Accepted Manuscript The Effect of Radiotherapy Dose on Survival in Stage III Non-Small Cell Lung Cancer Patients undergoing Definitive Chemoradiotherapy M. Koshy , MD R. Malik , MD D.J. Sher , MD, MPH M. Spiotto , MD, Ph.D U. Mahmood , MD B. Ayodgan , Ph.D R.R. Weichselbaum , MD PII:
S1525-7304(14)00111-9
DOI:
10.1016/j.cllc.2014.05.004
Reference:
CLLC 280
To appear in:
Clinical Lung Cancer
Received Date: 1 April 2014 Revised Date:
7 May 2014
Accepted Date: 19 May 2014
Please cite this article as: Koshy M, Malik R, Sher DJ, Spiotto M, Mahmood U, Ayodgan B, Weichselbaum RR, The Effect of Radiotherapy Dose on Survival in Stage III Non-Small Cell Lung Cancer Patients undergoing Definitive Chemoradiotherapy, Clinical Lung Cancer (2014), doi: 10.1016/ j.cllc.2014.05.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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M. Koshy MD1,2, R. Malik MD2, D. J. Sher MD, MPH3, M. Spiotto MD, Ph.D1,2, U. Mahmood MD4,
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B. Ayodgan Ph.D1,2, R. R. Weichselbaum MD1,2
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Department of Radiation Oncology, University of Illinois at Chicago, Chicago, IL, USA. Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL, USA. 3 Department of Radiation Oncology, Rush University Medical Center, Chicago, IL, USA 4 Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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The Effect of Radiotherapy Dose on Survival in Stage III Non-Small Cell Lung Cancer Patients undergoing Definitive Chemoradiotherapy
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Sources of Funding: None
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Running Title: Radiation Dose in Stage III Lung Cancer
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Keywords: Chemoradiation, Lung, Dose
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Corresponding Author:
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Dr. Matthew Koshy
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Department of Radiation and Cellular Oncology
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University of Chicago
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5758 South Maryland Avenue, M/C 9006,
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Chicago, IL 60637, USA
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Email: [email protected]
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Phone: (312) 996-3631
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Fax:
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Conflict of Interest: All authors state they have no conflict of interest.
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ACCEPTED MANUSCRIPT 3 Microabstract: This study examined if increasing radiation doses was associated with improved
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survival in patients with clinical stage III lung cancer in the National Cancer Database treated
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with definitive concurrent chemoradiation. There was no survival benefit associated with increasing
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radiotherapy doses greater than 59.4Gy.
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ACCEPTED MANUSCRIPT 4 Abstract:
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Background:
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This study examined trends in the radiotherapy dose prescribed and the impact of dose escalation on
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survival in patients with stage III lung cancer.
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Methods:
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Radiation dose prescription patterns were analyzed for 38,848 patients in the National Cancer Database
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with clinical stage III disease who underwent concurrent chemoradiation between 2004-2011 to a dose
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between 57-80Gy. Survival information was available for patients diagnosed from 2004-2006 (n =
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12,024). Overall survival (OS) was estimated using Kaplan Meier methods. Cox proportional hazard
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regression was used to estimate hazard ratios (HR).
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Results:
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The percentage of patients treated to ≥ 64Gy increased from 50% in 2004 to 62% in 2011 (p < 0.001).
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The five year OS was 12% for patients treated between 57-59.3Gy, 14% for 59.4-62.9Gy, 16% for 63-
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66Gy, 16% for 66.1-73.9Gy, and 13% for 74-80Gy (p< 0.0001). On multivariate analysis, the estimated
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HR (95% Confidence Interval) was 1.3 (1.1-1.6) for 57-59.3Gy, 1.0 (0.9-1.2) for 59.4-62.9Gy, 0.9 (0.9-1.2)
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for 63-66Gy, 0.9 (0.8-1.1) for 66.1-73.9Gy and 1.0 (ref) for the 74-80Gy cohort. There was no significant
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difference in the HR for the dose groups above 59.4Gy when compared to the 74-80Gy cohort.
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Conclusions:
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There was no improvement in overall survival with radiotherapy dose escalation beyond 59.4Gy for
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patients with unresectable clinical stage III lung cancer treated with chemoradiaton.
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Introduction The treatment of unresectable clinical stage III non-small lung cancer (NSCLC) with definitive chemoradiation is associated with a poor prognosis. The goals of therapy include treatment of
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micrometastatic disease with chemotherapy and control of thoracic disease with radiation therapy 1, 2.
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Radiation dose escalation may further improve control of thoracic disease by increasing tumor
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cell kill in order to improve overall survival. Non-randomized prospective trials as well as a meta-analysis
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have confirmed this dose escalation hypothesis revealing that higher radiotherapy doses were
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associated with improved local control and survival 3-6. However, a recent phase III study compared the
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standard dose of 60Gy to the high dose of 74Gy and found no benefit with higher doses of radiation 7.
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Given these conflicting results, the optimal radiotherapy dose remains unclear. Furthermore, it is
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unknown whether an intermediate dose level that lies between 60Gy to 74Gy is associated with an
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improved survival.
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To address these contrary observations, this study used the National Cancer Database to analyze the patterns of prescribed radiation dose in order to determine the extent to which radiation dose
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impacted survival among patients with unresectable stage III disease. This allowed for an analysis of a
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much larger cohort of patients treated with a variety of different radiation doses compared to
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previously published studies.
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Methods
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The study examined the National Cancer Database (NCDB) which is a hospital based cancer
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registry that collects data from the American College of Surgeons (ACos) Commission on Cancer (CoC)
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accredited facilities 8. The database is jointly sponsored by the ACoS and the American Cancer Society. It
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includes approximately 70% of all malignant cancers diagnosed in the United States. The database
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status, first course of treatment, and overall survival. The NCDB collects data using national
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standardized procedures and uses the same data elements, definitions and transmission standards as
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other national cancer registry systems including the National Cancer Institute Surveillance, Epidemiology
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and End Results (SEER) program and the National Program of Cancer Registries 9. Furthermore, the
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NCDB has established specific criteria to ensure the data submitted meets certain quality benchmarks.
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Data and Study Population
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Eligible patients had histologically confirmed first primary non-small cell lung cancer and
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received all or part of their first course of treatment at ACoS Coc accredited facilities 10. In the database,
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there were 186,139 patients aged 19 years and older with clinical stage III disease treated from 2004-
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2011 who did not undergo surgery. Cohorts which were excluded included 15.8% of patients who
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underwent no therapy, 15.7% who underwent chemotherapy alone, 9.5% who underwent radiation
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therapy alone, 22.7% who underwent sequential chemotherapy and radiation, and 15.5 % who had
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inadequate radiation dose information. The final cohort consisted 38,848 patients who underwent
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definitive concurrent chemoradiotherapy and received a total radiotherapy dose between 57Gy – 80Gy.
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A dose of 57-80Gy was selected as a range based on the commonly used radiation doses in previously
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published phase II and III studies that examined definitive chemoradiotherapy 2, 6, 11-17.
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The ACoS CoC requires programs to have a minimum of 5 years of follow-up for each patient
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before recording information on survival. After the initial 5 year follow, the vital status and follow-up
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time are updated on an annual basis. Therefore, the survival analysis was only conducted on patients
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diagnosed from 2004-2006 and included 12,024 patients. Risk factors included in the analysis included
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total radiation dose, histology, T stage, N stage (according to the 6th edition American Joint Committee
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on Cancer Stage), age at diagnosis, gender, insurance type, race/ethnicity, and facility type. The
ACCEPTED MANUSCRIPT 7 Charleson-Deyo index was computed to permit adjustment for comorbidities. The follow-up time was
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defined as the time from diagnosis to date of death from any cause or from diagnosis to date of last
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contact for those who were alive at last contact. The variables and categorizations used were based on
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previously published data sets examining prognostic factors in lung cancer patients 18, 19. Four groups
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based on radiation dose were formed as follows: 1. 57-59.3Gy represented an under dose compared to
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the standard dose in phase III studies, 2. 59.4-62.9Gy represented the standard dose used on phase III
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studies, 3. 63Gy to 66Gy and 4. 66.1Gy-73.9Gy represented two higher dose groups compared to the
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standard and 4. 74-80Gy represented the high dose studied on phase II and III studies. Three types of
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treatment facilities were included in the classification scheme used by the CoC accreditation program
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and include 1. Community cancer programs, 2. Comprehensive community cancer programs and 3.
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Academic Research Programs. Community cancer centers treat at least 300 cancer patients a year, and
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comprehensive community cancer programs treat 650 patients annually. Academic research programs
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are affiliated with medical schools, have residency programs, conduct research and have no minimum
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caseload requirements.
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Statistical Analysis
Estimates of overall survival stratified by the radiation dose received were calculated using the
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Kaplan-Meier survival estimates. The long-rank test was utilized to estimate whether there were
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differences in overall survival by radiation dose. Differences by patient and facility characteristics were
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estimated using the chi-squared test. All statistical tests were two sided, and a 0.05 level of significance
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was used.
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Multivariable Cox proportional hazards (PHs) regression models were used to assess the
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importance of the radiation dose group as an independent predictor of overall survival. All statistically
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significant data on patient and facility characteristics on univariate analysis were included in the
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estimated in models adjusting for the covariates of interest. Radiation dose could not be analyzed as a
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continuous variable because the doses analyzed from 57-80Gy were not equally distributed. To further
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explore the effect of radiation dose on survival, a separate multivariable hazard model was used with 10
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dose categories with each category representing 10% of the cohort (Decile analysis). Data were analyzed
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using SAS version 9.3 and JMP version 10 (SAS Institute, Cary, NC).
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Results
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A total of 38,848 of patients were included in the analysis examining radiation dose practice
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patterns from 2004-2011. The median radiotherapy dose was 64.8Gy. The median number of fractions delivered was 35. The median overall time for radiation treatment was 52 days. Figure 1 shows the
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distribution of the radiation doses among the cohort. The percentage of patients receiving ≥ 64Gy was
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50% in 2004 and increased to 62% in 2011, (p < 0.001) (Figure 2).
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The survival analysis was performed on patients who had at least a minimum of 5 years of follow-up (patients diagnosed from 2004-2006) and included 12,024 patients. The median follow-up was
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68 months in surviving patients. The median age at diagnosis was 66. Patient characteristics for those
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included in the survival analysis are shown in Table 1. The median and five year overall survival (OS) for the cohort was 16.8 months and 15%. The five
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year OS was 12% for patients treated between 57-59.3Gy, 14% for 59.4-62.9Gy, 16% for 63-66Gy, 16%
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for 66.1-73.9Gy, and 13% for 74-80Gy (p< 0.0001) (Figure 3).
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On multivariate analysis (performed on patients diagnosed from 2004-2006), the estimated HR
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(95% Confidence Interval) was 1.3 (1.1-1.6) for 57-59.3Gy, 1.0 (0.9-1.2) for 59.4-62.9Gy, 0.9 (0.8-1.1) for
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63-73.9Gy and 1.0 (ref) for the 74-80Gy cohort (Table 2). There was no significant difference in the HR
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analysis performed with 10 dose categories (decile analysis) with each category representing 10% of the
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cohort also found no significant difference in the HR for groups treated above 59.4Gy when compared to
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the 74-80Gy group.
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Discussion
This study revealed that radiation dose escalation greater than 59.4Gy did not impact survival in
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patients with stage III NSCLC treated with definitive chemoradiation. Standard concurrent
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chemoradiation is associated with a local failure rate of approximately 30% 12, 16, 20-24. Groups have
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hypothesized that radiation dose escalation would increase tumor cell kill which would lead to improved
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survival 3, 25-27. There were several non-randomized prospective studies that examined radiation dose
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escalation above 74Gy and reported encouraging results with an improved overall survival compared to
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historical cohorts. However, these favorable outcomes may have biased by more advanced imaging such
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as PET and brain MRI that were used in the more modern studies but were not used in the historical
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cohorts2, 6, 7, 15, 28.
RTOG 0617 was a phase III study which compared high dose (74Gy) vs. standard dose radiation
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(60Gy) as one of its study endpoints. It revealed a worse median overall survival of 19.5 months for the
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74Gy arm vs. 28.7 months for the 60Gy arm (p = 0.0007) 7. There were 10 treatment related deaths in
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the 74Gy arm vs. 2 treatment related deaths in the 60Gy arm. In contrast, our results revealed no
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survival detriment to using high doses of radiation compared to standard doses. This differences may be
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attributable to the large difference in patient numbers between the two studies (464 patients vs. 12,024
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patients) where regression to the mean is more likely with a greater number of cases. Also, it could be
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explained by the limitation that the observational data is partly confounded by the radiation dose
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received, where physicians were more likely to give smaller volumes higher radiation doses perhaps
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resulting in less treatment related deaths. Following the results of RTOG 0617 it remained unclear whether an intermediate dose between
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60Gy and 74Gy could be associated with an improved survival. The results from this study allowed for
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the comparison of multiple dose levels treated between 57Gy to 80Gy. Importantly, they show no
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intermediate dose between 59.4Gy and 80Gy where survival was improved compared to other dose
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groups. It is likely that the marginal benefit of radiotherapy dose escalation was mitigated by worsening
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toxicity seen with higher radiotherapy doses and the competing risk of systemic failure seen in the
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clinical stage III patient population29. A recent meta-analysis also showed that factors including
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increasing age and the use of carboplatin/paclitaxel chemotherapy could also contribute to worse high
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grade toxicity outcomes among patients who undergo concurrent chemoradiation which could further
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diminish any benefit seen with dose escalation 30. Also, delivery of high radiotherapy doses to the lungs
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is technically challenging and noncompliance with standard radiaton protocol guidelines could also lead
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to worse survival as evidenced by two recent meta-analyses 31, 32.
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Within the past several years there have been a number of advancements in radiotherapy planning and delivery such as the use of intensity modulated radiation therapy (IMRT). As this analysis
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only extends to the year 2006, it likely included only a very few number of patients treated with this
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technique. A recent SEER Medicare analysis compared IMRT to 3D conformal technique and found both
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techniques to be associated with a similar overall survival and similar toxicity risks 33. Previous research
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with the National Cancer Database also found no difference in survival between IMRT and 3D conformal
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techniques 34. Results from the quality of life analysis from RTOG 0617 revealed that 23% of patients
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treated with IMRT had a clinically meaningful decline in patient reported quality of life outcomes
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compared to 47% of patients treated with 3D conformal technique (p=0.005) 35. Further research will be
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needed to determine if advanced techniques such as IMRT can significantly improve the therapeutic
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ratio.
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scans that impact overall survival via stage migration were not included. Nevertheless, we limited our
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survival analysis to 2004-2006 which likely minimized any differences in staging procedures. While all
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patients in this study received chemotherapy concurrent with radiation therapy, we cannot account for
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the types, number of agents and cycles used. Finally, this database also does not have detailed
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information on radiation target volumes, planning margins, and isodose prescriptions. Furthermore,
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there is no information regarding local control, dose to the normal tissues or toxicities.
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This study is the largest observational series to examine the role of dose escalation in stage III non-small cell lung cancer and revealed that radiotherapy doses for stage III lung cancer have increased
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from 2004 to 2011, and that there is no survival benefit towards escalating doses greater than 59.4Gy.
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Clinical Practice Points -
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There is conflicting data regarding the role of dose escalation in patients with stage III nonsmall cell lung cancer undergoing definitive chemoradiation.
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This study found no survival benefit with escalating doses greater than 59.4Gy.
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35. Movsas B, Hu C, Sloan J et al. Quality of life (QOL) analysis of the randomized radiation (RT)
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dose-escalation NSCLC trial (RTOG 0617): The rest of the story. Int J Radiat Oncol Biol Phys
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2013; 87: S1-S2. Available from URL:
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http://linkinghub.elsevier.com/retrieve/pii/S0360301613006822?showall=true.
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Figure Legend: Figure 1: Distribution of Radiation Doses from 2004-2011 Figure 2: Radiation Dose Trends from 2004-2011 Figure 3: Five year overall survival among clinical stage III non-small cell lung cancer patients stratified by dose group, 2004-2006 (n = 12,024) (p < 0.001).
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Categories
Total (n=12,024)
%
Male Female
7117 4907
59.2% 40.8%
White Black Other Hispanic Unknown
10110 1425 218 194 77
84.1% 11.9% 1.8% 1.6% 0.6%
418
3.5%
4211
35.0%
720 6447 228
6.0% 53.6% 1.9%
8410 2747 867
69.9% 22.8% 7.2%
2004 2005 2006
3872 4064 4088
32.2% 33.8% 34.0%
TX T1 T2 T3 T4
378 1586 3867 2119 4074
3.1% 13.2% 32.2% 17.6% 33.9%
N0 N1
1083 712
9.0% 5.9%
Gender
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Not Insured Private Insurance/managed Care Medicaid Medicare Other Government Comorbidities
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Table 1: Patient Characteristics among Clinical Stage III Non-small Cell Lung Cancer Patients, National Cancer Database 2004-2006 (n=12,024)
N Stage
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N2 N3
7569 2660
62.9% 22.1%
3A 3B
5794 6230
48.2% 51.8%
18-59 60-69 70-79 80+
3415 4175 3608 826
28.4% 34.7% 30.0% 6.9%
Large Cell NSCLC NOS Squamous Adenocarcinoma
538 3868 4436 3182
4.5% 32.2% 36.9% 26.5%
286 3827 4180 3512 219
2.4% 31.8% 34.8% 29.2% 1.8%
1629
13.5%
7291
60.6%
3104
25.8%
Age at Diagnosis
57Gy - 59.3Gy 59.4Gy - 62.9Gy 63Gy - 66Gy 66.1Gy – 73.9Gy 74 - 80Gy
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Histology
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Table 2: Multivariate Cox Proportional Hazard Model Predicting Overall Survival among Stage III NSCLC Patients, NCDB 2004-2006 (n=12,024)
Hazard Ratio
95% CI Lower Limit Upper Limit
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1.00 0.92 0.80 0.95
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0.83
0.90
0.86 0.70 0.80
0.97 0.93 1.11
0.89
0.79
0.99
0.97 0.95 0.95
0.85 0.85 0.79
1.10 1.07 1.14
1.00 1.13 1.20
1.08 1.11
1.18 1.29
1.00 0.93 0.91
0.89 0.87
0.97 0.96
1.00 1.48 1.79 1.98 2.10
1.00 1.21 1.34 1.41
2.20 2.65 2.95 3.10
1.00 1.20
1.08
1.34
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1.00 0.86
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1.00
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1.14 1.28
1.33 1.52
1.00 1.04 1.23 1.40
0.98 1.15 1.30
1.10 1.31 1.54
1.00 1.14 1.15 1.12
1.03 1.04 1.00
1.26 1.28 1.24
0.97
0.92
1.03
0.97
0.90
1.02
1.00 1.28 1.03 0.94 0.94
1.06 0.89 0.81 0.81
1.55 1.19 1.08 1.09
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1.23 1.40
1.00
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N2 N3 Age at Diagnosis 19-59 60-69 70-79 80+ Histology Large Cell NSCLC NOS Squamous Adenocarcinoma Facility Type Community Cancer Program Comprehensive Community Cancer Program Academic Research Program Dose Category 74Gy-80Gy 57Gy - 59.3Gy 59.4Gy - 62.9Gy 63Gy - 66Gy 66.1Gy – 73.9Gy
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S1525-7304(14)00111-9
DOI:
10.1016/j.cllc.2014.05.004
Reference:
CLLC 280
To appear in:
Clinical Lung Cancer
Received Date: 1 April 2014 Revised Date:
7 May 2014
Accepted Date: 19 May 2014
Please cite this article as: Koshy M, Malik R, Sher DJ, Spiotto M, Mahmood U, Ayodgan B, Weichselbaum RR, The Effect of Radiotherapy Dose on Survival in Stage III Non-Small Cell Lung Cancer Patients undergoing Definitive Chemoradiotherapy, Clinical Lung Cancer (2014), doi: 10.1016/ j.cllc.2014.05.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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M. Koshy MD1,2, R. Malik MD2, D. J. Sher MD, MPH3, M. Spiotto MD, Ph.D1,2, U. Mahmood MD4,
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B. Ayodgan Ph.D1,2, R. R. Weichselbaum MD1,2
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Department of Radiation Oncology, University of Illinois at Chicago, Chicago, IL, USA. Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL, USA. 3 Department of Radiation Oncology, Rush University Medical Center, Chicago, IL, USA 4 Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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The Effect of Radiotherapy Dose on Survival in Stage III Non-Small Cell Lung Cancer Patients undergoing Definitive Chemoradiotherapy
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Sources of Funding: None
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Running Title: Radiation Dose in Stage III Lung Cancer
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Keywords: Chemoradiation, Lung, Dose
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Corresponding Author:
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Dr. Matthew Koshy
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Department of Radiation and Cellular Oncology
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University of Chicago
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5758 South Maryland Avenue, M/C 9006,
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Chicago, IL 60637, USA
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Email: [email protected]
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Phone: (312) 996-3631
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Fax:
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No. of Words/Characters in Abstract – 214/1425
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No. Of Words/Characters in Manuscript – 3795/25,370
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(312) 996-9265
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Conflict of Interest: All authors state they have no conflict of interest.
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survival in patients with clinical stage III lung cancer in the National Cancer Database treated
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with definitive concurrent chemoradiation. There was no survival benefit associated with increasing
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radiotherapy doses greater than 59.4Gy.
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Background:
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This study examined trends in the radiotherapy dose prescribed and the impact of dose escalation on
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survival in patients with stage III lung cancer.
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Methods:
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Radiation dose prescription patterns were analyzed for 38,848 patients in the National Cancer Database
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with clinical stage III disease who underwent concurrent chemoradiation between 2004-2011 to a dose
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between 57-80Gy. Survival information was available for patients diagnosed from 2004-2006 (n =
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12,024). Overall survival (OS) was estimated using Kaplan Meier methods. Cox proportional hazard
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regression was used to estimate hazard ratios (HR).
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Results:
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The percentage of patients treated to ≥ 64Gy increased from 50% in 2004 to 62% in 2011 (p < 0.001).
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The five year OS was 12% for patients treated between 57-59.3Gy, 14% for 59.4-62.9Gy, 16% for 63-
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66Gy, 16% for 66.1-73.9Gy, and 13% for 74-80Gy (p< 0.0001). On multivariate analysis, the estimated
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HR (95% Confidence Interval) was 1.3 (1.1-1.6) for 57-59.3Gy, 1.0 (0.9-1.2) for 59.4-62.9Gy, 0.9 (0.9-1.2)
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for 63-66Gy, 0.9 (0.8-1.1) for 66.1-73.9Gy and 1.0 (ref) for the 74-80Gy cohort. There was no significant
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difference in the HR for the dose groups above 59.4Gy when compared to the 74-80Gy cohort.
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Conclusions:
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There was no improvement in overall survival with radiotherapy dose escalation beyond 59.4Gy for
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patients with unresectable clinical stage III lung cancer treated with chemoradiaton.
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Introduction The treatment of unresectable clinical stage III non-small lung cancer (NSCLC) with definitive chemoradiation is associated with a poor prognosis. The goals of therapy include treatment of
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micrometastatic disease with chemotherapy and control of thoracic disease with radiation therapy 1, 2.
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Radiation dose escalation may further improve control of thoracic disease by increasing tumor
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cell kill in order to improve overall survival. Non-randomized prospective trials as well as a meta-analysis
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have confirmed this dose escalation hypothesis revealing that higher radiotherapy doses were
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associated with improved local control and survival 3-6. However, a recent phase III study compared the
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standard dose of 60Gy to the high dose of 74Gy and found no benefit with higher doses of radiation 7.
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Given these conflicting results, the optimal radiotherapy dose remains unclear. Furthermore, it is
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unknown whether an intermediate dose level that lies between 60Gy to 74Gy is associated with an
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improved survival.
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To address these contrary observations, this study used the National Cancer Database to analyze the patterns of prescribed radiation dose in order to determine the extent to which radiation dose
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impacted survival among patients with unresectable stage III disease. This allowed for an analysis of a
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much larger cohort of patients treated with a variety of different radiation doses compared to
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previously published studies.
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Methods
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The study examined the National Cancer Database (NCDB) which is a hospital based cancer
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registry that collects data from the American College of Surgeons (ACos) Commission on Cancer (CoC)
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accredited facilities 8. The database is jointly sponsored by the ACoS and the American Cancer Society. It
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includes approximately 70% of all malignant cancers diagnosed in the United States. The database
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status, first course of treatment, and overall survival. The NCDB collects data using national
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standardized procedures and uses the same data elements, definitions and transmission standards as
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other national cancer registry systems including the National Cancer Institute Surveillance, Epidemiology
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and End Results (SEER) program and the National Program of Cancer Registries 9. Furthermore, the
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NCDB has established specific criteria to ensure the data submitted meets certain quality benchmarks.
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Data and Study Population
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Eligible patients had histologically confirmed first primary non-small cell lung cancer and
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received all or part of their first course of treatment at ACoS Coc accredited facilities 10. In the database,
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there were 186,139 patients aged 19 years and older with clinical stage III disease treated from 2004-
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2011 who did not undergo surgery. Cohorts which were excluded included 15.8% of patients who
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underwent no therapy, 15.7% who underwent chemotherapy alone, 9.5% who underwent radiation
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therapy alone, 22.7% who underwent sequential chemotherapy and radiation, and 15.5 % who had
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inadequate radiation dose information. The final cohort consisted 38,848 patients who underwent
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definitive concurrent chemoradiotherapy and received a total radiotherapy dose between 57Gy – 80Gy.
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A dose of 57-80Gy was selected as a range based on the commonly used radiation doses in previously
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published phase II and III studies that examined definitive chemoradiotherapy 2, 6, 11-17.
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The ACoS CoC requires programs to have a minimum of 5 years of follow-up for each patient
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before recording information on survival. After the initial 5 year follow, the vital status and follow-up
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time are updated on an annual basis. Therefore, the survival analysis was only conducted on patients
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diagnosed from 2004-2006 and included 12,024 patients. Risk factors included in the analysis included
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total radiation dose, histology, T stage, N stage (according to the 6th edition American Joint Committee
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on Cancer Stage), age at diagnosis, gender, insurance type, race/ethnicity, and facility type. The
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defined as the time from diagnosis to date of death from any cause or from diagnosis to date of last
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contact for those who were alive at last contact. The variables and categorizations used were based on
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previously published data sets examining prognostic factors in lung cancer patients 18, 19. Four groups
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based on radiation dose were formed as follows: 1. 57-59.3Gy represented an under dose compared to
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the standard dose in phase III studies, 2. 59.4-62.9Gy represented the standard dose used on phase III
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studies, 3. 63Gy to 66Gy and 4. 66.1Gy-73.9Gy represented two higher dose groups compared to the
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standard and 4. 74-80Gy represented the high dose studied on phase II and III studies. Three types of
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treatment facilities were included in the classification scheme used by the CoC accreditation program
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and include 1. Community cancer programs, 2. Comprehensive community cancer programs and 3.
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Academic Research Programs. Community cancer centers treat at least 300 cancer patients a year, and
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comprehensive community cancer programs treat 650 patients annually. Academic research programs
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are affiliated with medical schools, have residency programs, conduct research and have no minimum
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caseload requirements.
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Statistical Analysis
Estimates of overall survival stratified by the radiation dose received were calculated using the
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Kaplan-Meier survival estimates. The long-rank test was utilized to estimate whether there were
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differences in overall survival by radiation dose. Differences by patient and facility characteristics were
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estimated using the chi-squared test. All statistical tests were two sided, and a 0.05 level of significance
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was used.
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Multivariable Cox proportional hazards (PHs) regression models were used to assess the
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importance of the radiation dose group as an independent predictor of overall survival. All statistically
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significant data on patient and facility characteristics on univariate analysis were included in the
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estimated in models adjusting for the covariates of interest. Radiation dose could not be analyzed as a
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continuous variable because the doses analyzed from 57-80Gy were not equally distributed. To further
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explore the effect of radiation dose on survival, a separate multivariable hazard model was used with 10
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dose categories with each category representing 10% of the cohort (Decile analysis). Data were analyzed
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using SAS version 9.3 and JMP version 10 (SAS Institute, Cary, NC).
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Results
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patterns from 2004-2011. The median radiotherapy dose was 64.8Gy. The median number of fractions delivered was 35. The median overall time for radiation treatment was 52 days. Figure 1 shows the
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distribution of the radiation doses among the cohort. The percentage of patients receiving ≥ 64Gy was
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50% in 2004 and increased to 62% in 2011, (p < 0.001) (Figure 2).
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The survival analysis was performed on patients who had at least a minimum of 5 years of follow-up (patients diagnosed from 2004-2006) and included 12,024 patients. The median follow-up was
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68 months in surviving patients. The median age at diagnosis was 66. Patient characteristics for those
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included in the survival analysis are shown in Table 1. The median and five year overall survival (OS) for the cohort was 16.8 months and 15%. The five
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year OS was 12% for patients treated between 57-59.3Gy, 14% for 59.4-62.9Gy, 16% for 63-66Gy, 16%
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for 66.1-73.9Gy, and 13% for 74-80Gy (p< 0.0001) (Figure 3).
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On multivariate analysis (performed on patients diagnosed from 2004-2006), the estimated HR
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(95% Confidence Interval) was 1.3 (1.1-1.6) for 57-59.3Gy, 1.0 (0.9-1.2) for 59.4-62.9Gy, 0.9 (0.8-1.1) for
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63-73.9Gy and 1.0 (ref) for the 74-80Gy cohort (Table 2). There was no significant difference in the HR
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analysis performed with 10 dose categories (decile analysis) with each category representing 10% of the
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cohort also found no significant difference in the HR for groups treated above 59.4Gy when compared to
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the 74-80Gy group.
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Discussion
This study revealed that radiation dose escalation greater than 59.4Gy did not impact survival in
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patients with stage III NSCLC treated with definitive chemoradiation. Standard concurrent
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chemoradiation is associated with a local failure rate of approximately 30% 12, 16, 20-24. Groups have
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hypothesized that radiation dose escalation would increase tumor cell kill which would lead to improved
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survival 3, 25-27. There were several non-randomized prospective studies that examined radiation dose
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escalation above 74Gy and reported encouraging results with an improved overall survival compared to
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historical cohorts. However, these favorable outcomes may have biased by more advanced imaging such
13
as PET and brain MRI that were used in the more modern studies but were not used in the historical
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cohorts2, 6, 7, 15, 28.
RTOG 0617 was a phase III study which compared high dose (74Gy) vs. standard dose radiation
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(60Gy) as one of its study endpoints. It revealed a worse median overall survival of 19.5 months for the
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74Gy arm vs. 28.7 months for the 60Gy arm (p = 0.0007) 7. There were 10 treatment related deaths in
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the 74Gy arm vs. 2 treatment related deaths in the 60Gy arm. In contrast, our results revealed no
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survival detriment to using high doses of radiation compared to standard doses. This differences may be
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attributable to the large difference in patient numbers between the two studies (464 patients vs. 12,024
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patients) where regression to the mean is more likely with a greater number of cases. Also, it could be
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explained by the limitation that the observational data is partly confounded by the radiation dose
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received, where physicians were more likely to give smaller volumes higher radiation doses perhaps
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resulting in less treatment related deaths. Following the results of RTOG 0617 it remained unclear whether an intermediate dose between
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60Gy and 74Gy could be associated with an improved survival. The results from this study allowed for
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the comparison of multiple dose levels treated between 57Gy to 80Gy. Importantly, they show no
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intermediate dose between 59.4Gy and 80Gy where survival was improved compared to other dose
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groups. It is likely that the marginal benefit of radiotherapy dose escalation was mitigated by worsening
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toxicity seen with higher radiotherapy doses and the competing risk of systemic failure seen in the
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clinical stage III patient population29. A recent meta-analysis also showed that factors including
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increasing age and the use of carboplatin/paclitaxel chemotherapy could also contribute to worse high
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grade toxicity outcomes among patients who undergo concurrent chemoradiation which could further
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diminish any benefit seen with dose escalation 30. Also, delivery of high radiotherapy doses to the lungs
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is technically challenging and noncompliance with standard radiaton protocol guidelines could also lead
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to worse survival as evidenced by two recent meta-analyses 31, 32.
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only extends to the year 2006, it likely included only a very few number of patients treated with this
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technique. A recent SEER Medicare analysis compared IMRT to 3D conformal technique and found both
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techniques to be associated with a similar overall survival and similar toxicity risks 33. Previous research
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with the National Cancer Database also found no difference in survival between IMRT and 3D conformal
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techniques 34. Results from the quality of life analysis from RTOG 0617 revealed that 23% of patients
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treated with IMRT had a clinically meaningful decline in patient reported quality of life outcomes
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compared to 47% of patients treated with 3D conformal technique (p=0.005) 35. Further research will be
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needed to determine if advanced techniques such as IMRT can significantly improve the therapeutic
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ratio.
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scans that impact overall survival via stage migration were not included. Nevertheless, we limited our
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survival analysis to 2004-2006 which likely minimized any differences in staging procedures. While all
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patients in this study received chemotherapy concurrent with radiation therapy, we cannot account for
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the types, number of agents and cycles used. Finally, this database also does not have detailed
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information on radiation target volumes, planning margins, and isodose prescriptions. Furthermore,
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there is no information regarding local control, dose to the normal tissues or toxicities.
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This study is the largest observational series to examine the role of dose escalation in stage III non-small cell lung cancer and revealed that radiotherapy doses for stage III lung cancer have increased
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from 2004 to 2011, and that there is no survival benefit towards escalating doses greater than 59.4Gy.
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Clinical Practice Points -
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There is conflicting data regarding the role of dose escalation in patients with stage III nonsmall cell lung cancer undergoing definitive chemoradiation.
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This study found no survival benefit with escalating doses greater than 59.4Gy.
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1. Videtic GM. Locally advanced non-small cell lung cancer: What is the optimal concurrent
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chemoradiation regimen? Cleve Clin J Med 2012;79 Electronic Suppl 1: eS32-7.
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2. Stinchcombe TE, Bogart JA. Novel approaches of chemoradiotherapy in unresectable stage
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IIIA and stage IIIB non-small cell lung cancer. Oncologist 2012;17: 682-693.
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3. Machtay M, Bae K, Movsas B et al. Higher biologically effective dose of radiotherapy is
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associated with improved outcomes for locally advanced non-small cell lung carcinoma treated
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with chemoradiation: An analysis of the radiation therapy oncology group. Int J Radiat Oncol
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Biol Phys 2012;82: 425-434.
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4. Bradley JD, Bae K, Graham MV et al. Primary analysis of the phase II component of a phase
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I/II dose intensification study using three-dimensional conformal radiation therapy and
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concurrent chemotherapy for patients with inoperable non-small-cell lung cancer: RTOG 0117. J
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Clin Oncol 2010;28: 2475-2480.
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5. Rosenman JG, Halle JS, Socinski MA et al. High-dose conformal radiotherapy for treatment of
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stage IIIA/IIIB non-small-cell lung cancer: Technical issues and results of a phase I/II trial. Int J
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Radiat Oncol Biol Phys 2002;54: 348-356.
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6. Schild SE, McGinnis WL, Graham D et al. Results of a phase I trial of concurrent chemotherapy
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and escalating doses of radiation for unresectable non-small-cell lung cancer. Int J Radiat Oncol
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Biol Phys 2006;65: 1106-1111.
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7. Bradley JD, Paulus R, Komaki R et al. A randomized phase III comparison of standard-dose (60
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gy) versus high-dose (74 gy) conformal chemoradiotherapy with or without cetuximab for stage
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III non-small cell lung cancer: Results on radiation dose in RTOG 0617. ASCO Meeting Abstracts
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2013;31: 7501.
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8. National Cancer Database. Available from URL: http://www.facs.org/cancer/ncdb/ .
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9. Raval MV, Bilimoria KY, Stewart AK, Bentrem DJ, Ko CY. Using the NCDB for cancer care
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improvement: An introduction to available quality assessment tools. J Surg Oncol 2009;99: 488-
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490.
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10. Commission on Cancer. Facility Oncology Registry Data Standards (FORDS); Revised for
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2007. Chicago, IL: American College of Surgeons; 2007.
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11. Hanna N, Neubauer M, Yiannoutsos C et al. Phase III study of cisplatin, etoposide, and
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concurrent chest radiation with or without consolidation docetaxel in patients with inoperable
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stage III non-small-cell lung cancer: The hoosier oncology group and U.S. oncology. J Clin Oncol
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2008;26: 5755-5760.
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12. Curran WJ,Jr, Paulus R, Langer CJ et al. Sequential vs. concurrent chemoradiation for stage
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III non-small cell lung cancer: Randomized phase III trial RTOG 9410. J Natl Cancer Inst
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2011;103: 1452-1460.
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13. Choy H, Devore RF,3rd, Hande KR et al. A phase II study of paclitaxel, carboplatin, and
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hyperfractionated radiation therapy for locally advanced inoperable non-small-cell lung cancer
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(a vanderbilt cancer center affiliate network study). Int J Radiat Oncol Biol Phys 2000;47: 931-
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937.
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14. Bradley J, Graham MV, Winter K et al. Toxicity and outcome results of RTOG 9311: A phase
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I-II dose-escalation study using three-dimensional conformal radiotherapy in patients with
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inoperable non-small-cell lung carcinoma. Int J Radiat Oncol Biol Phys 2005;61: 318-328.
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15. Socinski MA, Blackstock AW, Bogart JA et al. Randomized phase II trial of induction
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chemotherapy followed by concurrent chemotherapy and dose-escalated thoracic conformal
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radiotherapy (74 gy) in stage III non-small-cell lung cancer: CALGB 30105. J Clin Oncol 2008;26:
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2457-2463.
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16. Belani CP, Choy H, Bonomi P et al. Combined chemoradiotherapy regimens of paclitaxel and
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Figure Legend: Figure 1: Distribution of Radiation Doses from 2004-2011 Figure 2: Radiation Dose Trends from 2004-2011 Figure 3: Five year overall survival among clinical stage III non-small cell lung cancer patients stratified by dose group, 2004-2006 (n = 12,024) (p < 0.001).
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Categories
Total (n=12,024)
%
Male Female
7117 4907
59.2% 40.8%
White Black Other Hispanic Unknown
10110 1425 218 194 77
84.1% 11.9% 1.8% 1.6% 0.6%
418
3.5%
4211
35.0%
720 6447 228
6.0% 53.6% 1.9%
8410 2747 867
69.9% 22.8% 7.2%
2004 2005 2006
3872 4064 4088
32.2% 33.8% 34.0%
TX T1 T2 T3 T4
378 1586 3867 2119 4074
3.1% 13.2% 32.2% 17.6% 33.9%
N0 N1
1083 712
9.0% 5.9%
Gender
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Not Insured Private Insurance/managed Care Medicaid Medicare Other Government Comorbidities
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T stage
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Table 1: Patient Characteristics among Clinical Stage III Non-small Cell Lung Cancer Patients, National Cancer Database 2004-2006 (n=12,024)
N Stage
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N2 N3
7569 2660
62.9% 22.1%
3A 3B
5794 6230
48.2% 51.8%
18-59 60-69 70-79 80+
3415 4175 3608 826
28.4% 34.7% 30.0% 6.9%
Large Cell NSCLC NOS Squamous Adenocarcinoma
538 3868 4436 3182
4.5% 32.2% 36.9% 26.5%
286 3827 4180 3512 219
2.4% 31.8% 34.8% 29.2% 1.8%
1629
13.5%
7291
60.6%
3104
25.8%
Age at Diagnosis
57Gy - 59.3Gy 59.4Gy - 62.9Gy 63Gy - 66Gy 66.1Gy – 73.9Gy 74 - 80Gy
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Table 2: Multivariate Cox Proportional Hazard Model Predicting Overall Survival among Stage III NSCLC Patients, NCDB 2004-2006 (n=12,024)
Hazard Ratio
95% CI Lower Limit Upper Limit
RI PT
Parameter Gender
1.00 0.92 0.80 0.95
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0.83
0.90
0.86 0.70 0.80
0.97 0.93 1.11
0.89
0.79
0.99
0.97 0.95 0.95
0.85 0.85 0.79
1.10 1.07 1.14
1.00 1.13 1.20
1.08 1.11
1.18 1.29
1.00 0.93 0.91
0.89 0.87
0.97 0.96
1.00 1.48 1.79 1.98 2.10
1.00 1.21 1.34 1.41
2.20 2.65 2.95 3.10
1.00 1.20
1.08
1.34
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1.00 0.86
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Male Female Race/Ethnicity White - Non hispanic Black Other Hispanic
1.00
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1.33 1.52
1.00 1.04 1.23 1.40
0.98 1.15 1.30
1.10 1.31 1.54
1.00 1.14 1.15 1.12
1.03 1.04 1.00
1.26 1.28 1.24
0.97
0.92
1.03
0.97
0.90
1.02
1.00 1.28 1.03 0.94 0.94
1.06 0.89 0.81 0.81
1.55 1.19 1.08 1.09
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1.23 1.40
1.00
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N2 N3 Age at Diagnosis 19-59 60-69 70-79 80+ Histology Large Cell NSCLC NOS Squamous Adenocarcinoma Facility Type Community Cancer Program Comprehensive Community Cancer Program Academic Research Program Dose Category 74Gy-80Gy 57Gy - 59.3Gy 59.4Gy - 62.9Gy 63Gy - 66Gy 66.1Gy – 73.9Gy
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