall Survival (proportion) P =.42 C PORT No. at risk: Time Since Diagnosis (months) C PORT No. at risk: C PORT Time Since Diagnosis (months) B Overall Survival (proportion) P =.19 C PORT D Overall Survival (proportion) P =.192 C PORT No. at risk: C PORT Time Since Diagnosis (months) No. at risk: C PORT Time Since Diagnosis (months) Fig 4. Kaplan-Meier curves for overall survival. Cohort one, R pn2 group, (A) before and (B) after propensity score matching. Cohort two, positive margins (R1-2) group, (C) before and (D) after PS matching. C PORT, chemotherapy followed by postoperative radiotherapy;, chemoradiotherapy. 5-year survival. 15 However, patients in the arm had worse grade $ 3 acute toxicities (91%) than those in the C TRT arm (86%), whereas late toxicities were similar. Most significantly, the rate of grade $ 3 esophageal toxicities was 22% with versus 4% with C TRT. Mucositis, nausea or vomiting, and other nonhematologic toxicities were also higher in the arm. Thus, one possible explanation for our finding that C PORT was associated with improved OS compared with is the lower toxicity with sequential treatment. Furthermore, patients who are recovering from the acute adverse effects of surgical resection may be less able to tolerate the higher toxicity of. These patients harbor, at most, microscopic rather than gross disease, and the improved local disease control seen with for unresectable locally advanced NSCLC 15 may not translate into improved outcomes in the postoperative setting. Even though is likely more toxic, patients in cohort one with more comorbidities were more likely to have received. However, after PS matching, the group still had worse OS, which suggests that the treatment sequence affects survival regardless of preexisting comorbidities. A recent NCDB analysis found that PORT was associated with improved survival in patients with stage II or III disease with positive margins, but it did not assess the effect of sequencing RT and chemotherapy. 8 Although there is no randomized evidence, current guidelines recommend for positive surgical margins (R1-2). 9,1 We found a 4.1-month improvement in median OS for patients with positive margins receiving C PORT compared with, although this did not reach statistical significance. It is possible there were too few patients with R1-2 resection to detect a difference. Additionally, most patients in cohort two had microscopic positive margins rather than gross residual tumor, and it is patients with the latter who hypothetically might derive the most benefit from. Furthermore, it is possible that the tumoricidal benefit of for positive margins balances with the increased toxicity of this approach, and thus, there was not a detectable difference in OS based on treatment sequencing in the R1-2 cohort. We also found that trends in use between 26 and 212 showed an increase in use of C PORT for patients in cohort one (R pn2) and a decrease in use of. For patients in cohort two jco.org 217 by American Society of Clinical Oncology 7

8 Francis et al Table 3. Patient Demographic and Clinical Characteristics After PS Matching Cohort One C PORT Total Cohort Two C PORT Total Characteristic No. % No. % No. % P No. % No. % No. % P Mean age, years (6 SD) 63.6 (6 9.6) 63.6 (6 9.2) 63.6 (6 9.4) (6 7.5) 64.7 (6 9.2) 64.6 (6 8.4).85 Sex Male Female Total Race White Black Hispanic Other Total CCS Total Grade differentiation Well NA Moderate Poor Undifferentiated NA Total Histology Squamous Adenocarcinoma Total Mean tumor size, mm (6 SD) 39.7 (6 62.7) 39. (6 33.9) 39.4 (6 5.3) (6 2.) 36.3 (6 2.5) 38.9 (6 2.3).16 Pathologic T stage.92.3 pt pt pt Total Pathologic N stage NA.83 pn NA pn1 NA pn Total Margin status NA.24 R NA R1 NA R2 NA Total Type surgery performed Lobectomy Pneumonectomy Total Total dose, Gy.87.4 Median IQR Abbreviations: C PORT, chemotherapy followed by postoperative radiotherapy; CCS, Charlson comorbidity score;, concurrent chemoradiotherapy; IQR, interquartile range; NA, not applicable; PS, propensity score; SD, standard deviation. (R1-2 margin), use of increased, whereas use of C PORT decreased over time. These findings suggest practice patterns have shifted toward concordance with consensus guideline recommendations over time. Our study has limitations. Data on recurrence, cancer-specific survival, type of chemotherapy, and number of cycles are not reported in the NCDB. Additionally, our study is a retrospective analysis of nonrandomized data, and although our analyses used PS-matching techniques to account for confounding as a result of measured covariates, confounding may have persisted among nonmeasured covariates; it is impossible to completely account for these limitations outside of a prospective randomized clinical trial. Although the NCDB captures a majority of cancer diagnoses, it is not a population-based database, and generalizability may be limited. Despite these limitations, our study has several strengths. Although some treatment details are not specified in the NCDB, we only included patients who had received chemotherapy and RT at accepted time points after surgery to ensure we captured the by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

9 Postoperative Radiotherapy and Chemotherapy Sequencing in NSCLC appropriate populations of interest for our questions. We also clearly defined two clinically distinct patient cohorts and separately analyzed the data with results that are clinically relevant to each group. Additionally, we found consistent results in both cohorts after PS analyses that accounted for potential differences between comparison groups. Taken together, our results contribute to the literature and suggestthatwhenportisadministeredtopatientswithrpn2 disease, there is a survival benefit with sequential C PORT compared with. We also found that sequential therapy is becoming the more frequent practice pattern over time for patients with R pn2 disease, and our results support this practice. In patients with positive margins, we found the use of to have increased over time, although we did not clearly identify a superior sequencing option. In conclusion, in the postoperative setting for patients with NSCLC with R resection and pn2 disease, sequential C PORT was associated with improved OS compared with. For patients with positive margins, there was not a clear association between treatment sequencing and survival. AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Disclosures provided by the authors are available with this article at jco.org. AUTHOR CONTRIBUTIONS Conception and design: Samual Francis, Andrew Orton, Randa Tao, Ying J. Hitchcock, Wallace Akerley, Kristine E. Kokeny Administrative support: Ying J. Hitchcock, Kristine E. Kokeny Collection and assembly of data: Samual Francis, Andrew Orton, Wallace Akerley Data analysis and interpretation: Samual Francis, Andrew Orton, Greg Stoddard, Wallace Akerley, Kristine E. Kokeny Manuscript writing: All authors Final approval of manuscript: All authors Accountable for all aspects of the work: All authors REFERENCES 1. 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Int J Radiat Oncol Biol Phys 77: , Budtz-Jørgensen E, Keiding N, Grandjean P, et al: Confounder selection in environmental epidemiology: Assessment of health effects of prenatal mercury exposure. Ann Epidemiol 17:27-35, Maldonado G, Greenland S: Simulation study of confounder-selection strategies. Am J Epidemiol 138: , Austin PC: An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivariate Behav Res 46: , Austin PC: Optimal caliper widths for propensity-score matching when estimating differences in means and differences in proportions in observational studies. Pharm Stat 1:15-161, Little RJ, Rubin DB: Causal effects in clinical and epidemiological studies via potential outcomes: Concepts and analytical approaches. Annu Rev Public Health 21: , 2 Affiliations Samual Francis, Andrew Orton, Randa Tao, Ying J. Hitchcock, Wallace Akerley, and Kristine E. Kokeny, University of Utah Huntsman Cancer Institute; Greg Stoddard, University of Utah, Salt Lake City, UT. nnn jco.org 217 by American Society of Clinical Oncology 9

10 Francis et al AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Sequencing of Postoperative Radiotherapy and Chemotherapy for Locally Advanced or Incompletely Resected Non Small-Cell Lung Cancer The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO s conflict of interest policy, please refer to or ascopubs.org/jco/site/ifc. Samual Francis No relationship to disclose Andrew Orton Research Funding: Elekta Greg Stoddard Consulting or Advisory Role: Prolung Randa Tao No relationship to disclose Ying J. Hitchcock No relationship to disclose Wallace Akerley No relationship to disclose Kristine E. Kokeny Stock or Other Ownership: Merit Medical Systems (I), Bard Medical (I) Honoraria: Merit Medical Systems (I) Consulting or Advisory Role: Merit Medical Systems (I) Travel, Accommodations, Expenses: Merit Medical Systems (I) 217 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

11 Postoperative Radiotherapy and Chemotherapy Sequencing in NSCLC Appendix Method of Propensity Score Matched Analysis To account for systematic differences in baseline characteristics in this nonrandomized cohort, we performed propensity score (PS) analysis. The PS is a balancing score that allows one to find a distribution such that measured baseline covariates are balanced between treated and untreated patients. The PS can be estimated using a logistic regression model in observational data sets. Although various methods exist for using the PS to remove effects of confounding, we used PS-matching methodology. 19 This was performed by one-to-one matching using a nearest-neighbor algorithm assuming independent observations and fixed weights and assuming that the variance of the outcome does not depend on the PS. Pairing between patient cases was limited to the region of common support. Caliper width was narrowed in a stepwise fashion until the covariate distributions were balanced after matching (Austin PC: Biom J 51: , 29). A caliper width of.2 was used for cohort one and.5 was used for cohort two. Balancing of groups after PS matching was verified using x 2 analysis for categorical variables and t test for continuous variables. Table A1. Codes Used for Patient Selection From Participant User Files From NCDB NCDB Data Label Description Codes Used for Inclusion tnm_clin_stage_group AJCC clinical stage group 1, 1A, 1B, 2, 2A, 2B, 3, 3A, 3B tnm_path_stage_group AJCC pathologic stage group 1, 1A, 1B, 2, 2A, 2B, 3, 3A, 3B cs_mets_at_dx Metastatic at diagnosis, 99 tnm_clin_m Clinical M stage tnm_path_m Pathologic M stage 88, X rx_summ_surg_prim_site Type of surgery at primary site 3, 33, 45, 46, 47, 48, 55, 56, 65, 66, 7 histology Squamous 87, 852, 884, 873, 883 histology Adenocarcinoma 814, 8255, 855, 826, 831, 8323, 848, 8481, 849, 8574 behavior Tumor behavior 3 rx_summ_chemo Chemotherapy 3 rad_treat_vol Radiation treatment volume 1, 11, 2, 21, 6, 98, 99 dx_lastcontact_death_months Date of last contact. 3 rx_summ_radiation Radiotherapy 1 rx_summ_surgrad_seq Sequencing of surgery and radiotherapy 3 tnm_path_t AJCC pathologic T stage 1, 1A, 2, 2A, 2B, 3 rx_summ_surgical_margins Surgical margins Cohort one: Cohort two: 2, 3 tnm_path_n AJCC pathologic N stage Cohort one: 2 Cohort two:, 1, 2 Abbreviations: AJCC, American Joint Committee on Cancer; NCDB, National Cancer Database. jco.org 217 by American Society of Clinical Oncology

12 Francis et al Table A2. Cox Proportional Hazards Analysis for Patients in Cohort One (pn2, R) Cox UVA Cox MVA Variable HR 95% CI P HR 95% CI P Age at diagnosis, years Per 1-year increase Sex Male 1. Reference 1. Reference Female CCS 1. Reference 1. Reference $ Grade differentiation Well 1. Reference 1. Reference Moderate Poor Undifferentiated Size of tumor, mm Per 1-mm increase Histology Squamous cell carcinoma 1. Reference Adenocarcinoma Total radiation dose, Gy Per.1-Gy increase Surgery type Lobectomy 1. Reference Pneumonectomy Adjuvant treatment sequencing C PORT 1. Reference 1. Reference Pathologic T stage pt1 1. Reference 1. Reference pt pt Abbreviations: C PORT, chemotherapy followed by postoperative radiotherapy; CCS, Charlson comorbidity score;, chemoradiotherapy; HR, hazard ratio; MVA, multivariable analysis; UVA, univariable analysis. 217 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

13 Postoperative Radiotherapy and Chemotherapy Sequencing in NSCLC Table A3. Cox Proportional Hazards Analysis for Patients in Cohort Two (positive margins [R1-2]) Cox UVA Cox MVA Variable HR 95% CI P HR 95% CI P Age at diagnosis, years Per 1-year increase Sex Male 1. Reference Female CCS 1. Reference $ Grade differentiation Well 1. Reference 1. Reference Moderate Poor Undifferentiated Size of tumor, mm Per 1-mm increase Histology Squamous cell carcinoma 1. Reference Adenocarcinoma Total radiation dose, Gy Per.1-Gy increase Surgery type Lobectomy 1. Reference Pneumonectomy Adjuvant treatment sequencing C PORT 1. Reference 1. Reference Pathologic T stage pt1 1. Reference 1. Reference pt pt Pathologic N stage pn 1. Reference 1. Reference pn pn Abbreviations: C PORT, chemotherapy followed by postoperative radiotherapy; CCS, Charlson comorbidity score;, chemoradiotherapy; HR, hazard ratio; MVA, multivariable analysis; UVA, univariable analysis. jco.org 217 by American Society of Clinical Oncology

14 Francis et al Subgroup No. HR (95% CI) CCS (1.9 to 2.13) (.87 to 2.1) (.31 to 1.32) Histology Squamous (.96 to 2.7) Adenocarcinoma (.96 to 1.69) Grade differentiation Well (.49 to 3.52) Moderate (.84 to 1.8) Poor (1. to 2.2) LVSI Negative (.91 to 3.57) Positive (.88 to 2.79) Pathologic T stage pt (.84 to 2.18) pt (1.2 to 1.92) pt (.46 to 2.14) Type of surgery performed Lobectomy (1.3 to 1.75) Pneumonectomy (.7 to 3.27) Total dose, Gy (1.36 to 7.79) 5 to (.79 to 1.44) (1.2 to 3.17) Overall (1.5 to 1.72) Favors Favors C PORT Fig A1. Forest plot after propensity score matching for cohort one (R pn2 group). C PORT, sequential chemotherapy followed by postoperative radiotherapy; CCS, Charlson comorbidity score;, chemoradiotherapy; HR, hazard ratio; LVSI, lymphovascular space invasion. 217 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

15 Postoperative Radiotherapy and Chemotherapy Sequencing in NSCLC Subgroup CCS 1 2+ Histology Squamous Adenocarcinoma Grade differentiation Moderate Poor LVSI Negative Positive Pathologic T stage pt1 pt2 pt3 Pathologic N stage pn pn1 pn2 Type of surgery performed Lobectomy Pneumonectomy Margin status R1 R2 Total dose, Gy Overall No Favors Favors C PORT HR (95% CI) 1.49 (.79 to 2.84) 1.42 (.7 to 2.88).61 (.13 to 2.74) 1.23 (.48 to 3.1) 1.44 (.85 to 2.46) 1.1 (.58 to 2.11) 1.64 (.87 to 3.9) 2.64 (.69 to 1.4) 1.49 (.43 to 5.12) 1.15 (.41 to 3.25) 1.34 (.76 to 2.36) 1.61 (.55 to 4.69) 1.75 (.63 to 4.84) 1.33 (.66 to 2.69) 1.15 (.55 to 2.41) 1.26 (.78 to 2.4) 3.23 (.62 to 16.75) 1.39 (.88 to 2.19).75 (.7 to 8.42) 1.4 (.72 to 2.72) 1.35 (.72 to 2.52) 1.34 (.86 to 2.9) Fig A2. Forest plot after propensity score matching for cohort two (positive margins [R1-2] group). C PORT, sequential chemotherapy followed by postoperative radiotherapy; CCS, Charlson comorbidity score;, chemoradiotherapy; HR, hazard ratio; LVSI, lymphovascular space invasion. jco.org 217 by American Society of Clinical Oncology