Improved Overall Survival with Aggressive Primary Tumor Radiotherapy for Patients with Metastatic Esophageal Cancer

Accepted Manuscript Improved overall survival with aggressive primary tumor radiotherapy for patients with metastatic esophageal cancer David M. Guttmann, MD MTR, Nandita Mitra, PhD, Justin Bekelman, MD, James M. Metz, MD, John Plastaras, MD PhD, Weiwei Feng, MS, Samuel Swisher-McClure, MD MSHP PII:

S1556-0864(17)30339-8

DOI:

10.1016/j.jtho.2017.03.026

Reference:

JTHO 566

To appear in:

Journal of Thoracic Oncology

Received Date: 23 January 2017 Revised Date:

28 March 2017

Accepted Date: 29 March 2017

Please cite this article as: Guttmann DM, Mitra N, Bekelman J, Metz JM, Plastaras J, Feng W, SwisherMcClure S, Improved overall survival with aggressive primary tumor radiotherapy for patients with metastatic esophageal cancer, Journal of Thoracic Oncology (2017), doi: 10.1016/j.jtho.2017.03.026. 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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Title: Improved overall survival with aggressive primary tumor radiotherapy for patients with metastatic esophageal cancer

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Authors: David M Guttmann, MD MTRa; Nandita Mitra, PhDb; Justin Bekelman, MDa; James M Metz, MDa; John Plastaras, MD PhDa; Weiwei Feng, MSb; Samuel Swisher-McClure, MD MSHPa a

Department of Radiation Oncology, Hospital of the University of Pennsylvania; 3400 Civic Center Boulevard, TRC 2 West; Philadelphia, PA 19104; United States of America b Department of Biostatistics and Epidemiology, University of Pennsylvania; 622 Blockley Hall, 423 Guardian Drive, Philadelphia, Pa 19104; United States of America

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Author Email addresses: David Guttmann: [email protected] Nandita Mitra: [email protected] Justin Bekelman: [email protected] James Metz: [email protected] John Plastaras: [email protected] Weiwei Feng: [email protected] Samuel Swisher-McClure: [email protected]

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Corresponding Author: David Marshall Guttmann, MD Department of Radiation Oncology University of Pennsylvania Perelman School of Medicine 3400 Civic Center Boulevard, TRC 2 West Philadelphia, PA 19104 United States of America [email protected] Phone: 215-662-2428 Fax: 215-615-1658

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Disclosures: None.

Conflict of interest: James M Metz has consultant positions with Varian Medical Systems and IBA. David Guttmann has no conflicts to disclose. Nandita Mitra has no conflicts to disclose. Justin Bekelman has no conflicts to disclose. John Plastaras has no conflicts to disclose. Weiwei Feng has no conflicts to disclose. Samuel Swisher-McClure has no conflicts to disclose.

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ABSTRACT:

Introduction: To characterize utilization and survival outcomes associated with primary tumor

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directed radiotherapy (PTDRT) in patients with newly diagnosed metastatic esophageal cancer.

Methods: We conducted an observational cohort study using the National Cancer Database to evaluate patients with newly diagnosed metastatic esophageal cancer between 2004-2012.

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Overall survival outcomes following treatment with chemotherapy + conventional palliative dose radiotherapy (<5040 cGy), chemotherapy + definitive dose radiotherapy (≥5040 cGy), or

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chemotherapy alone, were compared using Cox proportional hazards models with inverse probability of treatment weighting using the propensity score. Potential unmeasured confounding was assessed through sensitivity analyses.

Results: The final cohort consisted of 12,683 patients: 57% were treated with chemotherapy

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alone, 24% were treated with chemotherapy + palliative dose radiotherapy, and 19% were treated with chemotherapy + definitive dose radiotherapy. Compared to chemotherapy alone,

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chemotherapy + definitive dose radiotherapy was associated with improved survival (median overall survival 8.3 versus 11.3 months; HR 0.72, [95% CI 0.70, 0.74], p≤0.001), whereas

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chemotherapy + palliative dose radiotherapy was associated with slightly inferior outcomes (median overall survival 8.3 months versus 7.5 months, HR 1.10 [1.07, 1.13] p≤0.001). These findings were robust to potential unmeasured confounding in sensitivity analyses. Additionally, landmark analyses confirmed these findings in patients surviving ≥12 months.

Conclusions: Definitive dose, but not conventional palliative dose, PTDRT is associated with improved overall survival in metastatic esophageal cancer, suggesting local control may be

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important to prognosis. These findings support integrating PTDRT into future clinical trials

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aimed at refining personalized treatment for patient with metastatic esophageal cancer.

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Key words: Esophageal Neoplasms; Neoplasm Metastasis; Radiotherapy; Radiation; Palliative care

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INTRODUCTION: Esophageal cancer is diagnosed in roughly 17,000 U.S. adults annually and up to half of

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these patients present with metastatic disease at initial diagnosis. Standard treatment approaches have remained largely unchanged over the past two decades and 5-year survival in this

population is under 5%.1,2 Significant primary tumor progression has been reported to occur in

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30-40% of patients with metastatic esophageal cancer treated by chemotherapy alone.3

Furthermore, primary tumor progression is a common cause of morbidity and mortality in this

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setting, often leading to dysphagia and subsequent malnutrition, chronic bleeding, and/or direct invasion of adjacent vital organs.4-7 Frequently, short course primary tumor directed radiotherapy (PTDRT) is offered to patients with metastatic esophageal cancer to palliate such symptoms. However, a growing body of evidence suggests survival benefits may be associated with aggressive therapy directed to primary tumor sites in patients with metastatic cancers.8-13

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We therefore examined recent utilization and survival outcomes associated with various regimens of PTDRT among patients with newly diagnosed metastatic esophageal cancer using a large national cancer registry. We hypothesized that definitive dose PTDRT would be associated

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with improved overall survival in patients with metastatic esophageal cancer.

Abbreviations: PTDRT: Primary tumor directed radiotherapy

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MATERIALS AND METHODS Patient selection We conducted an observational cohort study to examine national level patterns of

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PTDRT utilization in patients with newly diagnosed metastatic esophageal cancer and to assess its impact on patient overall survival. Our study sample was drawn from the NCDB from 20042012. This national database is jointly sponsored by the American College of Surgeons and the

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American Cancer society, drawing on hospital registry data from over 1,500 Commission on Cancer-accredited facilities in the United States and Puerto Rico. The NCDB represents roughly

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70 percent of new cancer diagnoses in this region. This study was granted exemption from the need for review by our Institutional Review Board.

Inclusion criteria for the analysis included all patients with metastatic primary invasive esophageal squamous cell carcinoma or adenocarcinoma (International Classification of Diseases

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for Oncology, 3rd Edition codes 150-159) treated with primary chemotherapy with or without radiation directed to the esophagus or stomach. Patients in whom radiotherapy was delivered to any other region were excluded. Patients staged as M1a prior to the update of the 7th edition of

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the AJCC staging manual in 2010 were reclassified as locally advanced and excluded, as were patients without evidence of a primary invasive tumor. Lastly, patients treated with radiation

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doses less than 20 Gy or greater than 72 Gy were excluded as these doses are not within the conventional range of palliative or definitive radiotherapy to the esophagus.

Patient cohorts and variables Patient cohorts were defined as those treated with chemotherapy alone, those treated with chemotherapy + conventional palliative dose (<5040 cGy) PTDRT, and those treated with

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chemotherapy + definitive dose (≥5040 cGy) PTDRT. This cutoff was chosen to reflect the dose that constitutes definitive treatment in the curative setting.14,15 Such a stratification would allow us to better assess the effect of definitive dose therapy, compared to chemotherapy, on outcomes

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without obscuring our findings by patients treated with palliative doses of radiation. Baseline characteristics of patients from these three cohorts were compared using chi-square tests.

Covariates examined included patient age, gender, race/ethnicity, population density (classified

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as metropolitan, urban, and rural), facility type (academic versus non-academic), facility

geographic region, primary insurance provider, education level (defined as percentage of the

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population in the patient’s home ZIP code not achieving a high school degree), income (the median income in the patient’s home ZIP code), Charlson/Deyo Comorbidity Score, histology, AJCC T- and N-stage, and treatment year.

Although not directly recorded in NCDB, the average dose per fraction was calculated by

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dividing the total radiation dose by the number of radiation treatments. Additionally, concurrent chemoradiation was defined as chemotherapy and radiation starting within 5 days of one another.

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Statistical Analysis

The primary objective was to assess the effect of radiotherapy to the primary tumor site

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on overall survival, as defined from the date of diagnosis until death or last follow up. The secondary objective was to characterize patterns of high dose radiotherapy utilization in metastatic esophageal cancer across the United States. Multivariable logistic regression was used to assess the independent effects of all

covariates on the odds of being treated with high dose radiation relative to low dose radiation or chemotherapy alone. To determine the association between radiotherapy use and overall

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survival, we then developed a Cox proportional hazards model to assess the independent effect of high dose radiotherapy and low dose radiotherapy on overall survival compared to chemotherapy alone. Proportional hazards assumptions were tested using Schoenfeld residuals

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tests and were not violated. Landmark analyses in patients surviving at least 3, 6, and 12 months were conducted to control for immortal time bias.16 We estimated a three-level propensity score to obtain the probabilities of high dose versus low dose PTDRT versus chemo only for each

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patient.17-19 To accomplish this, we used the “twang” package in R which uses generalized

boosted models and bootstrapping to produce inverse probability weights (IPTW) in studies

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where more than two treatments are being compared. Our final Cox model incorporated these weights based on the propensity score to account for confounding due to measured confounders.20

Finally, to assess the robustness of our findings to potential unmeasured confounders, we

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conducted a regression-based sensitivity analysis21 using presence of high volume metastatic disease as a potential unmeasured confounding variable in our Cox model. We estimated its prevalence would be 50% in our population, and would correspond to a hazard ratio of death

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between 1.5-3.0 based on the published literature. 22-24 The difference in median time between chemotherapy and radiation in patients treated

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with sequential therapy was determined by Wilcoxon Rank Sum test. All analyses were performed in R version 3.3.2 (The R foundation for Statistical

Computing, Vienna, Austria 2016). For all analyses, a p-value ≤ 0.05 was considered to be statistically significant.

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RESULTS Population and Patterns of Care After applying our inclusion and exclusion criteria, our final cohort consisted of 12,683

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patients. 7,274 (57%) were treated with chemotherapy alone, 2,983 were treated with

chemotherapy + palliative dose PTDRT, (24%) and 2,426 were treated with chemotherapy + definitive dose PTDRT (19%) (See Figure, Supplementary Data 1). In the low dose arm, dose

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per fraction spanned between 180-350 cGy. In contrast, 85% of patients in the high dose arm were treated in fractions <200 cGy (see Figure, Supplemental Data 2).

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The majority of patients included were male (85%), of non-Hispanic white race (86%), resided in metropolitan locations (78%), and covered by Medicare or commercial insurance (83% combined). 78% were without significant comorbid illness and 75% had tumors of adenocarcinoma histology (Table 1). Among patients treated with radiotherapy, 2,333 (43%)

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received sequential chemotherapy (of whom 58% received chemotherapy followed by radiation), 2,772 (51%) received concurrent chemotherapy, and in 304 (6%) patients there was insufficient data to determine sequence. Concurrent chemotherapy was more common in patients treated

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with high dose radiotherapy compared to those treated with low dose radiotherapy (59% vs. 45%, OR 1.78, 95% CI [1.60, 2.00] p<0.001). Patients treated sequentially more often were

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treated with chemotherapy first (median days between starting radiation and starting chemotherapy=9 (IQR=74) for the overall population). This timespan was longer in patients the definitive dose PTDRT cohort compared to the palliative cohort (median 14 vs. 6 days, p<0.001). Regarding chemotherapy regimens in the population, 81% received multi-agent chemotherapy and 10% received single-agent chemotherapy, and regimen was unknown in 9%.

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On multivariable analysis, clinical stage T3 versus T1 disease predicted for a higher rate of high dose PTDRT relative to low dose radiation or chemotherapy only (28% vs. 15%; OR 2.95, 95% CI [2.53, 3.46], p<0.001), as did African American race relative to non-Hispanic

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Whites (26% vs. 18%; OR 1.34, 95% CI [1.16, 1.56], p<0.001). Additional factors associated with increased utilization of high dose PTDRT included age >80 years, Mountain facility

location, and non-Medicare/non-Medicaid government insurance status. Conversely, rates of

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high dose PTDRT were lower in patients with adenocarcinoma histology relative to squamous cell carcinoma (16% vs. 29%; OR 0.57, 95% CI [0.51, 0.63], p<0.001). Other factors predicting

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for less use of high dose PTDRT included treatment at an academic facility, Mid-Atlantic facility location, and Charlson/Deyo Comorbidity Index score of 2 or more (Table 2). In addition, there was a statistically significant increase in utilization of chemotherapy alone over time (ptrend<0.001, Figure 1).

Factors associated with healthcare disparity, such as insurance

between treatment groups.

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Overall Survival

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provider, income, and educational attainment, were not distributed significantly differently

The median follow up was 19.8 months (Range 0.33-122.5) for patients alive at the end

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of the study period and 8.4 months (Range 0-122.5) overall. On multivariable analysis, receipt of high-dose radiotherapy was associated with a statistically significant improvement in overall survival relative to no radiotherapy (Median OS: 11.2 versus 8.4 months; HR 0.72, [95% CI 0.68, 0.75], p≤0.001, Table 3). In contrast, low dose radiation was associated with worse overall survival relative to chemotherapy alone, though the magnitude of the difference was small (Median OS: 7.6 months versus 8.4 months, HR 1.07, [95% CI 1.02, 1.12], p=0.004). An

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interaction term was introduced into the model to assess a potential interaction between use of radiation and concurrent versus sequential chemoradiation. In patients who were treated with radiation, neither the use of concurrent chemoradiation (p=0.08), nor the interaction between

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concurrent chemoradiation and low dose radiotherapy (p=0.44), nor high dose radiotherapy (p=0.14) was statistically significant. In addition, our model did not reveal a meaningful

interaction between histology and treatment cohort (HR=0.95 [95% CI 0.95, 0.99], p=0.05).

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In our second analysis using propensity score weighting, receipt of high dose

radiotherapy remained statistically significantly associated with improved overall survival

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relative to chemotherapy alone (IPTW model HR 0.72, [95% CI 0.70, 0.74], p<0.001, Table 3). In the IPTW model, median survival was 11.3 months in the high dose PTDRT cohort and 8.3 months in the chemotherapy alone cohort. This corresponded to 1 and 2 year overall survival estimates of 47% vs. 34% and 19% vs. 12%, respectively. Low dose radiotherapy again had a

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marginally detrimental effect on overall survival (Figure 2, Table 3). Landmark analyses of patients surviving a minimum of 3, 6, and 12 months were conducted to control for the effect of immortal time bias. In all circumstances, the effect of high

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dose radiotherapy remained significantly associated with improved overall survival (Table 4). To evaluate the potential effects of unmeasured confounding in our Cox regression

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model, we conducted a sensitivity analysis to estimate the effect of a hypothetical confounder on the observed association between high dose PTDRT on survival (see Table, Supplemental Data 3). In our analysis, a strong confounder (HR=2.0) would need to be 5 times more prevalent in the chemotherapy alone cohort to nullify the significance of our findings. A very strong confounder (HR=3.0) would still have to be 2.5 times more prevalent in the chemotherapy alone cohort to render the results no longer statistically significant.

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DISCUSSION In this large national observational cohort study of 12,683 patients with metastatic esophageal cancer, we found a significant association between receipt of definitive dose

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radiotherapy to the primary tumor and overall survival. Conventional palliative dose

radiotherapy, by contrast, was not associated with improved survival. The association remained statistically significant in propensity score weighted models accounting for a large number of

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measured confounders, sensitivity analyses assessing the potential effects of unmeasured

confounding, and landmark analyses accounting for immortal time bias. These findings may

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suggest that an aggressive approach combining chemotherapy with definitive doses of radiotherapy in selected patients with metastatic esophageal cancer can lead to improved survival outcomes compared to chemotherapy alone. Finally, our patterns of care analysis indicated that chemotherapy alone continued to remain the predominant treatment strategy in this population, a

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trend which increased over the study period.

Our findings support the hypothesis that primary tumor local control may play an important role in the survival outcomes of patients with newly diagnosed metastatic esophageal

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cancer. Mechanistically, this approach is rational given the life-threatening risks posed by an esophageal tumor that are independent of a patient’s systemic disease burden. This concept is

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consistent with prior data demonstrating an association between treatment of locoregional disease and survival in metastatic esophageal cancer. For example, esophagectomy in patients with metastatic disease has been correlated with better survival outcomes in at least two single institution retrospective studies.25,26 The addition of thoracic lymph node dissection in this context was also associated with improve survival in a prior SEER analysis.27 Additionally, a 60 patient prospective randomized Phase II study in metastatic esophageal cancer suggested that radiation to the primary tumor to 5040 cGy may provide an overall survival benefit compared to

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chemotherapy alone.28 Population-level data using the SEER registry have also demonstrated an association between receipt of radiotherapy and overall survival in metastatic esophageal cancer.29 However, this analysis was limited by the lack of any data regarding receipt of

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chemotherapy in the study population as well as limited radiation treatment details including dose. The current study represents the largest and most statistically rigorous comparison of survival outcomes in patients with metastatic esophageal cancer treated with aggressive primary

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tumor directed therapy and it is the first to our knowledge to evaluate the impact of radiation dose in this context.

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Currently, the standard of care in metastatic esophageal cancer involves chemotherapy using multi-agent platinum-containing regimens, with palliative radiotherapy as indicated for symptomatic management of dysphagia, pain, bleeding, and fistula. This approach is based on prospective trials conducted within the last 10 years resulting in median overall survivals

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reported at around 9 months.22,30-32 Our survival estimates for patients treated without radiotherapy are consistent with these outcomes (median survival of 8.3 months in the propensity-score adjusted cohort), yet are improved by an average of 3 months in patients treated

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with doses of radiotherapy that are consistent with a definitive course14,15. By contrast, in our study lower doses of radiation were associated with worse survival compared to chemotherapy

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alone, although the magnitude of the difference was small. An explanation for this may be evident after comparing radiation fractionation schemes between cohorts. Patients in the lower dose cohort were more often treated in a manner consistent with pure palliation, using larger fraction sizes to a low cumulative dose—a strategy that expedites treatment and minimizes acute effects, but with less expectation of local control. Therefore, these patients overall have been less favorable due to disease burden, comorbidity, or some other unmeasured factor. However,

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we posit that definitive dose PTDRT may have a role in improving survival in well-selected patients—those whose survival is most threatened by failure to achieve local control of the primary tumor. Such patients may include those with large tumors threatening airway invasion,

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those with severe luminal obstruction, those lower systemic burden of metastatic disease whose treatment of the primary tumor might prevent seeding further metastatic spread. As in any

aggressive oncologic approach, only patients with the best performance status and with the most

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robust multidisciplinary and social support should be considered for this approach.

Previous efforts have focused on how best to incorporate radiation therapy into the

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management of metastatic esophageal cancer. Most recently, the randomized TROG 03.01 Phase III trial comparing radiation to concurrent chemoradiation in 220 patients with metastatic esophageal cancer demonstrated no change in dysphagia response between the two approaches, with increased toxicity in the concurrent chemoradiation arm.33 The radiation doses used in this

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study were within a palliative range of 30-35 Gy. While the trial was not powered to specifically assess the effect of these treatments on overall survival, median survival in both arms was similar (210 days versus 203 days). Similarly in our study, concurrent delivery of chemotherapy and

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radiation was not associated with improved survival, irrespective of RT dose, suggesting that patients need not undergo the substantial toxicity of concurrent chemoradiation to experience a

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survival benefit from high dose PTDRT in clinical practice. Our study results suggest that providers did attempt to select patients most likely to

benefit from high dose PTDRT. For example, patients with adenocarcinoma were approximately half as likely to receive RT compared to patients with squamous histology, which may reflect a bias in perceived radiosensitivity of squamous cell carcinoma compared to adenocarcinoma.34 Further, patients with higher Charlson/Deyo comorbidity score were significantly less likely to

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receive this more aggressive treatment and, while patients with higher T stage were more likely to be treated with high dose PTDRT, this was not true for the most advanced (T4) cases. Additionally, the use of chemotherapy alone significantly increased over the study period. This

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could reflect improvements in chemotherapy with the publication of several important trials demonstrating equivalent efficacy with easier and less toxic regimens for metastatic esophageal cancer.22,30 Lastly, there was interestingly no evidence of significant disparities in use of high

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dose PTDRT with respect to insurance provider, educational attainment, or income.

The primary limitation of this study is that due to lack of randomization, selection bias

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may favor patients who received definitive dose radiotherapy. These patients may have been generally healthier with less extensive metastatic disease and this source of bias could affect our observed results. However, we attempted to address this concern by 1) balancing treatment groups with respect to measured confounders through multivariable regression with propensity

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score weighting, and 2) by conducting sensitivity analyses to model the effect of unmeasured confounding factors. With regard to measured confounders, the extent of medical comorbidity, as assessed by the distribution of Charlson/Deyo comorbidity score was not significantly

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different in our patient cohorts. Further, we attempted to estimate disease extent by T and N stage; however information was missing on these factors in a significant number of patients.

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With regard to unmeasured confounders, such as hypothetically systemic burden of metastatic disease and/or overall performance status, our sensitivity analysis demonstrated that our findings are robust; such a factor would need be 2.5 to 5 times as prevalent in the low dose arm, and confer a 2-3 fold higher risk of death, to render our findings non-significant. Our conclusions are also consistent with prior literature and mechanistically plausible, strengthening the observed relationship between high dose radiotherapy and survival.

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In conclusion, we observed an association between the use of definitive dose radiotherapy and improved overall survival in patients with newly diagnosed metastatic esophageal cancer treated in the United States. However, the use of PTDRT in general appears to

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be declining over time. The patient survival outcomes observed in our study following

chemotherapy and high dose PTDRT compare very favorably with patient survival following chemotherapy alone in prior prospective trials.22,30-32 These observations support the conduct of

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further clinical studies integrating high dose PTDRT as part of initial treatment in this setting.

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ACKNOWLEDGEMENTS The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytic or statistical methodology employed, or the conclusions drawn from

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these data by the investigator.

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Van Cutsem E, Moiseyenko VM, Tjulandin S, et al: Phase III study of docetaxel

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and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol 24:4991-7, 2006 32.

Al-Batran SE, Pauligk C, Homann N, et al: The feasibility of triple-drug

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chemotherapy combination in older adult patients with oesophagogastric cancer: a randomised trial of the Arbeitsgemeinschaft Internistische Onkologie (FLOT65+). Eur J Cancer 49:835-42,

33.

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Penniment MG, Harvey JA, Wong R, et al: Best Practice in Advanced Esophageal

Cancer: A Report on Trans-Tasman Radiation Oncology Group TROG 03.01 and NCIC CTG ES.2 Multinational Phase 3 Study in Advanced Esophageal Cancer (OC) Comparing Quality of

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Life (QOL) and Palliation of Dysphagia in Patients Treated With Radiation Therapy (RT) or Chemoradiation Therapy (CRT). International Journal of Radiation Oncology • Biology • Physics 90:S3, 2014

van Hagen P, Hulshof MC, van Lanschot JJ, et al: Preoperative

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chemoradiotherapy for esophageal or junctional cancer. N Engl J Med 366:2074-84, 2012

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FIGURE LEGENDS Figure 1. Temporal trends in use of chemotherapy alone and chemotherapy with low or high dose radiotherapy in metastatic esophageal cancer. The Spearman test for trend was significant

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for the trend of increasing utilization of chemotherapy alone over time (p-trend<0.001).

Figure 2. Inverse probability of treatment weighting adjusted overall survival in patients with metastatic esophageal cancer treated with chemotherapy alone (No RT), radiation doses <5040

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cGy, or radiation doses ≥5040 cGy. The shaded region surrounding each line represents upper

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and lower bounds of 95% confidence interval. For the comparison HR 0.72, [95% CI 0.70,

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0.74], p=<0.001.

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Table 1. Patient Characteristics RT≥5040 cGy 2426

Total 12683

789 (11) 3286 (45) 2770 (38) 429 (6)

317 (11) 1283 (43) 1117 (37) 266 (9)

205 (8) 1048 (43) 993 (41) 180 (7)

1311 (10) 5617 (44) 4880 (38) 875 (7)

6194 (85) 1080 (15)

2454 (82) 529 (18)

1963 (81) 463 (19)

10611 (84) 2072 (16)

6286 (86) 544 (7) 257 (4) 187 (3)

2445 (82) 341 (11) 108 (4) 89 (3)

1938 (80) 312 (13) 94 (4) 82 (3)

10669 (84) 1197 (9) 459 (4) 358 (3)

5648 (78) 1159 (16) 144 (2) 323 (4)

2292 (77) 499 (17) 70 (2) 122 (4)

1841 (76) 432 (18) 53 (2) 100 (4)

9781 (77) 2090 (16) 267 (2) 545 (4)

4276 (60) 2873 (40)

2031 (69) 914 (31)

1688 (70) 709 (30)

7995 (63) 4496 (35)

475 (7) 1331 (18) 1393 (19) 3002 (41) 286 (4) 662 (9) 125 (2)

179 (6) 409 (14) 601 (20) 1254 (42) 145 (5) 357 (12) 38 (1)

167 (7) 367 (15) 470 (19) 1006 (41) 118 (5) 269 (11) 29 (1)

821 (6) 2107 (17) 2464 (19) 5262 (41) 549 (4) 1288 (10) 192 (2)

3075 (42) 2972 (41) 517 (7) 301 (4) 71 (1) 338 (5)

1129 (38) 1329 (45) 272 (9) 148 (5) 66 (2) 39 (1)

956 (39) 1103 (45) 192 (8) 91 (4) 43 (2) 41 (2)

5160 (41) 5404 (43) 981 (8) 540 (4) 180 (1) 418 (3)

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RT<5040 cGy 2983

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Total no. Age, y ≤ 49 50-64 65-79 ≥ 80 Gender Men Women Race Non-Hispanic White Non-Hispanic Black Hispanic Other County size Metropolitan Urban Rural Unknown Facility Type Non-Academic Academic Facility Location New England Middle Atlantic South Atlantic Midwest Mountain Pacific Unknown Insurance status Commercial Insurance Medicare Medicaid Uninsured Other Government Unknown Education

No RT 7274

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483 (16) 711 (24) 737 (25) 933 (31) 119 (4)

848 (12) 1247 (17) 1936 (27) 2891 (40) 352 (5)

398 (13) 549 (18) 878 (29) 1039 (35) 119 (4)

5676 (78) 1241 (17) 357 (5)

2331 (78) 524 (18) 128 (4)

1920 (79) 397 (16) 109 (4)

9927 (78) 2162 (17) 594 (5)

1353 (19) 5460 (75) 461 (6)

815 (27) 1982 (66) 186 (6)

865 (36) 1463 (60) 98 (4)

3033 (24) 8905 (70) 745 (6)

696 (10) 325 (4) 1301 (18) 1094 (15) 3858 (53)

182 (6) 217 (7) 885 (30) 474 (16) 1225 (41)

159 (7) 226 (9) 859 (35) 364 (15) 818 (34)

1037 (8) 768 (6) 3045 (24) 1932 (15) 5901 (47)

1088 (15) 4091 (56) 2095 (29)

464 (16) 1856 (62) 663 (22)

417 (17) 1604 (66) 405 (17)

1969 (16) 7551 (60) 3163 (25)

574 (8) 572 (8) 662 (9) 763 (10) 799 (11) 957 (13) 931 (13) 1000 (14) 1016 (14)

298 (10) 288 (10) 282 (9) 333 (11) 328 (11) 361 (12) 382 (13) 323 (11) 388 (13)

267 (11) 246 (10) 290 (12) 292 (12) 290 (12) 269 (11) 285 (12) 262 (11) 225 (9)

1139 (9) 1106 (9) 1234 (10) 1388 (11) 1417 (11) 1587 (13) 1598 (13) 1585 (12) 1629 (13)

350 (14) 447 (18) 658 (27) 858 (35) 113 (5)

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386 (16) 588 (24) 573 (24) 766 (32) 113 (5)

1892 (15) 2872 (23) 3120 (25) 4215 (33) 584 (5)

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1023 (14) 1573 (22) 1810 (25) 2516 (35) 352 (5)

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≥29% 20%-28.9% 14%-19.9% <14% Unknown Income <30,000 30,000-35,000 35,000-45,999 >46,000 Unknown Charlson/Deyo Comorbidity Score 0 1 ≥2 Histology Squamous cell carcinoma Adenocarcinoma Unknown T stage T1 T2 T3 T4 Unknown N stage Node Negative Node Positive Unknown Year 2004 2005 2006 2007 2008 2009 2010 2011 2012

1596 (13) 2243 (18) 3472 (27) 4788 (38) 584 (5)

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Table 2. Factors associated with receipt of high dose radiotherapy

18% 22%

1.29 [1.17, 1.42]

Multivariable OR [95% CI] p

0.27 0.026 <0.001

1.00 [0.88, 1.15] 1.08 [0.91, 1.27] 1.55 [1.26, 1.92]

0.91 0.36 <0.001

<0.001

1.1 [0.99, 1.22]

0.077

1.72 [1.53, 1.94] 1.13 [0.93, 1.36] 1.31 [1.06, 1.62]

<0.001 0.21 0.012

1.34 [1.16, 1.56] 1.10 [0.89, 1.35] 1.19 [0.94, 1.50]

<0.001 0.41 0.16

1.10 [1.00, 1.21] 1.17 [0.91, 1.49] 0.94 [0.79, 1.12]

0.055 0.21 0.48

1.01 [0.90, 1.12] 1.03 [0.79, 1.34] 1.03 [0.81, 1.32]

0.92 0.86 0.76

0.65 [0.60, 0.70]

<0.001

0.63 [0.58, 0.68]

<0.001

20% 17% 19% 19% 21% 21% 15%

0.80 [0.68, 0.94] 1.06 [0.90, 1.24] 1.03 [0.89, 1.20] 1.26 [1.02, 1.57] 1.30 [1.09, 1.55] 0.74 [0.53, 1.02]

0.008 0.51 0.66 0.036 0.004 0.066

0.88 [0.74, 1.05] 0.94 [0.80, 1.12] 1.10 [0.94, 1.29] 1.44 [1.14, 1.81] 1.25 [1.04, 1.51] *

0.17 0.56 0.20 0.001 0.013 *

19% 20% 20% 17%

1.21 [1.12, 1.30] 1.32 [1.15, 1.52] 1.17 [0.98, 1.40]

<0.001 <0.001 0.083

1.04 [0.92, 1.16] 1.16 [1.00, 1.35] 1.06 [0.87, 1.29]

0.60 0.056 0.54

18% 26% 20% 23% 19% 21% 20% 18%

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1.07 [0.95, 1.21] 1.15 [1.02, 1.30] 1.57 [1.32, 1.87]

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16% 19% 20% 21%

21% 16%

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Univariable OR [95% CI]

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2.26 [1.67, 3.08] 0.35 [0.27, 0.45]

<0.001 <0.001

2.15 [1.56, 2.96] 0.38 [0.29, 0.50]

<0.001 <0.001

20% 20% 18% 18% 19%

0.97 [0.87, 1.09] 0.85 [0.76, 0.96] 0.79 [0.71, 0.89] 0.78 [0.64, 0.94]

0.64 0.006 <0.001 0.008

1.07 [0.93, 1.23] 0.98 [0.84, 1.13] 0.94 [0.80, 1.11] 0.84 [0.64, 1.1]

0.35 0.73 0.466 0.195

22% 20% 19% 18% 19%

0.91 [0.80, 1.03] 0.90 [0.80, 1.01] 0.74 [0.66, 0.83] 0.75 [0.62, 0.91]

0.13 0.081 <0.001 0.003

0.95 [0.82, 1.10] 1.00 [0.86, 1.17] 0.92 [0.78, 1.09] *

0.48 0.99 0.32 *

0.99 [0.90, 1.09] 0.89 [0.75, 1.05]

0.85 0.16

0.96 [0.87, 1.06] 0.84 [0.70, 1.01]

0.42 0.071

0.51 [0.47, 0.55] 0.50 [0.42, 0.58]

<0.001 <0.001

0.57 [0.51, 0.63] 0.54 [0.46, 0.65]

<0.001 <0.001

15% 29% 28% 19% 14%

2.78 [2.30, 3.38] 2.74 [2.36, 3.18] 1.56 [1.34, 1.83] 1.08 [0.94, 1.24]

<0.001 <0.001 <0.001 0.28

2.77 [2.27, 3.39] 2.95 [2.53, 3.46] 1.47 [1.25, 1.74] 1.17 [1.01, 1.36]

<0.001 <0.001 <0.001 0.036

21% 21% 13%

1.04 [0.95, 1.15] 0.63 [0.56, 0.71]

0.30 0.019

0.96 [0.86, 1.07] 0.73 [0.64, 0.83]

0.40 0.030

23% 22% 24% 21% 20% 17% 18%

0.95 [0.80, 1.12] 0.88 [0.75, 1.03] 0.83 [0.71, 0.97] 0.79 [0.67, 0.92] 0.67 [0.57, 0.78] 0.73 [0.62, 0.85]

0.53 0.11 0.022 0.003 <0.001 <0.001

0.91 [0.76, 1.08] 0.83 [0.70, 0.99] 0.78 [0.66, 0.92] 0.70 [0.59, 0.83] 0.61 [0.52, 0.72] 0.66 [0.56, 0.78]

0.292 0.038 0.003 <0.001 <0.001 <0.001

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19% 18% 18%

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24% 10%

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2011 2012

17% 14%

0.59 [0.51, 0.69] 0.61 [0.53, 0.71]

<0.001 <0.001

0.54 [0.46, 0.64] 0.54 [0.46, 0.64]

Percentages on the right-hand column reflect the percentage of each subgroup treated with high

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dose radiotherapy as a percentage of all patients in that subgroup. RT, Radiotherapy. OR, odds

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ratio. *, not analyzed due to collinearity.

<0.001 <0.001

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Table 3. Multivariable Cox Proportional Hazards model for overall survival

0.004 <0.001

1.00 [0.93, 1.07] 0.99 [0.91, 1.07] 1.22 [1.10, 1.35]

0.99 0.71 <0.001

0.92 [0.87, 0.96]

<0.001

0.93 [0.86, 1.00] 0.78 [0.70, 0.87] 0.88 [0.78, 0.99]

0.044 <0.001 0.037

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1.01 [0.96, 1.07] 0.95 [0.83, 1.08] 1.02 [0.90, 1.15]

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1.10 [1.07, 1.13] 0.72 [0.70, 0.74]

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1.07 [1.02, 1.12] 0.72 [0.68, 0.75]

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Radiation dose No RT <5040 ≥5040 cGy Age, y ≤ 49 50-64 65-79 ≥ 80 Gender Men Women Race Non-Hispanic White Non-Hispanic Black Hispanic Other County size Metropolitan Urban Rural Unknown Facility Type Non-Academic Academic Facility Location New England Middle Atlantic South Atlantic Midwest Mountain Pacific Insurance status Commercial Insurance Medicare Medicaid Uninsured

Propensity-score weighted HR [95% CI] p

0.67 0.42 0.77

0.92 [0.88, 0.96]

<0.001

0.96 [0.88, 1.05] 1.05 [0.96, 1.14] 1.05 [0.97, 1.13] 1.02 [0.91, 1.15] 1.00 [0.91, 1.09]

0.38 0.29 0.22 0.71 0.92

1.09 [1.03, 1.16] 1.20 [1.11, 1.30] 1.17 [1.06, 1.29]

0.002 <0.001 0.001

<0.001 <0.001

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Covariate adjusted HR [95% CI] p

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0.28 0.46 0.97 0.89

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0.44 0.34 0.21

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0.76 0.37

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Other Government 1.03 [0.88, 1.20] Unknown 0.95 [0.85, 1.06] Education ≥29% 20%-28.9% 0.96 [0.90, 1.03] 14%-19.9% 0.97 [0.90, 1.05] <14% 1.00 [0.93, 1.08] Unknown 1.01 [0.89, 1.15] Income <30,000 30,000-35,000 0.97 [0.90, 1.05] 35,000-45,999 0.96 [0.89, 1.04] >46,000 0.95 [0.87, 1.03] Unknown Charlson/Deyo Comorbidity Score 0 1 1.15 [1.09, 1.21] ≥2 1.33 [1.22, 1.45] Histology Squamous cell carcinoma Adenocarcinoma 0.99 [0.94, 1.04] Unknown 1.25 [1.15, 1.36] T stage T1 T2 0.87 [0.79, 0.96] T3 0.92 [0.85, 0.99] T4 1.13 [1.04, 1.22] Unknown 1.05 [0.98, 1.13] N stage Node Negative Node Positive 1.06 [1.01, 1.12] Unknown 1.10 [1.03, 1.17] Year 2004 2005 1.01 [0.93, 1.10] 2006 0.90 [0.83, 0.98] 2007 0.92 [0.85, 0.99] 2008 0.89 [0.82, 0.96] 2009 0.86 [0.79, 0.93] 2010 0.84 [0.77, 0.91] 2011 0.80 [0.74, 0.87]

<0.001 <0.001 0.73 <0.001 0.006 0.023 0.004 0.17 0.025 <0.001 0.84 0.013 0.037 0.003 <0.001 <0.001 <0.001

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0.84 [0.78, 0.91]

<0.001

RT, Radiotherapy . HR, Hazard ratio. For clarity, only propensity-score weighted hazard ratios

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Table 4. Landmark analysis, patients surviving at least 3, 6, and 12 months

Radiation dose No RT <5040 cGy ≥5040 cGy

Patients surviving at least 6 months Univariable Multivariable 1.11 [1.05, 1.17] <0.001 1.11 [1.05, 1.18] <0.001 0.81 [0.77, 0.86] <0.001 0.83 [0.78, 0.88] <0.001

Radiation dose No RT <5040 cGy ≥5040 cGy

Patients surviving at least 12 months Univariable Multivariable 0.99 [0.91, 1.08] 0.87 1.03 [0.94, 1.13] 0.53 0.80 [0.74, 0.87] <0.001 0.85 [0.78, 0.92] <0.001

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Radiation dose

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No RT <5040 cGy ≥5040 cGy

Patients surviving at least 3 months Univariable Multivariable HR [95% CI] p HR [95% CI] p 1.15 [1.10, 1.21] <0.001 1.14 [1.09, 1.20] <0.001 0.81 [0.77, 0.85] <0.001 0.82 [0.77, 0.86] <0.001

Hazard ratios determined by multivariable Cox proportional hazards regression for patients

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surviving at least 3 or 6 months. RT, Radiotherapy.

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LIST OF SUPPLEMENTARY MATERIAL

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Supplemental Data 1-3.pdf

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