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The Addition of Chemotherapy to Radiation Therapy Improves Survival in Elderly Patients with Stage III Non–Small Cell Lung Cancer

Open ArchivePublished:January 08, 2018DOI:https://doi.org/10.1016/j.jtho.2017.11.135

      Abstract

      Introduction

      Elderly patients account for the majority of lung cancer diagnoses but are poorly represented in clinical trials. We evaluated the overall survival (OS) of elderly patients with stage III NSCLC treated with definitive radiation compared with that of patients treated with definitive chemoradiation.

      Methods

      We conducted a comparative effectiveness study of radiation therapy versus chemoradiation in elderly (≥70 years old) patients with stage III NSCLC not treated surgically diagnosed from 2003 to 2014; the patients were identified by using the National Cancer Database. Two cohorts were evaluated: patients (n = 5023) treated with definitive radiation (≥59.4 Gy) and patients (n = 18,206) treated with definitive chemoradiation. Chemoradiation was further defined as concurrent (radiation and chemotherapy started within 30 days of each other) or sequential (radiation started >30 days after chemotherapy). We compared OS between the treatment groups by using the Kaplan-Meier method and Cox proportional hazards regression before and after propensity score matching (PSM).

      Results

      Treatment with chemoradiation was associated with improved OS versus that with radiation both before PSM (hazard ratio [HR] = 0.66, 95% confidence interval [CI]: 0.64–0.68, p < 0.001) and after PSM (HR = 0.67, 95% CI: 0.64–0.70, p < 0.001). Relative to concurrent chemoradiation, sequential chemoradiation was associated with a 9% reduction in the risk for death (HR = 0.91, 95% CI: 0.85–0.96, p = 0.002).

      Conclusions

      We found that definitive chemoradiation resulted in a survival advantage compared with definitive radiation in elderly patients. Sequential chemotherapy and radiation was superior to concurrent chemoradiation. Although prospective trials are needed, this analysis suggests that chemoradiation should be strongly considered for elderly patients and the optimal sequencing of chemotherapy and radiation remains an unanswered question for this patient population.

      Keywords

      Introduction

      Stage III NSCLC represents 30% of all new lung cancer diagnoses and is a heterogeneous disease requiring a multidisciplinary treatment approach.
      • Crino L.
      • Weder W.
      • van Meerbeeck J.
      • Felip E.
      ESMO Guidelines Working Group
      Early stage and locally advanced (non-metastatic) non-small-cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      Nearly 70% of all lung cancer diagnoses and more than 70% of lung cancer deaths in the United States occur in patients 65 years of age or older.

      National Cancer Institute. SEER stat fact sheets: lung and bronchus cancer. http://seer.Cancer.Gov/csr/1975_2014/; Accessed June 13, 2017.

      However, elderly individuals are underrepresented in clinical trials, making treatment decisions in this population challenging.
      • Sacher A.G.
      • Le L.W.
      • Leighl N.B.
      • Coate L.E.
      Elderly patients with advanced NSCLC in phase III clinical trials: are the elderly excluded from practice-changing trials in advanced NSCLC?.
      • Langer C.J.
      Neglected and underrepresented subpopulations: elderly and performance status 2 patients with advanced-stage non-small-cell lung cancer.
      • Lewis J.H.
      • Kilgore M.L.
      • Goldman D.P.
      • et al.
      Participation of patients 65 years of age or older in cancer clinical trials.
      Overall, the available data guiding decision making in elderly individuals are limited. A multicenter retrospective review based on the Netherlands Cancer Registry reported no improvement in overall survival (OS) for patients age 70 years or older who were treated with concurrent chemoradiation (CCRT) compared with that of patients treated with sequential chemoradiation (SCRT) or radiation therapy (RT) alone.
      • Driessen E.J.
      • Bootsma G.P.
      • Hendriks L.E.
      • et al.
      Stage III non-small cell lung cancer in the elderly: patient characteristics predictive for tolerance and survival of chemoradiation in daily clinical practice.
      In contrast, two additional studies, including a subset analysis of two prospective trials and a Surveillance, Epidemiology, and End Results–Medicare analysis, demonstrated a survival benefit for chemoradiation (CRT).
      • Davidoff A.J.
      • Gardner J.F.
      • Seal B.
      • Edelman M.J.
      Population-based estimates of survival benefit associated with combined modality therapy in elderly patients with locally advanced non-small cell lung cancer.
      • Schild S.E.
      • Mandrekar S.J.
      • Jatoi A.
      • et al.
      The value of combined-modality therapy in elderly patients with stage III nonsmall cell lung cancer.
      Given the conflicting and scant data on this patient population, the optimal treatment strategy for stage III NSCLC in elderly individuals needs to be further defined.
      The objective of this study was to compare OS in elderly patients treated with RT alone with OS in elderly patients treated with CRT by using the National Cancer Database (NCDB). We hypothesized that patients who received CRT would have improved OS compared with those treated with RT alone.

      Materials and Methods

      The NCDB, which is a combined effort of the Commission on Cancer (CoC) of the American College of Surgeons and the American Cancer Society, is a nationwide hospital-based database that contains de-identified hospital registry data from more than 1500 accredited facilities, representing more than 70% of newly diagnosed cancer cases in the United States.
      • Bilimoria K.Y.
      • Stewart A.K.
      • Winchester D.P.
      • Co C.Y.
      The National Cancer Database: a powerful initiative to improve cancer care in the United States.
      The NCDB collects data on patient demographics and comorbidities, tumor characteristics and staging details, primary therapies administered, and OS. The CoC’s NCDB and the hospitals participating in the CoC NCDB are the source of the de-identified data, and they have not verified and are not responsible for either the statistical validity of the data analysis or the conclusions presented in this study.

      Patient Selection

      Patients in whom stage III NSCLC was diagnosed from 2003 to 2014 were collected from the NCDB participant user file, with additional inclusion and exclusion criteria summarized in Figure 1. We defined elderly patients as those age 70 years or older, as previously defined in numerous studies.
      • Atagi S.
      • Kawahara M.
      • Yokoyama A.
      • et al.
      Thoracic radiotherapy with or without daily low-dose carboplatin in elderly patients with non-small-cell lung cancer: a randomised, controlled, phase 3 trial by the Japan Clinical Oncology Group (JCOG0301).
      • Quoix E.
      • Zalcman G.
      • Oster J.P.
      • et al.
      Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial.
      • Stinchcombe T.E.
      • Zhang Y.
      • Vokes E.E.
      • et al.
      Pooled analysis of individual patient data on concurrent chemoradiotherapy for stage III non-small-cell lung cancer in elderly patients compared with younger patients who participated in US National Cancer Institute cooperative group studies.
      The transition to the seventh edition of the American Joint Committee on Cancer (AJCC) staging system occurred in 2010; consequently, our patient cohort consisted of patients staged by using both the sixth and seventh editions of the AJCC staging system. Patients with clinical T4N0M0 disease based on the AJCC sixth edition were excluded, as they could be either clinical stage II (T3 N0 M0) or stage IV (M1a [malignant pleural or pericardial effusion]) based on the AJCC seventh edition. Because the focus of this study was on patients not treated surgically, those treated with any type of surgical procedure were excluded. Additional exclusion criteria included unknown RT or chemotherapy details, treatment with regional or total RT doses of 80 Gy or higher, treatment with more than 45 fractions of RT, treatment with immunotherapy, no treatment, treatment with chemotherapy alone, and treatment with palliative doses of RT (<59.4 Gy). After exclusion, patients were categorized as having received definitive RT alone (≥59.4 Gy) or definitive CRT (≥59.4 Gy). Patients in the CRT group were considered to have received CCRT if chemotherapy was delivered within 30 days before or after initiation of RT, whereas SCRT was defined as RT delivered more than 30 days after initiation of chemotherapy, as defined in a prior study.
      • Wang E.H.
      • Rutter C.E.
      • Corso C.D.
      • et al.
      Patients selected for definitive concurrent chemoradiation at high-volume facilities achieve improved survival in stage III non-small-cell lung cancer.
      Details regarding radiation treatment technique (e.g., three-dimensional conformal RT versus intensity-modulated RT) were available for 35% of the patient population. Rather than exclude patients with an unknown treatment technique, we chose not to include this variable in our analysis. Patients with unknown demographic data were excluded. For the urban or rural code, the 2013 classification codes were used, whereas income was determined by using the 2008–2012 code. Finally, patients with less than 1 month of follow-up were excluded from the analysis to limit immortal time bias.
      • Park H.S.
      • Gross C.P.
      • Makarov D.V.
      • Yu J.B.
      Immortal time bias: a frequently unrecognized threat to validity in the evaluation of postoperative radiotherapy.
      Figure thumbnail gr1
      Figure 1Study flow diagram for analytic cohorts. NCDB, National Cancer Database; AJCC, American Joint Committee on Cancer; SBRT, stereotactic body radiation therapy.

      Study Variables

      We dichotomized the following baseline covariates: sex (male versus female), race (white versus nonwhite), median income (≥$48,000 versus <$48,000), primary insurance payer (private versus nonprivate), county location (metropolitan versus urban or rural), facility type (academic versus community versus comprehensive community versus integrated network programs), chemotherapy agents used (multiagent regimen versus single-agent regimen), and clinical stage group (IIIB versus IIIA). The Charlson-Deyo score, a measure of comorbidity, was dichotomized as 0 (no comorbities) or 1 (≥1 comorbidity). The variables age and distance to the nearest facility were analyzed as continuous variables.

      Statistical Methods

      The primary objective of this study was to evaluate OS in elderly patients treated with CRT versus with RT alone. We also sought to evaluate the impact of number of chemotherapy agents used (multiagent CRT versus RT alone, single-agent CRT versus RT, and multiagent CRT versus single-agent CRT). Additional analysis included comparison of OS in patients in the CRT group treated with CCRT versus with SCRT. Differences in patient characteristics between patients treated with CRT and those treated with RT were tested by using the χ2 test for categorical variables and the t test for continuous variables. Survival was estimated by using the Kaplan-Meier method, and the log-rank test was used to compare survival curves. Cox regression analysis was used to test the association between treatment and demographic variables with OS on univariate analysis. Variables with a p value of 0.10 or less on univariate analysis were included in the multivariate model.
      Propensity score matching (PSM) was performed to reduce potential selection bias. Logistic regression was used to identify predictors of treatment with definitive CRT versus definitive RT alone. Patients treated with CRT were matched with those receiving radiation alone by a 1:1 nearest available neighbor match without replacement by using an algorithm described by Coca-Perraillon.

      Coca-Perraillon M. Local and global optimal propensity score matching. Paper presented at: SAS Global Forum 2007 Conference. April 16–19, 2007; Orlando, FL.

      The caliper size was calculated as 20% of the SD of the propensity score as described by Rosenbaum et al.
      • Rosenbaum P.R.
      • Rubin D.B.
      Constructing a control-group using multivariate matched sampling methods that incorporate the propensity score.
      Common support of the propensity score distributions was evaluated graphically, and balance was evaluated by computing the standardized difference of the covariates across the two groups.

      Lanehart RE, Rodriguez de Gil, P, Kim ES, et al. Propensity score analysis and assessment of propensity score approaches using SAS procedures. Paper presented at: SAS Global Forum 2012 Conference. April 22–25, 2012; Orlando, FL.

      After PSM, OS was estimated by the Kaplan-Meier method and Cox regression was used to perform univariate and multivariate analysis. The exact same approach was used to perform PSM for patients receiving CCRT versus SCRT. All statistical analyses were performed with SAS, version 9.4 (SAS Institute, Inc., Cary, NC).

      Results

      Patient Characteristics

      We identified 5023 elderly patients treated with RT alone and 18,206 patients treated with CRT. The median radiation dose was 64.8 Gy (interquartile range [IQR] 61.2–66.6 Gy) over a median of 34 fractions (range 33–36) in the CRT group and 64.8 Gy (IQR 60.0–66.6 Gy) over a median of 33 (range 30–35) in the RT group. The radiation was delivered with conventional fraction sizes with a median daily fraction size of 1.8 Gy (range 1.8–2.0 Gy) in the CRT group and 2.0 Gy (range 1.8–2.0 Gy) in the RT group. Several imbalances in characteristics existed between patients in the RT group and those in the CRT group (Table 1). Most notably, patients in the CRT group were more likely to have stage IIIB disease (36.7% versus 32.5% [p < 0.001]), but they were also more likely to have no comorbidities (62.9% versus 58.7% [p < 0.001]) and be younger (75.8 versus 79.4 years [p < 0.001]) compared with patients in the RT group. Most patients in the CRT group received multiagent chemotherapy (86% [n = 15,715]). In the CRT cohort, most were treated with CCRT (87% [n = 15,840]) with a median time between the start of radiation and chemotherapy of 0 days (IQR from –1 [RT first] to 0 days). The median time from the start of chemotherapy to radiation in the SCRT group was 82 days (IQR 56–112 days).
      Table 1Patient Characteristics
      CharacteristicRadiation Therapy Alone (n = 5023)Chemoradiation (n = 18,206)p Value
      The p values are from the χ2 test for categorical variables and the t test for continuous variables.
      Age, mean (SD), y79.4 (5.4)75.8 (4.4)<0.001
      Sex<0.001
       Male2750 (54.7%)10,540 (57.9%)
       Female2273 (45.3%)7666 (42.1%)
      Race0.005
       White4398 (87.6%)16,197 (89.0%)
       Nonwhite625 (12.4%)2009 (11.0%)
      Charlson-Deyo score<0.001
       02949 (58.7%)11,450 (62.9%)
       >12074 (41.3%)6756 (37.1%)
      Median income<0.001
       ≥$48,0002522 (50.2%)9825 (54.0%)
       <48,0002501 (49.8%)8381 (46.0%)
      Primary insurance payer0.74
       Private491 (9.8%)1751 (9.6%)
       Nonprivate4532 (90.2%)16,455 (90.4%)
      County location0.045
       Metropolitan4062 (80.9%)14,489 (79.6%)
       Nonmetropolitan961 (19.1%)3717 (20.4%)
      Distance to closest facility, mean (SD)15.9 (41.4)20.4 (74.7)<0.001
      Facility type0.98
       Academic1243 (24.8%)4502 (24.7%)
       Nonacademic3780 (75.2%)13,704 (75.3%)
      Clinical stage group<0.001
       IIIA3390 (67.5%)11,523 (63.3%)
       IIIB1633 (32.5%)6683 (36.7%)
      Days to start of radiation, mean (SD)47.9 (40.2)55.5 (46.5)<0.001
      Radiation therapy dose, median (IQR)64.8 (60.0–66.6) Gy64.8 (61.2–66.6) Gy0.67
      Elapsed days of radiation, median (IQR)50 (45–55)51 (47–56)0.51
      Days to start of chemotherapy, median (IQR)N/A36 (25–54)N/A
      Type of chemotherapy
       MultiagentN/A15,715 (86.3%)N/A
       Single-agent/unknownN/A2491 (13.7%)N/A
      Type of chemoradiation
       ConcurrentN/A15,840 (87.0%)N/A
       SequentialN/A2366 (13.0%)N/A
      IQR, interquartile range; N/A, not applicable.
      a The p values are from the χ2 test for categorical variables and the t test for continuous variables.

      Predictors of Receiving CRT versus RT

      We identified both clinical and demographic variables associated with elderly patients receiving definitive CRT treatment (Supplementary Table 1). On univariate analysis, younger age, male sex, white race, higher income, living in a nonmetropolitan county, stage IIIB disease, increased distance from the treating hospital, and a Charlson-Deyo score less than 1 were associated with higher odds of receiving CRT. All of these covariates, except for living in a metropolitan county, were independently associated with higher odds of receiving CRT on multivariate logistic regression analysis and were used to calculate propensity scores. After PSM, the propensity score distributions between the two groups showed nearly ideal common support (Supplementary Fig. 1A). The covariates were well balanced between the two treatment groups after PSM with standardized differences between the covariates well below 10% (Supplementary Table 2).

      Predictors of Receiving CCRT versus SCRT

      Supplementary Table 3 demonstrates that among patients in the CRT group, factors associated with receipt of CCRT compared with SCRT included male sex, treatment at a nonacademic treatment facility, stage IIIA disease, and higher comorbidity index. All of these factors remained significant on multivariate logistic regression analysis and were used to calculate propensity scores. Supplementary Figure 1B and Supplementary Table 4 demonstrate that PSM resulted in well-balanced groups.

      Survival Outcomes in the CRT Cohort versus in the RT Cohort

      At the time of analysis, 19,041 of the 23,229 patients had died. The median follow-up for all elderly patients was 15.5 months (IQR 8.3–28.8 months) and the median follow-up for survivors was 30.7 months (IQR 19.1–49.8 months). We used Cox univariate and multivariate analyses to identify patient and treatment factors associated with OS (Supplementary Table 5). Factors independently associated with improved OS included younger age, female sex, nonwhite race, treatment at an academic facility, higher income, living in a metropolitan county, stage IIIA versus stage IIIB disease, closer distance to the treatment hospital, Charlson-Deyo score less than 1, longer time to start of RT, and CRT versus RT alone.
      Before PSM, the median OS was 18.1 months (95% confidence interval [CI]: 17.8–18.5 months) for patients treated with CRT and 12.2 months (95% CI: 11.7–12.6 months) for patients treated with RT (p < 0.001) (Fig. 2A). With PSM, a CRT therapy match was successfully identified for 4718 of the 5023 patients treated with RT (caliper size of 0.03 based on a propensity score SD of 0.13). In the matched cohort, the survival advantage of CRT over RT alone persisted, with median OS times of 17.2 months (95% CI: 16.6–17.8) and 12.2 months (95% CI: 11.8–12.6), respectively (p < 0.001) (Fig. 2B).
      Figure thumbnail gr2
      Figure 2Overall survival of patients treated with definitive chemoradiation (CRT) compared with that of patients treated with definitive radiation therapy (RT) alone. Unmatched patient population (A) and propensity score–matched elderly patients (B). All curves represent actual survival as estimated by the Kaplan-Meier method.
      On univariate analysis in the matched cohort of elderly patients receiving CRT versus RT, factors associated with worse OS included older age, male sex, white race, nonacademic treatment facility, nonmetropolitan location, stage IIIB disease, Charlson-Deyo score higher than 0, and treatment with RT alone (Supplementary Table 6). After adjustment for confounders, CRT corresponded to a 33% reduction in the risk for death (hazard ratio [HR] = 0.67, 95% CI: 0.64–0.70, p < 0.001) (Table 2). The benefit of CRT was greater for elderly patients treated with multiagent chemotherapy (HR = 0.64, 95% CI: 0.61–0.67, p < 0.001) (Fig. 3B and Table 2) than for those treated with single-agent chemotherapy (HR = 0.83, 95% CI: 0.75–0.92, p < 0.001) (Fig. 3A and Table 2). As demonstrated in Figure 3C and Table 2, for elderly patients treated with CRT, multiagent chemotherapy resulted in a 21% decrease in the HR for death compared with that for patients treated with single-agent chemotherapy (HR = 0.79, 95% CI: 0.71–0.88, p < 0.001).
      Table 2Multivariate Analysis of Overall Survival for Chemoradiation versus Radiation Therapy Alone and Concurrent Chemoradiation versus Sequential Chemotherapy and Radiation after Propensity Score Matching
      VariableCRT vs. RT Cohorts (n = 9436)CCRT vs. SCRT Cohorts (n = 4732)
      HR95% CIp ValueHR95% CIp Value
      Age1.011.01–1.02<0.0011.021.01–1.02<0.001
      Female vs. male0.840.81–0.88<0.0010.820.77–0.88<0.001
      White vs. nonwhite1.181.10–1.26<0.0011.121.01–1.240.03
      Academic vs. nonacademic0.950.90–1.000.050.900.84–0.970.005
      Private vs. nonprivate insuranceNSNSNSNSNSNS
      Median income (≥$48,000 vs. <$48,000)0.960.91–1.000.070.960.90–1.030.23
      County location (metropolitan vs. nonmetropolitan)0.970.91–1.020.230.980.90–1.060.58
      Clinical stage IIIB vs. stage IIIA1.181.12–1.23<0.0011.161.09–1.24<0.001
      Distance to closest facility
      Log of distance (miles) used for analysis.
      NSNSNSNSNSNS
      Charlson-Deyo score (1 vs. 0)1.081.03–1.13<0.0011.151.08–1.23<0.001
      CRT vs. RT alone0.670.64–0.70<0.001N/AN/AN/A
      SCRT vs. CCRTN/AN/AN/A0.910.85–0.960.002
      Single-agent CRT vs. RT alone0.830.75–0.92<0.001N/AN/AN/A
      Multiagent CRT vs. RT alone0.640.61–0.67<0.001N/AN/AN/A
      Multiagent vs. Single-agent chemotherapy
      In patients receiving chemoradiation.
      0.790.71–0.88<0.0010.740.65–0.960.002
      Days to start of radiation
      HR is 0.996 (95% confidence interval, 0.995–0.997).
      1.001.00–1.00<0.001N/AN/AN/A
      CRT, chemoradiation; RT, radiation therapy; CCRT, concurrent chemoradiation; SCRT, sequential chemotherapy and radiation; HR, hazard ratio; CI, confidence interval; NS, p value > 0.10 on univariate analysis; N/A, not applicable.
      a Log of distance (miles) used for analysis.
      b In patients receiving chemoradiation.
      c HR is 0.996 (95% confidence interval, 0.995–0.997).
      Figure thumbnail gr3
      Figure 3Overall survival of patients treated with either single-agent (sCRT) or multiagent chemoradiation (mCRT) compared with that of patients treated with radiation therapy alone (RT). (A) Comparison of sCRT versus definitive RT alone. (B) mCRT versus definitive RT alone. (C) Comparison of mCRT versus sCRT. All analysis was performed using the propensity score–matched patients, and all curves represent actual survival as estimated by the Kaplan-Meier method.

      Survival Outcomes in Patients Treated with CCRT versus with SCRT

      Elderly patients treated with definitive CRT were further subdivided into those treated with CCRT and those treated with SCRT on the basis of timing of initiation of radiation and chemotherapy. Of the 18,203 patients treated with definitive CRT, 15,840 received CCRT and 2366 received SCRT. The median OS was significantly higher in patients treated with SCRT than in those treated with CCRT: 20.0 months (95% CI: 19.1–20.9) versus 17.8 months (95% CI: 17.4–18.2) (p < 0.001) (Fig. 4A). PSM identified a CCRT match for all 2366 patients treated with SCRT (caliper size of 0.004 based on a propensity score SD of 0.02). Supplementary Table 6 demonstrates the univariate OS analysis in the matched CCRT versus SCRT cohorts. On multivariate analysis, SCRT corresponded to a 9% reduction in the risk for death (HR = 0.91, 95% CI: 0.85–0.96, p = 0.002) (Table 2 and Fig. 4B). We performed a sensitivity analysis in which the definition of CCRT was restricted to patients who received chemotherapy within 14 days of the initiation of RT, and the survival benefit of SCRT over CCRT persisted.
      Figure thumbnail gr4
      Figure 4Overall survival of patients treated with definitive concurrent chemoradiation (Con CRT) and definitive sequential chemoradiation (Seq CRT). Unmatched patient population (A) versus propensity score–matched elderly patients (B). All curves represent actual survival as estimated by the Kaplan-Meier method.

      Discussion

      Treatment of elderly individuals with locally advanced NSCLC is challenging, and with an aging population, it will remain an issue for the U.S. health care system for the foreseeable future.
      • Pallis A.G.
      • Gridelli C.
      • Wedding U.
      • et al.
      Management of elderly patients with NSCLC; updated expert's opinion paper: EORTC Elderly Task Force, Lung Cancer Group and International Society for Geriatric Oncology.
      To our knowledge, our study represents the largest reported cohort of elderly patients with stage III NSCLC not treated surgically. We found that combined modality therapy with radiation and chemotherapy results in improved OS compared with radiation alone in elderly patients and that sequential therapy appears superior to concurrent therapy.
      We found a significant OS benefit with the addition of chemotherapy to definitive RT, with a 33% reduction in risk of death. Prior studies evaluating combined modality therapy in elderly patients have reported conflicting results. For example, a retrospective study using the Netherlands Cancer Registry also evaluated elderly (≥70 years old) patients with unresectable stage III NSCLC and reported no survival benefit with CCRT and increased toxicity.
      • Driessen E.J.
      • Bootsma G.P.
      • Hendriks L.E.
      • et al.
      Stage III non-small cell lung cancer in the elderly: patient characteristics predictive for tolerance and survival of chemoradiation in daily clinical practice.
      In contrast, a second analysis of patients aged 65 years or older compared CCRT with RT alone and demonstrated a survival benefit (13.7 versus 10.5 months [p = .05]) for CRT compared with for RT alone.
      • Schild S.E.
      • Mandrekar S.J.
      • Jatoi A.
      • et al.
      The value of combined-modality therapy in elderly patients with stage III nonsmall cell lung cancer.
      However, the rates of grade 3 or higher toxicity were significantly higher in the CRT group (89.9%) versus in the RT-alone group (32.4%). Similarly, Davidoff et al. found that CRT had a significant survival benefit when compared to RT alone (12.0 versus 7.6 months) in patients 66 years of age and older.
      • Davidoff A.J.
      • Gardner J.F.
      • Seal B.
      • Edelman M.J.
      Population-based estimates of survival benefit associated with combined modality therapy in elderly patients with locally advanced non-small cell lung cancer.
      In general, limited prospective data of CRT versus RT alone in elderly patients with stage III NSCLC exist. Two trials from Japan have evaluated CRT versus RT in elderly patients, the first of which was stopped early on account of four deaths in the CRT arm.
      • Atagi S.
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      • Tamura T.
      • et al.
      Standard thoracic radiotherapy with or without concurrent daily low-dose carboplatin in elderly patients with locally advanced non-small cell lung cancer: a phase III trial of the Japan Clinical Oncology Group (JCOG9812).
      In a subsequent phase III trial that completed accrual, Atagi et al. found that CRT improved OS compared to RT alone in 197 patients older than 70 years (HR = 0.68).
      • Atagi S.
      • Kawahara M.
      • Yokoyama A.
      • et al.
      Thoracic radiotherapy with or without daily low-dose carboplatin in elderly patients with non-small-cell lung cancer: a randomised, controlled, phase 3 trial by the Japan Clinical Oncology Group (JCOG0301).
      The chemotherapy in this trial included single-agent low-dose carboplatin (30 mg/m2 for 20 days). There were higher rates of grade 3 or 4 hematologic toxicity and grade 3 infection in the CRT group, although rates of grade 3 or 4 radiation pneumonitis and late lung toxicity were similar between the groups. In a recent meta-analysis of the 243 patients treated on both Japanese trials and an additional 164 elderly patients from the 2006 analysis of CRT using platinum compounds that was reported by Auperin et al., the use of CRT was associated with a 34% reduction in the HR for death, which is similar to the 33% reduction seen in our study that included over 9,000 patients in the matched cohort.
      • Dawe D.E.
      • Christiansen D.
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      • et al.
      Chemoradiotherapy versus radiotherapy alone in elderly patients with stage III non-small cell lung cancer: a systematic review and meta-analysis.
      Additionally, we found a modest but significant 15% reduction in the risk for death when nonstandard single-agent chemotherapy is used.
      In this NCDB analysis, we found that survival in elderly patients treated with SCRT had a 9% reduction in risk for death compared with CCRT. This finding is in contrast to the results of the 2010 meta-analysis by Auperin et al., which demonstrated an OS benefit with CCRT versus with SCRT for patients with locally advanced NSCLC.
      • Auperin A.
      • Le Pechoux C.
      • Rolland E.
      • et al.
      Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer.
      Elderly individuals were underrepresented in that analysis, with only 15% of patients age 70 years or older. Our results were similar to those from the Surveillance, Epidemiology, and End Results–Medicare database study reported by Davidoff et al., which that found an increased mortality risk with CCRT compared with that with SCRT.
      • Davidoff A.J.
      • Gardner J.F.
      • Seal B.
      • Edelman M.J.
      Population-based estimates of survival benefit associated with combined modality therapy in elderly patients with locally advanced non-small cell lung cancer.
      However, this finding from our analysis must be taken with caution. Because the NCDB does not collect duration of chemotherapy treatment, it is not possible to determine whether patients in the SCRT group received combined modality therapy at the time of radiation.
      The toxicity of combined modality therapy is a central issue in the management of elderly patients.
      • Stinchcombe T.E.
      • Zhang Y.
      • Vokes E.E.
      • et al.
      Pooled analysis of individual patient data on concurrent chemoradiotherapy for stage III non-small-cell lung cancer in elderly patients compared with younger patients who participated in US National Cancer Institute cooperative group studies.
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      Several studies have found significantly higher rates of toxicity in patients receiving CRT versus RT alone.
      • Driessen E.J.
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      In a recent pooled analysis of patients with stage III NSCLC treated with CRT in one of 16 U.S. National Cancer Institute cooperative group studies, the 832 elderly patients (≥70 years old) experienced more toxicity, a higher rate of treatment-related death, and worse OS compared with the 2768 nonelderly patients.
      • Stinchcombe T.E.
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      • et al.
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      Given the strict eligibility criteria and close follow-up required in clinical trials, the rates of adverse events and/or deaths and survival outcomes are likely worse in the nonclinical trial elderly population. Nonetheless, our results demonstrate that elderly patients treated with CRT had survival superior to that of elderly patients treated with RT alone. This underscores the importance of identifying and incorporating tools such as the Comprehensive Geriatric Assessment or Vulnerable Elders Survey-13 into the treatment decision-making process.
      • Pallis A.G.
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      • et al.
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      • et al.
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      Completion of the Comprehensive Geriatric Assessment can help predict risk for toxicity with treatment, and it can be used to fine-tune treatment recommendations
      • Puts M.T.
      • Hardt J.
      • Monette J.
      • Girre V.
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      ; its use has been endorsed by the International Society for Geriatric Oncology and the European Organization for Research and Treatment of Cancer.
      • Pallis A.G.
      • Fortpied C.
      • Wedding U.
      • et al.
      EORTC Elderly Task Force position paper: approach to the older cancer patient.
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      This study has several limitations. The NCDB is a retrospective database with inherent weaknesses that include incomplete data, selection bias, and unmeasured confounders. One major limitation of the NCDB is that performance status is not captured. Instead, the Charlson-Deyo score, which measures the number of comorbidities that each patient has, is collected. We fully recognize that there is no single variable or group of variables in any data set that can accurately reflect the treatment decision for an individual patient. Therefore, although PSM was utilized to minimize treatment selection bias, imbalances in unmeasured variables between the treatment cohorts likely remain. The NCDB does not collect several key chemotherapy details, including specific agents used and the duration/number of cycles delivered. This makes it impossible to determine whether patients received consolidation chemotherapy. Also, although an OS benefit was observed with definitive CRT versus with definitive RT alone, there are no available data in the NCDB regarding critically important end points of toxicity, quality of life, and cause of death.
      Nonetheless, we feel that there are several strengths to be noted. This is by far the largest analysis of CRT versus RT (and CCRT versus SCRT) in elderly patients to date. Although chemotherapy details are limited in the NCDB, the RT data are much more complete. The RT doses captured in the NCDB are those that were delivered, not those intended, and we ensured that patients received definitive doses of RT (≥59.4 Gy) to be included in this analysis. Although the exact chemotherapy regimen is not reported, the NCDB does collect data on whether one agent or more than one agent was used. We feel that the analysis of survival by number of chemotherapy agents used provides a useful framework for how to approach the elderly patient with stage III NSCLC.
      Treatment of elderly patients with stage III NSCLC should involve a multidisciplinary discussion. All patients not eligible for surgery should first be considered for CRT, with either concurrent or sequential radiation. On the basis of our findings, multiagent chemotherapy is preferred over single-agent regimens in suitable patients. When multiagent chemotherapy is not feasible, a single-agent regimen is supported by our results, as well as by those of Atagi et al.
      • Atagi S.
      • Kawahara M.
      • Yokoyama A.
      • et al.
      Thoracic radiotherapy with or without daily low-dose carboplatin in elderly patients with non-small-cell lung cancer: a randomised, controlled, phase 3 trial by the Japan Clinical Oncology Group (JCOG0301).
      When chemotherapy is contraindicated or not recommended, definitive RT alone should be considered.
      In conclusion, we found that definitive CRT is superior to definitive RT in elderly patients with stage III NSCLC not treated surgically. We also found that in patients who received CRT, sequential chemotherapy and RT resulted in better OS than in those who received CCRT. Although the optimal methodology for deciding on appropriate therapy in these patients is unknown, future clinical trials in stage III NSCLC should prioritize inclusion of elderly patients to help further tailor therapeutic decisions for this expanding patient population.

      Acknowledgments

      This work was supported in part by the National Institutes of Health (grant P30 CA16058).

      Supplementary Data

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