Disparities in survival after trimodality therapy for esophageal adenocarcinoma

Disparities in survival after trimodality therapy for esophageal adenocarcinoma SUMMARY Trimodality therapy with neoadjuvant chemoradiation followed by surgery has emerged as the standard of care for the treatment of locally advanced esophageal cancer. Yet, there is considerable variation in survival within this population. We sought to analyze factors associated with survival after trimodality therapy in esophageal adenocarcinoma. We identified 4,679 patients from the National Cancer Database (NCDB) of the American College of Surgeons who received chemotherapy and radiation prior to surgery for esophageal adenocarcinoma from 2006 to 2013. We excluded patients with stage IV disease and unknown pathological nodal status. We performed regression analyses using a Cox proportional hazards model to identify independent predictors of overall survival. On multivariate analysis, pathologic characteristics associated with decreased overall survival included stage, lymphovascular invasion, and positive surgical margins. Insurance status, age, and comorbidity index were also associated with decreased survival. We found that pathologically node-positive patients who received additional adjuvant chemotherapy were associated with improved survival. Compared to private insurance, Medicaid (HR 1.45, CI 1.22–1.73, P < 0.0001), Medicare (HR 1.17, CI 1.04–1.31, P = 0.0082), or having no insurance (HR 1.50, CI 1.17–1.92, P = 0.0012) were all negative predictors of overall survival. In patients with esophageal adenocarcinoma who have undergone trimodality therapy, a number of different factors are associated with overall survival. In particular, socioeconomic factors relating to access to care are independent predictors of survival. Despite receiving the standard of care, treatment disparities persist in this population of patients. INTRODUCTION Each year, an estimated 15,690 deaths are expected from esophageal cancer, with only 19% of esophageal cancer patients surviving at five years.1 Trimodality therapy with neoadjuvant chemoradiation followed by surgery has been shown to improve survival compared to surgery alone for the treatment of locally advanced esophageal cancer.2 The findings of the CROSS trial have provided the basis for current National Comprehensive Cancer Network (NCCN) guidelines for the role of neoadjuvant therapy in the management of esophageal cancer; however, there is considerable variation in survival in this population.3 In addition, barriers to receiving neoadjuvant therapy are multifactorial, including age, comorbidities, and insurance status.4,5 As current NCCN guidelines recommend surveillance after trimodality therapy, identifying factors associated with survival after trimodality therapy remains an area of investigation. Recently, socioeconomic factors such as insurance status have been shown to be an independent predictor of survival in other forms of cancer.6,7 A retrospective study using the National Cancer Database (NCDB) demonstrated a survival benefit with adjuvant chemotherapy after trimodality therapy in pathologically node-positive esophageal adenocarcinoma patients.8 Yet, even in cancers where NCCN guidelines include adjuvant therapy, socioeconomic factors can serve as barriers to receive adjuvant treatment.9 In this study, we sought to analyze a variety of factors, including insurance status and adjuvant chemotherapy, to identify independent predictors of survival after trimodality therapy in esophageal adenocarcinoma. METHODS An Institutional Review Board approved retrospective analysis of the NCDB for patients who underwent esophagectomy for esophageal cancer from 2006 to 2013. The NCDB is a comprehensive clinical oncology database comprised of information from over 1500 Commission on Cancer (CoC)-accredited institutions, accounting for approximately 70% of newly diagnosed cancer cases across the United States. We performed stepwise inclusion and exclusion counts on an initial subset of patients identified to have a diagnosis of esophageal cancer as defined by the International Classification for Diseases, 3rd edn. Inclusion criteria included patients aged 18–90 years who underwent esophagectomy for esophageal adenocarcinoma, whom were treated with either neoadjuvant chemoradiotherapy only or neoadjuvant chemoradiotherapy and adjuvant chemotherapy. We excluded patients with stage IV disease, unknown pathological nodal status, a history of prior malignancy, and those with no followup information. TNM staging was assessed according to the American Joint Commission on Cancer 7th ed. staging definitions. Overall patient demographics and tumor characteristics were recorded and compared between groups. Hospital types were reported on the basis of cancer program categories as designated by the CoC.10 Insurance types reported included patients either with private insurance, not insured, or with Medicaid or Medicare. Medicaid is a government insurance program primarily for patients with limited income. Medicare is a government insurance program, which covers people age 65 or older, regardless of income. Wilcoxon-Mann-Whitney rank sum tests were performed for continuous variables and chi-squared tests for categorical data. A multivariate analysis was performed using a Cox proportional hazards model to identify potential independent predictors of overall survival such as age, gender, ethnicity, neoadjuvant/adjuvant therapy, socioeconomic status, insurance status, tumor characteristics, and surgical margin status. RESULTS A total of 4679 patients were identified from the NCDB who received neoadjuvant chemoradiotherapy followed by surgery for esophageal adenocarcinoma. Patient demographics are demonstrated in the Table 1. The median age was 62 years (interquartile range (IQR): 55–68), with 4217 (90%) patients being male. The vast majority of patients receiving trimodality therapy (4306; 92.0%) did not receive adjuvant chemotherapy. Table 1 Patient demographics, stage I–III esophageal adenocarcinoma after trimodality therapy, N = 4679.     All      N = 4679      N (%)  Age  Median (IQR+)  62 (55–68)  Adjuvant chemotherapy  No  4306 (92)    Yes  373 (8)  Distance to hospital  <6 miles  969 (21)    6–15 miles  1107 (24)    15.1–44 miles  1356 (29)    >44 miles  1247 (27)  Sex  Male  4217 (90)    Female  462 (10)  Hospital type  Comprehensive  1479 (32)    Academic/research  2583 (55)    Community  254 (5)    Integrated network  264 (6)    Not given for age <40  89 (2)    Other or unknown  10 (0)  Primary insurance  Private insurance  2551 (55)    Medicaid  224 (5)    Medicare  1742 (37)    Not insured  110 (2)    Insurance status unknown  52 (1)  Reporting sources  Single facility NCDB report  3149 (67)    Multiple  1530 (33)  Income quartiles  <$30,000  429 (9)    $30,000–$35,999  827 (18)    $36,000–$45,999  1353 (29)    $46,000+  1899 (41)    Not available  171 (4)  High school non-Graduate rate quartiles  Q1 > = 29%  499 (11)    Q2 20–28.9%  1089 (23)    Q3 14–19.9%  1220 (26)    Q4 < 14%  1700 (36)    Not available  171 (4)  Urban/rural  Metro > 1 million  1932 (41)    Metro 250,000–1 million  974 (21)    Metro < 250,000  566 (12)    Urban > 20,000  394 (8)    Urban/rural < 20,000  646 (14)    Unknown  167 (4)  Age group  21–55  1239 (26)    56–62  1261 (27)    63–68  1158 (25)    69–89  1021 (22)  Diagnosis time period  2006–2008  1601 (34)    2009–2011  2169 (46)    2012–2013  909 (19)  Race/ethnicity  White  4499 (96)    Black  74 (2)    Hispanic white  86 (2)    Asian/Pacific islanders  20 (0)  Charlson index group  Low risk  3459 (74)    Intermediate risk  1001 (21)    High risk  219 (5)  Surgical approach  Open or unspecified  1370 (29)    Minimally invasive  564 (12)    Minimally invasive → open  71 (2)    Unknown surgical approach  2674 (57)  Grade  Well differentiated  190 (4)    Moderately differentiated  1608 (34)    Poorly differentiated  2160 (46)    Undifferentiated  74 (2)    Unknown grade  647 (14)  Tumor size  <3  949 (20)    3–4.9  1030 (22)    5+  1406 (30)    Unknown size  1294 (28)  Lymphovascular invasion  Not present  1354 (29)    Present  336 (7)    Not applicable  38 (1)    Unknown  2951 (63)  T pathologic group  T1  851 (18)    T2  959 (20)    T3  1887 (40)    T4  56 (1)    T0/Tis  694 (15)    TX  232 (5)  N pathologic group  N−  2771 (59)    N+  1908 (41)  Examined nodes  0–7  1271 (27)    8–12  1102 (24)    13–18  1066 (23)    19–83  1089 (23)    Unknown # nodes  151 (3)  Stage  I  842 (18)    II  2097 (45)    III  1740 (37)  Surgical margins  Negative  4326 (92)    Positive  279 (6)    Margins unknown/not applicable  74 (2)      All      N = 4679      N (%)  Age  Median (IQR+)  62 (55–68)  Adjuvant chemotherapy  No  4306 (92)    Yes  373 (8)  Distance to hospital  <6 miles  969 (21)    6–15 miles  1107 (24)    15.1–44 miles  1356 (29)    >44 miles  1247 (27)  Sex  Male  4217 (90)    Female  462 (10)  Hospital type  Comprehensive  1479 (32)    Academic/research  2583 (55)    Community  254 (5)    Integrated network  264 (6)    Not given for age <40  89 (2)    Other or unknown  10 (0)  Primary insurance  Private insurance  2551 (55)    Medicaid  224 (5)    Medicare  1742 (37)    Not insured  110 (2)    Insurance status unknown  52 (1)  Reporting sources  Single facility NCDB report  3149 (67)    Multiple  1530 (33)  Income quartiles  <$30,000  429 (9)    $30,000–$35,999  827 (18)    $36,000–$45,999  1353 (29)    $46,000+  1899 (41)    Not available  171 (4)  High school non-Graduate rate quartiles  Q1 > = 29%  499 (11)    Q2 20–28.9%  1089 (23)    Q3 14–19.9%  1220 (26)    Q4 < 14%  1700 (36)    Not available  171 (4)  Urban/rural  Metro > 1 million  1932 (41)    Metro 250,000–1 million  974 (21)    Metro < 250,000  566 (12)    Urban > 20,000  394 (8)    Urban/rural < 20,000  646 (14)    Unknown  167 (4)  Age group  21–55  1239 (26)    56–62  1261 (27)    63–68  1158 (25)    69–89  1021 (22)  Diagnosis time period  2006–2008  1601 (34)    2009–2011  2169 (46)    2012–2013  909 (19)  Race/ethnicity  White  4499 (96)    Black  74 (2)    Hispanic white  86 (2)    Asian/Pacific islanders  20 (0)  Charlson index group  Low risk  3459 (74)    Intermediate risk  1001 (21)    High risk  219 (5)  Surgical approach  Open or unspecified  1370 (29)    Minimally invasive  564 (12)    Minimally invasive → open  71 (2)    Unknown surgical approach  2674 (57)  Grade  Well differentiated  190 (4)    Moderately differentiated  1608 (34)    Poorly differentiated  2160 (46)    Undifferentiated  74 (2)    Unknown grade  647 (14)  Tumor size  <3  949 (20)    3–4.9  1030 (22)    5+  1406 (30)    Unknown size  1294 (28)  Lymphovascular invasion  Not present  1354 (29)    Present  336 (7)    Not applicable  38 (1)    Unknown  2951 (63)  T pathologic group  T1  851 (18)    T2  959 (20)    T3  1887 (40)    T4  56 (1)    T0/Tis  694 (15)    TX  232 (5)  N pathologic group  N−  2771 (59)    N+  1908 (41)  Examined nodes  0–7  1271 (27)    8–12  1102 (24)    13–18  1066 (23)    19–83  1089 (23)    Unknown # nodes  151 (3)  Stage  I  842 (18)    II  2097 (45)    III  1740 (37)  Surgical margins  Negative  4326 (92)    Positive  279 (6)    Margins unknown/not applicable  74 (2)  IQR, interquartile range; NCDB, National Cancer Database. View Large Table 1 Patient demographics, stage I–III esophageal adenocarcinoma after trimodality therapy, N = 4679.     All      N = 4679      N (%)  Age  Median (IQR+)  62 (55–68)  Adjuvant chemotherapy  No  4306 (92)    Yes  373 (8)  Distance to hospital  <6 miles  969 (21)    6–15 miles  1107 (24)    15.1–44 miles  1356 (29)    >44 miles  1247 (27)  Sex  Male  4217 (90)    Female  462 (10)  Hospital type  Comprehensive  1479 (32)    Academic/research  2583 (55)    Community  254 (5)    Integrated network  264 (6)    Not given for age <40  89 (2)    Other or unknown  10 (0)  Primary insurance  Private insurance  2551 (55)    Medicaid  224 (5)    Medicare  1742 (37)    Not insured  110 (2)    Insurance status unknown  52 (1)  Reporting sources  Single facility NCDB report  3149 (67)    Multiple  1530 (33)  Income quartiles  <$30,000  429 (9)    $30,000–$35,999  827 (18)    $36,000–$45,999  1353 (29)    $46,000+  1899 (41)    Not available  171 (4)  High school non-Graduate rate quartiles  Q1 > = 29%  499 (11)    Q2 20–28.9%  1089 (23)    Q3 14–19.9%  1220 (26)    Q4 < 14%  1700 (36)    Not available  171 (4)  Urban/rural  Metro > 1 million  1932 (41)    Metro 250,000–1 million  974 (21)    Metro < 250,000  566 (12)    Urban > 20,000  394 (8)    Urban/rural < 20,000  646 (14)    Unknown  167 (4)  Age group  21–55  1239 (26)    56–62  1261 (27)    63–68  1158 (25)    69–89  1021 (22)  Diagnosis time period  2006–2008  1601 (34)    2009–2011  2169 (46)    2012–2013  909 (19)  Race/ethnicity  White  4499 (96)    Black  74 (2)    Hispanic white  86 (2)    Asian/Pacific islanders  20 (0)  Charlson index group  Low risk  3459 (74)    Intermediate risk  1001 (21)    High risk  219 (5)  Surgical approach  Open or unspecified  1370 (29)    Minimally invasive  564 (12)    Minimally invasive → open  71 (2)    Unknown surgical approach  2674 (57)  Grade  Well differentiated  190 (4)    Moderately differentiated  1608 (34)    Poorly differentiated  2160 (46)    Undifferentiated  74 (2)    Unknown grade  647 (14)  Tumor size  <3  949 (20)    3–4.9  1030 (22)    5+  1406 (30)    Unknown size  1294 (28)  Lymphovascular invasion  Not present  1354 (29)    Present  336 (7)    Not applicable  38 (1)    Unknown  2951 (63)  T pathologic group  T1  851 (18)    T2  959 (20)    T3  1887 (40)    T4  56 (1)    T0/Tis  694 (15)    TX  232 (5)  N pathologic group  N−  2771 (59)    N+  1908 (41)  Examined nodes  0–7  1271 (27)    8–12  1102 (24)    13–18  1066 (23)    19–83  1089 (23)    Unknown # nodes  151 (3)  Stage  I  842 (18)    II  2097 (45)    III  1740 (37)  Surgical margins  Negative  4326 (92)    Positive  279 (6)    Margins unknown/not applicable  74 (2)      All      N = 4679      N (%)  Age  Median (IQR+)  62 (55–68)  Adjuvant chemotherapy  No  4306 (92)    Yes  373 (8)  Distance to hospital  <6 miles  969 (21)    6–15 miles  1107 (24)    15.1–44 miles  1356 (29)    >44 miles  1247 (27)  Sex  Male  4217 (90)    Female  462 (10)  Hospital type  Comprehensive  1479 (32)    Academic/research  2583 (55)    Community  254 (5)    Integrated network  264 (6)    Not given for age <40  89 (2)    Other or unknown  10 (0)  Primary insurance  Private insurance  2551 (55)    Medicaid  224 (5)    Medicare  1742 (37)    Not insured  110 (2)    Insurance status unknown  52 (1)  Reporting sources  Single facility NCDB report  3149 (67)    Multiple  1530 (33)  Income quartiles  <$30,000  429 (9)    $30,000–$35,999  827 (18)    $36,000–$45,999  1353 (29)    $46,000+  1899 (41)    Not available  171 (4)  High school non-Graduate rate quartiles  Q1 > = 29%  499 (11)    Q2 20–28.9%  1089 (23)    Q3 14–19.9%  1220 (26)    Q4 < 14%  1700 (36)    Not available  171 (4)  Urban/rural  Metro > 1 million  1932 (41)    Metro 250,000–1 million  974 (21)    Metro < 250,000  566 (12)    Urban > 20,000  394 (8)    Urban/rural < 20,000  646 (14)    Unknown  167 (4)  Age group  21–55  1239 (26)    56–62  1261 (27)    63–68  1158 (25)    69–89  1021 (22)  Diagnosis time period  2006–2008  1601 (34)    2009–2011  2169 (46)    2012–2013  909 (19)  Race/ethnicity  White  4499 (96)    Black  74 (2)    Hispanic white  86 (2)    Asian/Pacific islanders  20 (0)  Charlson index group  Low risk  3459 (74)    Intermediate risk  1001 (21)    High risk  219 (5)  Surgical approach  Open or unspecified  1370 (29)    Minimally invasive  564 (12)    Minimally invasive → open  71 (2)    Unknown surgical approach  2674 (57)  Grade  Well differentiated  190 (4)    Moderately differentiated  1608 (34)    Poorly differentiated  2160 (46)    Undifferentiated  74 (2)    Unknown grade  647 (14)  Tumor size  <3  949 (20)    3–4.9  1030 (22)    5+  1406 (30)    Unknown size  1294 (28)  Lymphovascular invasion  Not present  1354 (29)    Present  336 (7)    Not applicable  38 (1)    Unknown  2951 (63)  T pathologic group  T1  851 (18)    T2  959 (20)    T3  1887 (40)    T4  56 (1)    T0/Tis  694 (15)    TX  232 (5)  N pathologic group  N−  2771 (59)    N+  1908 (41)  Examined nodes  0–7  1271 (27)    8–12  1102 (24)    13–18  1066 (23)    19–83  1089 (23)    Unknown # nodes  151 (3)  Stage  I  842 (18)    II  2097 (45)    III  1740 (37)  Surgical margins  Negative  4326 (92)    Positive  279 (6)    Margins unknown/not applicable  74 (2)  IQR, interquartile range; NCDB, National Cancer Database. View Large On multivariate analysis, pathologic characteristics associated with decreased overall survival included stage, lymphovascular invasion, and positive surgical margins (Fig. 1). Insurance status, age, and comorbidity index were also associated with decreased survival. We found that patients who received additional adjuvant chemotherapy had a trend toward improved overall survival (HR 0.87, CI 0.76–1.01, P = 0.0636). Treatment at an academic/research hospital, as well as greater lymph node yields, was associated with improved overall survival. Compared to private insurance, Medicare (HR 1.17, CI 1.04–1.31, P = 0.0082), Medicaid (HR 1.45, CI 1.22–1.73, P < 0.0001), or having no insurance (HR 1.50, CI 1.17–1.92, P = 0.0012) were all negative predictors of overall survival. Patients who received adjuvant chemotherapy were more likely to have private insurance (69 vs. 53%, P < 0.0001). Fig. 1 View largeDownload slide Multivariate hazard ratios and 95% confidence intervals, overall cohort. *Hospital type is not reported routinely in this national database for patients under the age of 40 in an effort to protect confidentiality. While this subgroup is not shown in this Figure, it was included in the analysis. Fig. 1 View largeDownload slide Multivariate hazard ratios and 95% confidence intervals, overall cohort. *Hospital type is not reported routinely in this national database for patients under the age of 40 in an effort to protect confidentiality. While this subgroup is not shown in this Figure, it was included in the analysis. On final pathology, 1908 (41%) patients had node-positive disease. In the node-positive subgroup, patients who underwent adjuvant chemotherapy had improved survival (HR 0.74, CI 0.63–0.88, P = 0.0005) (Fig. 2), whereas adjuvant chemotherapy was not associated with improved survival in the node-negative subgroup. Compared to private insurance, Medicaid (HR 1.40, CI 1.09–1.80, P = 0.0081) or having no insurance (HR 1.71, CI 1.24–2.35, P = 0.0011) were negative predictors of overall survival in node-positive patients. Median overall survival in patients with node-positive disease who received adjuvant chemotherapy was 30.9 months, in contrast to 23.1 months in patients who did not (log-rank p-value, 0.0001), shown in Figure 3. Fig. 2 View largeDownload slide Multivariate hazard ratios and 95% confidence intervals, Node-positive cohort. *Hospital type is not reported routinely in this national database for patients under the age of 40 in an effort to protect confidentiality. While this subgroup is not shown in this Figure, it was included in the analysis. Fig. 2 View largeDownload slide Multivariate hazard ratios and 95% confidence intervals, Node-positive cohort. *Hospital type is not reported routinely in this national database for patients under the age of 40 in an effort to protect confidentiality. While this subgroup is not shown in this Figure, it was included in the analysis. Fig. 3 View largeDownload slide Overall survival probability stratified by adjuvant chemotherapy, node-positive patients. Fig. 3 View largeDownload slide Overall survival probability stratified by adjuvant chemotherapy, node-positive patients. DISCUSSION Significant disparities in esophageal cancer outcomes are known.4,5 Previous research has found that much of the disparities in outcomes is attributable to differences in treatment, with non-White patients and lower socioeconomic status patients less likely to receive surgery.4 In this study, we found that certain socioeconomic factors such as insurance status and rural setting continued to be associated with survival even among patients who all received standard of care, trimodality therapy. These socioeconomic factors are often associated with comorbidities, but in our multivariate analysis, each was independently associated with survival. Many of the significant sociodemographic factors were related to access to tertiary care (insurance status, hospital type, location). In fact, insurance status was a stronger predictor of survival than many other factors, including the use of adjuvant chemotherapy. This leads us to wonder: Why do sociodemographic disparities persist? Why may outcomes be different when patients with different social determinants of health receive the same treatment? Perhaps these findings highlight the notion that medical care in patients with esophageal cancer or other malignancies does not simply end after receiving the indexed treatment, and that surveillance in itself is equally important in the care of these patients. For example, in other malignancies, adherence to posttreatment surveillance has been shown to be associated with improved overall survival.11 Currently, NCCN guidelines recommend the following as part of surveillance: history and physical examinations every 3–6 months for 1–2 years, every 6–12 months for 3–5 years, and annually thereafter, with laboratory testing and imaging as indicated and stratified by pathologic staging.12 Patients undergoing esophagectomy may also be a patient population with unique long-term needs. Studies have found that although overall long-term quality of life is similar to the general populations, certain symptoms, such as aspiration, persist after esophagectomy.13 There are also emerging data regarding the impact of social determinants of health on life expectancy beyond just treatment disparities.14 Another interesting finding was the impact of adjuvant chemotherapy on survival. Although not part of NCCN guidelines, 8% of patients in this study received adjuvant chemotherapy. Similar to a recent publication by Burt et al., we found that adjuvant chemotherapy was associated with a lower risk of death in patients with residual nodal disease (ypTanyN+), but not among all patients.8 It is unclear why these patients were offered adjuvant therapy, but it does not appear to be random. Patients were much more likely to be given adjuvant chemotherapy if they had node-positive disease. As such, limitations of this study include its retrospective, observational design. Inherent to this is selection bias, as we do not have information on why or why not adjuvant chemotherapy was administered. Unfortunately, the NCDB does not have data on perioperative morbidity or details on chemotherapy and radiation regimens/techniques, both of which could potentially significantly impact decision-making. Not all data with regards to all variables were available, as indicated by some categories of ‘unknown’ or ‘absence of data.’ For example, hospital type is not recorded for patients under the age of 40 due to an effort to maintain confidentiality in accordance with national regulations. Finally, the NCDB does not incorporate data from all hospitals in the United States, and thus perhaps this patient population may not be truly representative of outcomes and practices nationwide. In conclusion, we found that in patients with esophageal adenocarcinoma who have undergone trimodality therapy, a number of different factors are associated with survival: biology of the disease, health of the patient, access to care, and adjuvant chemotherapy. Characteristics such as advanced pathologic stage, positive margins, octogenarians, and patients with comorbidities are, as expected, associated with decreased survival. However, sociodemographic factors relating to access to care are also important predictors of survival. Despite receiving the standard of care, treatment disparities persist in this population of patients. References 1 Siegel R L, Miller K D, Jemal A. Cancer statistics, 2016. CA Cancer J Clin  2016; 66: 7– 30. Google Scholar CrossRef Search ADS PubMed  2 Shapiro J, van Lanschot J J, Hulshof M C et al.   Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol  2015; 16: 1090– 8. Google Scholar CrossRef Search ADS PubMed  3 Ajani J A, D’Amico T A, Almhanna K et al.   Esophageal and esophagogastric junction cancers, version 1.2015. J Natl Compr Canc Netw  2015; 13: 194– 227. Google Scholar CrossRef Search ADS PubMed  4 Revels S L, Morris A M, Reddy R M, Akateh C, Wong S L. Racial disparities in esophageal cancer outcomes. Ann Surg Oncol  2013: 20; 1136– 41. doi:10.1245/s10434-012-2807-3. Google Scholar CrossRef Search ADS PubMed  5 Merkow R P, Bilimoria K Y, McCarter M D, Chow W B, Ko C Y, Bentrem D J. Use of multimodality neoadjuvant therapy for esophageal cancer in the United States: assessment of 987 hospitals. Ann Surg Oncol  2012; 19: 357– 64. Google Scholar CrossRef Search ADS PubMed  6 Markt S C, Lago-Hernandez C A, Miller R E et al.   Insurance status and disparities in disease presentation, treatment, and outcomes for men with germ cell tumors. Cancer  2016; 122: 3127– 35. Google Scholar CrossRef Search ADS PubMed  7 Rong X, Yang W, Garzon-Muvdi T et al.   Influence of insurance status on survival of adults with glioblastoma multiforme: a population-based study. Cancer  2016; 122: 3157– 65. Google Scholar CrossRef Search ADS PubMed  8 Burt B M, Groth S S, Sada Y H et al.   Utility of Adjuvant chemotherapy after neoadjuvant chemoradiation and esophagectomy for esophageal cancer. Ann Surg  2017; 266: 297– 304. Google Scholar CrossRef Search ADS PubMed  9 Lin C C, Bruinooge S S, Kirkwood M K et al.   Association between geographic access to cancer care, insurance, and receipt of chemotherapy: geographic distribution of oncologists and travel distance. J Clin Oncol  2015; 33: 3177– 85. Google Scholar CrossRef Search ADS PubMed  10 Commission on Cancer: About Program Categories. https://www.facs.org/quality-programs/cancer/coc/apply/categories. Accessed August 1, 2018. 11 Deutschmann M W, Sykes K J, Harbison J, Cabrera-Muffly C, Shnayder Y. The impact of compliance in posttreatment surveillance in head and neck squamous cell carcinoma. JAMA Otolaryngol Head Neck Surg  2015; 141: 519– 25. Google Scholar CrossRef Search ADS PubMed  12 NCCN Guidelines® & Clinical Resources. https://www.nccn.org/professionals/physician_gls/default.aspx. Accessed August 1, 2018. 13 Derogar M, Lagergren P. Health-related quality of life among 5-year survivors of esophageal cancer surgery: a prospective population-based study. J Clin Oncol  2012; 30: 413– 8. Google Scholar CrossRef Search ADS PubMed  14 Djarv T, Lagergren P. Six-month postoperative quality of life predicts long-term survival after oesophageal cancer surgery. Eur J Cancer  2011; 47: 530– 5. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Diseases of the Esophagus Oxford University Press

Disparities in survival after trimodality therapy for esophageal adenocarcinoma

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The International Society for Diseases of the Esophagus
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© The Author(s) 2018. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
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1120-8694
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1442-2050
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10.1093/dote/doy020
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Abstract

SUMMARY Trimodality therapy with neoadjuvant chemoradiation followed by surgery has emerged as the standard of care for the treatment of locally advanced esophageal cancer. Yet, there is considerable variation in survival within this population. We sought to analyze factors associated with survival after trimodality therapy in esophageal adenocarcinoma. We identified 4,679 patients from the National Cancer Database (NCDB) of the American College of Surgeons who received chemotherapy and radiation prior to surgery for esophageal adenocarcinoma from 2006 to 2013. We excluded patients with stage IV disease and unknown pathological nodal status. We performed regression analyses using a Cox proportional hazards model to identify independent predictors of overall survival. On multivariate analysis, pathologic characteristics associated with decreased overall survival included stage, lymphovascular invasion, and positive surgical margins. Insurance status, age, and comorbidity index were also associated with decreased survival. We found that pathologically node-positive patients who received additional adjuvant chemotherapy were associated with improved survival. Compared to private insurance, Medicaid (HR 1.45, CI 1.22–1.73, P < 0.0001), Medicare (HR 1.17, CI 1.04–1.31, P = 0.0082), or having no insurance (HR 1.50, CI 1.17–1.92, P = 0.0012) were all negative predictors of overall survival. In patients with esophageal adenocarcinoma who have undergone trimodality therapy, a number of different factors are associated with overall survival. In particular, socioeconomic factors relating to access to care are independent predictors of survival. Despite receiving the standard of care, treatment disparities persist in this population of patients. INTRODUCTION Each year, an estimated 15,690 deaths are expected from esophageal cancer, with only 19% of esophageal cancer patients surviving at five years.1 Trimodality therapy with neoadjuvant chemoradiation followed by surgery has been shown to improve survival compared to surgery alone for the treatment of locally advanced esophageal cancer.2 The findings of the CROSS trial have provided the basis for current National Comprehensive Cancer Network (NCCN) guidelines for the role of neoadjuvant therapy in the management of esophageal cancer; however, there is considerable variation in survival in this population.3 In addition, barriers to receiving neoadjuvant therapy are multifactorial, including age, comorbidities, and insurance status.4,5 As current NCCN guidelines recommend surveillance after trimodality therapy, identifying factors associated with survival after trimodality therapy remains an area of investigation. Recently, socioeconomic factors such as insurance status have been shown to be an independent predictor of survival in other forms of cancer.6,7 A retrospective study using the National Cancer Database (NCDB) demonstrated a survival benefit with adjuvant chemotherapy after trimodality therapy in pathologically node-positive esophageal adenocarcinoma patients.8 Yet, even in cancers where NCCN guidelines include adjuvant therapy, socioeconomic factors can serve as barriers to receive adjuvant treatment.9 In this study, we sought to analyze a variety of factors, including insurance status and adjuvant chemotherapy, to identify independent predictors of survival after trimodality therapy in esophageal adenocarcinoma. METHODS An Institutional Review Board approved retrospective analysis of the NCDB for patients who underwent esophagectomy for esophageal cancer from 2006 to 2013. The NCDB is a comprehensive clinical oncology database comprised of information from over 1500 Commission on Cancer (CoC)-accredited institutions, accounting for approximately 70% of newly diagnosed cancer cases across the United States. We performed stepwise inclusion and exclusion counts on an initial subset of patients identified to have a diagnosis of esophageal cancer as defined by the International Classification for Diseases, 3rd edn. Inclusion criteria included patients aged 18–90 years who underwent esophagectomy for esophageal adenocarcinoma, whom were treated with either neoadjuvant chemoradiotherapy only or neoadjuvant chemoradiotherapy and adjuvant chemotherapy. We excluded patients with stage IV disease, unknown pathological nodal status, a history of prior malignancy, and those with no followup information. TNM staging was assessed according to the American Joint Commission on Cancer 7th ed. staging definitions. Overall patient demographics and tumor characteristics were recorded and compared between groups. Hospital types were reported on the basis of cancer program categories as designated by the CoC.10 Insurance types reported included patients either with private insurance, not insured, or with Medicaid or Medicare. Medicaid is a government insurance program primarily for patients with limited income. Medicare is a government insurance program, which covers people age 65 or older, regardless of income. Wilcoxon-Mann-Whitney rank sum tests were performed for continuous variables and chi-squared tests for categorical data. A multivariate analysis was performed using a Cox proportional hazards model to identify potential independent predictors of overall survival such as age, gender, ethnicity, neoadjuvant/adjuvant therapy, socioeconomic status, insurance status, tumor characteristics, and surgical margin status. RESULTS A total of 4679 patients were identified from the NCDB who received neoadjuvant chemoradiotherapy followed by surgery for esophageal adenocarcinoma. Patient demographics are demonstrated in the Table 1. The median age was 62 years (interquartile range (IQR): 55–68), with 4217 (90%) patients being male. The vast majority of patients receiving trimodality therapy (4306; 92.0%) did not receive adjuvant chemotherapy. Table 1 Patient demographics, stage I–III esophageal adenocarcinoma after trimodality therapy, N = 4679.     All      N = 4679      N (%)  Age  Median (IQR+)  62 (55–68)  Adjuvant chemotherapy  No  4306 (92)    Yes  373 (8)  Distance to hospital  <6 miles  969 (21)    6–15 miles  1107 (24)    15.1–44 miles  1356 (29)    >44 miles  1247 (27)  Sex  Male  4217 (90)    Female  462 (10)  Hospital type  Comprehensive  1479 (32)    Academic/research  2583 (55)    Community  254 (5)    Integrated network  264 (6)    Not given for age <40  89 (2)    Other or unknown  10 (0)  Primary insurance  Private insurance  2551 (55)    Medicaid  224 (5)    Medicare  1742 (37)    Not insured  110 (2)    Insurance status unknown  52 (1)  Reporting sources  Single facility NCDB report  3149 (67)    Multiple  1530 (33)  Income quartiles  <$30,000  429 (9)    $30,000–$35,999  827 (18)    $36,000–$45,999  1353 (29)    $46,000+  1899 (41)    Not available  171 (4)  High school non-Graduate rate quartiles  Q1 > = 29%  499 (11)    Q2 20–28.9%  1089 (23)    Q3 14–19.9%  1220 (26)    Q4 < 14%  1700 (36)    Not available  171 (4)  Urban/rural  Metro > 1 million  1932 (41)    Metro 250,000–1 million  974 (21)    Metro < 250,000  566 (12)    Urban > 20,000  394 (8)    Urban/rural < 20,000  646 (14)    Unknown  167 (4)  Age group  21–55  1239 (26)    56–62  1261 (27)    63–68  1158 (25)    69–89  1021 (22)  Diagnosis time period  2006–2008  1601 (34)    2009–2011  2169 (46)    2012–2013  909 (19)  Race/ethnicity  White  4499 (96)    Black  74 (2)    Hispanic white  86 (2)    Asian/Pacific islanders  20 (0)  Charlson index group  Low risk  3459 (74)    Intermediate risk  1001 (21)    High risk  219 (5)  Surgical approach  Open or unspecified  1370 (29)    Minimally invasive  564 (12)    Minimally invasive → open  71 (2)    Unknown surgical approach  2674 (57)  Grade  Well differentiated  190 (4)    Moderately differentiated  1608 (34)    Poorly differentiated  2160 (46)    Undifferentiated  74 (2)    Unknown grade  647 (14)  Tumor size  <3  949 (20)    3–4.9  1030 (22)    5+  1406 (30)    Unknown size  1294 (28)  Lymphovascular invasion  Not present  1354 (29)    Present  336 (7)    Not applicable  38 (1)    Unknown  2951 (63)  T pathologic group  T1  851 (18)    T2  959 (20)    T3  1887 (40)    T4  56 (1)    T0/Tis  694 (15)    TX  232 (5)  N pathologic group  N−  2771 (59)    N+  1908 (41)  Examined nodes  0–7  1271 (27)    8–12  1102 (24)    13–18  1066 (23)    19–83  1089 (23)    Unknown # nodes  151 (3)  Stage  I  842 (18)    II  2097 (45)    III  1740 (37)  Surgical margins  Negative  4326 (92)    Positive  279 (6)    Margins unknown/not applicable  74 (2)      All      N = 4679      N (%)  Age  Median (IQR+)  62 (55–68)  Adjuvant chemotherapy  No  4306 (92)    Yes  373 (8)  Distance to hospital  <6 miles  969 (21)    6–15 miles  1107 (24)    15.1–44 miles  1356 (29)    >44 miles  1247 (27)  Sex  Male  4217 (90)    Female  462 (10)  Hospital type  Comprehensive  1479 (32)    Academic/research  2583 (55)    Community  254 (5)    Integrated network  264 (6)    Not given for age <40  89 (2)    Other or unknown  10 (0)  Primary insurance  Private insurance  2551 (55)    Medicaid  224 (5)    Medicare  1742 (37)    Not insured  110 (2)    Insurance status unknown  52 (1)  Reporting sources  Single facility NCDB report  3149 (67)    Multiple  1530 (33)  Income quartiles  <$30,000  429 (9)    $30,000–$35,999  827 (18)    $36,000–$45,999  1353 (29)    $46,000+  1899 (41)    Not available  171 (4)  High school non-Graduate rate quartiles  Q1 > = 29%  499 (11)    Q2 20–28.9%  1089 (23)    Q3 14–19.9%  1220 (26)    Q4 < 14%  1700 (36)    Not available  171 (4)  Urban/rural  Metro > 1 million  1932 (41)    Metro 250,000–1 million  974 (21)    Metro < 250,000  566 (12)    Urban > 20,000  394 (8)    Urban/rural < 20,000  646 (14)    Unknown  167 (4)  Age group  21–55  1239 (26)    56–62  1261 (27)    63–68  1158 (25)    69–89  1021 (22)  Diagnosis time period  2006–2008  1601 (34)    2009–2011  2169 (46)    2012–2013  909 (19)  Race/ethnicity  White  4499 (96)    Black  74 (2)    Hispanic white  86 (2)    Asian/Pacific islanders  20 (0)  Charlson index group  Low risk  3459 (74)    Intermediate risk  1001 (21)    High risk  219 (5)  Surgical approach  Open or unspecified  1370 (29)    Minimally invasive  564 (12)    Minimally invasive → open  71 (2)    Unknown surgical approach  2674 (57)  Grade  Well differentiated  190 (4)    Moderately differentiated  1608 (34)    Poorly differentiated  2160 (46)    Undifferentiated  74 (2)    Unknown grade  647 (14)  Tumor size  <3  949 (20)    3–4.9  1030 (22)    5+  1406 (30)    Unknown size  1294 (28)  Lymphovascular invasion  Not present  1354 (29)    Present  336 (7)    Not applicable  38 (1)    Unknown  2951 (63)  T pathologic group  T1  851 (18)    T2  959 (20)    T3  1887 (40)    T4  56 (1)    T0/Tis  694 (15)    TX  232 (5)  N pathologic group  N−  2771 (59)    N+  1908 (41)  Examined nodes  0–7  1271 (27)    8–12  1102 (24)    13–18  1066 (23)    19–83  1089 (23)    Unknown # nodes  151 (3)  Stage  I  842 (18)    II  2097 (45)    III  1740 (37)  Surgical margins  Negative  4326 (92)    Positive  279 (6)    Margins unknown/not applicable  74 (2)  IQR, interquartile range; NCDB, National Cancer Database. View Large Table 1 Patient demographics, stage I–III esophageal adenocarcinoma after trimodality therapy, N = 4679.     All      N = 4679      N (%)  Age  Median (IQR+)  62 (55–68)  Adjuvant chemotherapy  No  4306 (92)    Yes  373 (8)  Distance to hospital  <6 miles  969 (21)    6–15 miles  1107 (24)    15.1–44 miles  1356 (29)    >44 miles  1247 (27)  Sex  Male  4217 (90)    Female  462 (10)  Hospital type  Comprehensive  1479 (32)    Academic/research  2583 (55)    Community  254 (5)    Integrated network  264 (6)    Not given for age <40  89 (2)    Other or unknown  10 (0)  Primary insurance  Private insurance  2551 (55)    Medicaid  224 (5)    Medicare  1742 (37)    Not insured  110 (2)    Insurance status unknown  52 (1)  Reporting sources  Single facility NCDB report  3149 (67)    Multiple  1530 (33)  Income quartiles  <$30,000  429 (9)    $30,000–$35,999  827 (18)    $36,000–$45,999  1353 (29)    $46,000+  1899 (41)    Not available  171 (4)  High school non-Graduate rate quartiles  Q1 > = 29%  499 (11)    Q2 20–28.9%  1089 (23)    Q3 14–19.9%  1220 (26)    Q4 < 14%  1700 (36)    Not available  171 (4)  Urban/rural  Metro > 1 million  1932 (41)    Metro 250,000–1 million  974 (21)    Metro < 250,000  566 (12)    Urban > 20,000  394 (8)    Urban/rural < 20,000  646 (14)    Unknown  167 (4)  Age group  21–55  1239 (26)    56–62  1261 (27)    63–68  1158 (25)    69–89  1021 (22)  Diagnosis time period  2006–2008  1601 (34)    2009–2011  2169 (46)    2012–2013  909 (19)  Race/ethnicity  White  4499 (96)    Black  74 (2)    Hispanic white  86 (2)    Asian/Pacific islanders  20 (0)  Charlson index group  Low risk  3459 (74)    Intermediate risk  1001 (21)    High risk  219 (5)  Surgical approach  Open or unspecified  1370 (29)    Minimally invasive  564 (12)    Minimally invasive → open  71 (2)    Unknown surgical approach  2674 (57)  Grade  Well differentiated  190 (4)    Moderately differentiated  1608 (34)    Poorly differentiated  2160 (46)    Undifferentiated  74 (2)    Unknown grade  647 (14)  Tumor size  <3  949 (20)    3–4.9  1030 (22)    5+  1406 (30)    Unknown size  1294 (28)  Lymphovascular invasion  Not present  1354 (29)    Present  336 (7)    Not applicable  38 (1)    Unknown  2951 (63)  T pathologic group  T1  851 (18)    T2  959 (20)    T3  1887 (40)    T4  56 (1)    T0/Tis  694 (15)    TX  232 (5)  N pathologic group  N−  2771 (59)    N+  1908 (41)  Examined nodes  0–7  1271 (27)    8–12  1102 (24)    13–18  1066 (23)    19–83  1089 (23)    Unknown # nodes  151 (3)  Stage  I  842 (18)    II  2097 (45)    III  1740 (37)  Surgical margins  Negative  4326 (92)    Positive  279 (6)    Margins unknown/not applicable  74 (2)      All      N = 4679      N (%)  Age  Median (IQR+)  62 (55–68)  Adjuvant chemotherapy  No  4306 (92)    Yes  373 (8)  Distance to hospital  <6 miles  969 (21)    6–15 miles  1107 (24)    15.1–44 miles  1356 (29)    >44 miles  1247 (27)  Sex  Male  4217 (90)    Female  462 (10)  Hospital type  Comprehensive  1479 (32)    Academic/research  2583 (55)    Community  254 (5)    Integrated network  264 (6)    Not given for age <40  89 (2)    Other or unknown  10 (0)  Primary insurance  Private insurance  2551 (55)    Medicaid  224 (5)    Medicare  1742 (37)    Not insured  110 (2)    Insurance status unknown  52 (1)  Reporting sources  Single facility NCDB report  3149 (67)    Multiple  1530 (33)  Income quartiles  <$30,000  429 (9)    $30,000–$35,999  827 (18)    $36,000–$45,999  1353 (29)    $46,000+  1899 (41)    Not available  171 (4)  High school non-Graduate rate quartiles  Q1 > = 29%  499 (11)    Q2 20–28.9%  1089 (23)    Q3 14–19.9%  1220 (26)    Q4 < 14%  1700 (36)    Not available  171 (4)  Urban/rural  Metro > 1 million  1932 (41)    Metro 250,000–1 million  974 (21)    Metro < 250,000  566 (12)    Urban > 20,000  394 (8)    Urban/rural < 20,000  646 (14)    Unknown  167 (4)  Age group  21–55  1239 (26)    56–62  1261 (27)    63–68  1158 (25)    69–89  1021 (22)  Diagnosis time period  2006–2008  1601 (34)    2009–2011  2169 (46)    2012–2013  909 (19)  Race/ethnicity  White  4499 (96)    Black  74 (2)    Hispanic white  86 (2)    Asian/Pacific islanders  20 (0)  Charlson index group  Low risk  3459 (74)    Intermediate risk  1001 (21)    High risk  219 (5)  Surgical approach  Open or unspecified  1370 (29)    Minimally invasive  564 (12)    Minimally invasive → open  71 (2)    Unknown surgical approach  2674 (57)  Grade  Well differentiated  190 (4)    Moderately differentiated  1608 (34)    Poorly differentiated  2160 (46)    Undifferentiated  74 (2)    Unknown grade  647 (14)  Tumor size  <3  949 (20)    3–4.9  1030 (22)    5+  1406 (30)    Unknown size  1294 (28)  Lymphovascular invasion  Not present  1354 (29)    Present  336 (7)    Not applicable  38 (1)    Unknown  2951 (63)  T pathologic group  T1  851 (18)    T2  959 (20)    T3  1887 (40)    T4  56 (1)    T0/Tis  694 (15)    TX  232 (5)  N pathologic group  N−  2771 (59)    N+  1908 (41)  Examined nodes  0–7  1271 (27)    8–12  1102 (24)    13–18  1066 (23)    19–83  1089 (23)    Unknown # nodes  151 (3)  Stage  I  842 (18)    II  2097 (45)    III  1740 (37)  Surgical margins  Negative  4326 (92)    Positive  279 (6)    Margins unknown/not applicable  74 (2)  IQR, interquartile range; NCDB, National Cancer Database. View Large On multivariate analysis, pathologic characteristics associated with decreased overall survival included stage, lymphovascular invasion, and positive surgical margins (Fig. 1). Insurance status, age, and comorbidity index were also associated with decreased survival. We found that patients who received additional adjuvant chemotherapy had a trend toward improved overall survival (HR 0.87, CI 0.76–1.01, P = 0.0636). Treatment at an academic/research hospital, as well as greater lymph node yields, was associated with improved overall survival. Compared to private insurance, Medicare (HR 1.17, CI 1.04–1.31, P = 0.0082), Medicaid (HR 1.45, CI 1.22–1.73, P < 0.0001), or having no insurance (HR 1.50, CI 1.17–1.92, P = 0.0012) were all negative predictors of overall survival. Patients who received adjuvant chemotherapy were more likely to have private insurance (69 vs. 53%, P < 0.0001). Fig. 1 View largeDownload slide Multivariate hazard ratios and 95% confidence intervals, overall cohort. *Hospital type is not reported routinely in this national database for patients under the age of 40 in an effort to protect confidentiality. While this subgroup is not shown in this Figure, it was included in the analysis. Fig. 1 View largeDownload slide Multivariate hazard ratios and 95% confidence intervals, overall cohort. *Hospital type is not reported routinely in this national database for patients under the age of 40 in an effort to protect confidentiality. While this subgroup is not shown in this Figure, it was included in the analysis. On final pathology, 1908 (41%) patients had node-positive disease. In the node-positive subgroup, patients who underwent adjuvant chemotherapy had improved survival (HR 0.74, CI 0.63–0.88, P = 0.0005) (Fig. 2), whereas adjuvant chemotherapy was not associated with improved survival in the node-negative subgroup. Compared to private insurance, Medicaid (HR 1.40, CI 1.09–1.80, P = 0.0081) or having no insurance (HR 1.71, CI 1.24–2.35, P = 0.0011) were negative predictors of overall survival in node-positive patients. Median overall survival in patients with node-positive disease who received adjuvant chemotherapy was 30.9 months, in contrast to 23.1 months in patients who did not (log-rank p-value, 0.0001), shown in Figure 3. Fig. 2 View largeDownload slide Multivariate hazard ratios and 95% confidence intervals, Node-positive cohort. *Hospital type is not reported routinely in this national database for patients under the age of 40 in an effort to protect confidentiality. While this subgroup is not shown in this Figure, it was included in the analysis. Fig. 2 View largeDownload slide Multivariate hazard ratios and 95% confidence intervals, Node-positive cohort. *Hospital type is not reported routinely in this national database for patients under the age of 40 in an effort to protect confidentiality. While this subgroup is not shown in this Figure, it was included in the analysis. Fig. 3 View largeDownload slide Overall survival probability stratified by adjuvant chemotherapy, node-positive patients. Fig. 3 View largeDownload slide Overall survival probability stratified by adjuvant chemotherapy, node-positive patients. DISCUSSION Significant disparities in esophageal cancer outcomes are known.4,5 Previous research has found that much of the disparities in outcomes is attributable to differences in treatment, with non-White patients and lower socioeconomic status patients less likely to receive surgery.4 In this study, we found that certain socioeconomic factors such as insurance status and rural setting continued to be associated with survival even among patients who all received standard of care, trimodality therapy. These socioeconomic factors are often associated with comorbidities, but in our multivariate analysis, each was independently associated with survival. Many of the significant sociodemographic factors were related to access to tertiary care (insurance status, hospital type, location). In fact, insurance status was a stronger predictor of survival than many other factors, including the use of adjuvant chemotherapy. This leads us to wonder: Why do sociodemographic disparities persist? Why may outcomes be different when patients with different social determinants of health receive the same treatment? Perhaps these findings highlight the notion that medical care in patients with esophageal cancer or other malignancies does not simply end after receiving the indexed treatment, and that surveillance in itself is equally important in the care of these patients. For example, in other malignancies, adherence to posttreatment surveillance has been shown to be associated with improved overall survival.11 Currently, NCCN guidelines recommend the following as part of surveillance: history and physical examinations every 3–6 months for 1–2 years, every 6–12 months for 3–5 years, and annually thereafter, with laboratory testing and imaging as indicated and stratified by pathologic staging.12 Patients undergoing esophagectomy may also be a patient population with unique long-term needs. Studies have found that although overall long-term quality of life is similar to the general populations, certain symptoms, such as aspiration, persist after esophagectomy.13 There are also emerging data regarding the impact of social determinants of health on life expectancy beyond just treatment disparities.14 Another interesting finding was the impact of adjuvant chemotherapy on survival. Although not part of NCCN guidelines, 8% of patients in this study received adjuvant chemotherapy. Similar to a recent publication by Burt et al., we found that adjuvant chemotherapy was associated with a lower risk of death in patients with residual nodal disease (ypTanyN+), but not among all patients.8 It is unclear why these patients were offered adjuvant therapy, but it does not appear to be random. Patients were much more likely to be given adjuvant chemotherapy if they had node-positive disease. As such, limitations of this study include its retrospective, observational design. Inherent to this is selection bias, as we do not have information on why or why not adjuvant chemotherapy was administered. Unfortunately, the NCDB does not have data on perioperative morbidity or details on chemotherapy and radiation regimens/techniques, both of which could potentially significantly impact decision-making. Not all data with regards to all variables were available, as indicated by some categories of ‘unknown’ or ‘absence of data.’ For example, hospital type is not recorded for patients under the age of 40 due to an effort to maintain confidentiality in accordance with national regulations. Finally, the NCDB does not incorporate data from all hospitals in the United States, and thus perhaps this patient population may not be truly representative of outcomes and practices nationwide. In conclusion, we found that in patients with esophageal adenocarcinoma who have undergone trimodality therapy, a number of different factors are associated with survival: biology of the disease, health of the patient, access to care, and adjuvant chemotherapy. Characteristics such as advanced pathologic stage, positive margins, octogenarians, and patients with comorbidities are, as expected, associated with decreased survival. However, sociodemographic factors relating to access to care are also important predictors of survival. Despite receiving the standard of care, treatment disparities persist in this population of patients. References 1 Siegel R L, Miller K D, Jemal A. Cancer statistics, 2016. CA Cancer J Clin  2016; 66: 7– 30. Google Scholar CrossRef Search ADS PubMed  2 Shapiro J, van Lanschot J J, Hulshof M C et al.   Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol  2015; 16: 1090– 8. Google Scholar CrossRef Search ADS PubMed  3 Ajani J A, D’Amico T A, Almhanna K et al.   Esophageal and esophagogastric junction cancers, version 1.2015. J Natl Compr Canc Netw  2015; 13: 194– 227. Google Scholar CrossRef Search ADS PubMed  4 Revels S L, Morris A M, Reddy R M, Akateh C, Wong S L. Racial disparities in esophageal cancer outcomes. Ann Surg Oncol  2013: 20; 1136– 41. doi:10.1245/s10434-012-2807-3. Google Scholar CrossRef Search ADS PubMed  5 Merkow R P, Bilimoria K Y, McCarter M D, Chow W B, Ko C Y, Bentrem D J. Use of multimodality neoadjuvant therapy for esophageal cancer in the United States: assessment of 987 hospitals. Ann Surg Oncol  2012; 19: 357– 64. Google Scholar CrossRef Search ADS PubMed  6 Markt S C, Lago-Hernandez C A, Miller R E et al.   Insurance status and disparities in disease presentation, treatment, and outcomes for men with germ cell tumors. Cancer  2016; 122: 3127– 35. Google Scholar CrossRef Search ADS PubMed  7 Rong X, Yang W, Garzon-Muvdi T et al.   Influence of insurance status on survival of adults with glioblastoma multiforme: a population-based study. Cancer  2016; 122: 3157– 65. Google Scholar CrossRef Search ADS PubMed  8 Burt B M, Groth S S, Sada Y H et al.   Utility of Adjuvant chemotherapy after neoadjuvant chemoradiation and esophagectomy for esophageal cancer. Ann Surg  2017; 266: 297– 304. Google Scholar CrossRef Search ADS PubMed  9 Lin C C, Bruinooge S S, Kirkwood M K et al.   Association between geographic access to cancer care, insurance, and receipt of chemotherapy: geographic distribution of oncologists and travel distance. J Clin Oncol  2015; 33: 3177– 85. Google Scholar CrossRef Search ADS PubMed  10 Commission on Cancer: About Program Categories. https://www.facs.org/quality-programs/cancer/coc/apply/categories. Accessed August 1, 2018. 11 Deutschmann M W, Sykes K J, Harbison J, Cabrera-Muffly C, Shnayder Y. The impact of compliance in posttreatment surveillance in head and neck squamous cell carcinoma. JAMA Otolaryngol Head Neck Surg  2015; 141: 519– 25. Google Scholar CrossRef Search ADS PubMed  12 NCCN Guidelines® & Clinical Resources. https://www.nccn.org/professionals/physician_gls/default.aspx. Accessed August 1, 2018. 13 Derogar M, Lagergren P. Health-related quality of life among 5-year survivors of esophageal cancer surgery: a prospective population-based study. J Clin Oncol  2012; 30: 413– 8. Google Scholar CrossRef Search ADS PubMed  14 Djarv T, Lagergren P. Six-month postoperative quality of life predicts long-term survival after oesophageal cancer surgery. Eur J Cancer  2011; 47: 530– 5. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

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Diseases of the EsophagusOxford University Press

Published: Mar 8, 2018

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