Abstract
Background
Multimodality treatment that includes esophagogastrectomy may represent the best option for curing accurately staged patients with esophageal cancer. We analyzed the impact of incomplete resection on outcomes after esophagogastrectomy for esophageal cancer.
Methods
The incidence of positive margins for patients who underwent esophagogastrectomy without induction therapy for pathologic T1-3N0-1M0 esophageal cancer of the mid and lower esophagus from 2003 to 2006 in the National Cancer Database was analyzed with multivariate logistic regression. The impact of positive margins on survival was assessed using Kaplan-Meier and Cox proportional hazards analysis.
Results
Positive margins occurred in 342 of 3,125 patients (10.9%) who met study criteria. Increasing clinical T status was an independent predictor of positive margins in multivariate analysis, but the chance of positive margins decreased with larger facility case volumes. The presence of clinical nodal disease was not predictive of an incomplete resection. The 5-year survival of patients with positive margins (13.8%, 95% confidence interval [CI]: 10.5% to 18.1%) was significantly worse than that for patients with negative margins (46.3%, 95% CI: 44.4% to 48.3%, p < 0.001). Both microscopic residual disease (hazard ratio 1.37, 95% CI: 1.16 to 1.60, p < 0.001) and gross residual disease (hazard ratio 1.98, 95% CI: 1.62 to 2.42, p < 0.001) predicted worse survival in multivariate analysis of the entire cohort. Receiving adjuvant chemoradiation therapy slightly improved 5-year survival of patients with positive margins (16.9%, 95% CI: 11.3% to 23.6%, versus 13.5%, 95% CI: 9% to 20.3%, p < 0.001).
Conclusions
Positive margins are associated with poor survival, and adjuvant therapy only marginally improved prognosis. Future studies are needed to better evaluate whether induction therapy can lower the incidence of positive margins.
Esophageal and gastroesophageal junction tumors are the eighth most common cancer worldwide [1]. The incidence of esophageal cancer in the developed world is increasing, with a histologic shift toward adenocarcinoma of the lower esophagus and gastroesophageal junction in the United States and Europe [2–4]. Several studies suggest that complete surgical resection provides the best chance for cure in patients who do not have distant metastases [5–7]. The National Comprehensive Cancer Network guidelines recommend surgery as a possible treatment for most cases of esophageal cancer that do not have invasion of unresectable structures or distant metastatic disease. Surgical resection alone can be curative for early stage superficial cancers, whereas multimodality therapy is increasingly accepted as the appropriate treatment for locally advanced tumors [8–13]. Although the role of surgery for esophageal cancer has been extensively examined, the outcomes impact of an incomplete resection has not been well characterized.
Using the National Cancer Data Base (NCDB), we investigated the incidence and factors associated with positive resection margins after esophagogastrectomy for esophageal cancer to provide quantitative evidence to both estimate prognosis and also potentially improve the treatment selection process for patients who may be at high risk for an incomplete resection. We assessed whether patients with positive margins have significantly worse survival rates than patients who underwent a complete resection. This study also was undertaken to test a secondary hypothesis that adjuvant therapy for positive margins can result in outcomes comparable to those observed when complete resection is performed.
Patients and Methods
A Duke University Institutional Review Board-approved retrospective analysis of the NCDB was performed. The NCDB is jointly administered by the Commission on Cancer of the American College of Surgeons and the American Cancer Society. It captures an estimated 70% of all newly diagnosed cancers in the United States, collecting data from more than 1,500 Commission on Cancer-approved facilities and containing more than 30 million records. As long-term survival data for patients in the version of the NCDB used in this study were only available through 2006, all patients diagnosed from 2003 to 2006 with pathologic T1-3N0-1M0 esophageal cancer of the mid and lower esophagus were included for analysis. The sixth edition of the American Joint Committee on Cancer (AJCC) staging system was used because it was contemporaneous with the collected NCDB data.
For the primary analysis, only patients undergoing esophagogastrectomy (defined using Facility Oncology Data Standards codes) for primary disease without induction therapy were included and categorized by margin status. The analysis was conditioned on 30-day survival to exclude early mortality, which would preclude the use of postoperative therapy.
Patients were stratified by margin status as described in the surgical pathology report. To identify factors associated with postoperative margin status, we examined the total study population, using multivariable logistic regression to estimate independent predictors of positive margins and adjusting for the same patient and disease characteristics. For this portion of the analysis, clinical T and N status were used (cT1-3N0-1M0), instead of pathologic status, which could not have been known before resection. As induction therapy may be associated with surgical margin status, we then conducted an exploratory analysis on a similar patient population but also included patients who were treated with induction therapy. Owing to limitations of the NCDB data before 2006, it was not possible to determine if patients who received postoperative chemotherapy also received induction therapy. Because survival data are only available through 2006, we conducted our exploratory analysis using 2006—the only year in which the data overlapped. The purpose of the analysis was to assess the implications of induction therapy in the context of our larger study’s hypotheses.
Survival data were obtained for the entire duration of the study period, 2003 to 2006. Unadjusted survival stratified by margin status was estimated using the Kaplan-Meier method. Independent predictors of survival after esophagogastrectomy were then modeled with Cox proportional hazards regression, including the following variables: margin status (defined as R1 microscopic and R2 macroscopic involvement), use of postoperative chemoradiotherapy (CRT), patient age, sex, race, Charlson/Deyo comorbidity score, pathologic T and N status, and facility case volume. Volume was based on the annual case volume of surgical resections for esophageal cancer, and was treated as a continuous variable to better estimate the effect of center experience on outcomes and treatments.
To evaluate whether postoperative CRT can rescue a patient with positive margins, we then excluded all patients with R0 resections, and the margin-positive cohort was grouped by the use of postoperative CRT versus a strategy of observation alone. Baseline characteristics and perioperative endpoints were compared between groups using Pearson’s χ2 test for discrete variables and Student’s t test for continuous variables. Independent predictors of survival among patients with positive margins were then estimated using the same Cox proportional hazards model applied to the full population. To assess whether postoperative CRT can rescue a patient with positive margins, survival of patients who had positive margins and were subsequently given postoperative CRT was compared with that of negative-margin patients who were treated with surgery alone and no adjuvant therapy.
No major model assumptions were violated, and a p value of less than 0.05 was considered statistically significant for all analyses. Missing data were handled with complete case analysis given the substantial completeness of the study cohort. All analyses were performed using R (version 3.1.2; R Foundation for Statistical Computing, Vienna, Austria).
Results
Incidence of Positive Margins
A total of 3,177 patients with pT1-3N0-1M0 esophageal cancer (adenocarcinomas 83.6% versus squamous cell carcinomas 16.4%) underwent resection during the study period. Patients missing margin status data (n = 52, 1.6%) were excluded from analysis, leaving 3,125 patients. Of the margin-positive patients, 12 (3.4%) were missing postoperative chemoradiation data and were omitted from subset analysis. That left 342 (10.9%) margin-positive patients; 218 (7%) with R1 microscopic disease, and 124 (4%) with R2 macroscopic disease.
Among the overall study population, Table 1 shows independent predictors of positive margins. One of the strongest predictors of positive margins was increasing clinical T status (hazard ratio [HR] 2.6 for T2, p = 0.014; and HR 7.4 for T3, p < 0.001). A patient’s nodal status was not independently predictive of margin status, nor was the specimen’s histology. Conversely, increasing facility volume was strongly predictive of negative margins after resection (odds ratio [OR] 0.13 per 10 annual cases, p = 0.009). Centers that performed more than 10 esophagogastrectomies per year for esophageal cancer had an increased R0 resection rate versus centers that performed fewer than 10 resections per year (94.8% versus 88.8%, p = 0.047).
Table 1.
Predictors of Positive Margins After Esophagogastrectomy, Multivariable Logistic Regression
| Risk Factor | Odds Ratio |
Lower 95% CI |
Upper 95% CI |
p Value |
|---|---|---|---|---|
| Age, per decade | 1.12 | 0.88 | 1.42 | 0.36 |
| Female | 0.92 | 0.47 | 1.79 | 0.80 |
| Race | ||||
| Black | 1.13 | 0.38 | 3.38 | 0.82 |
| Other | 0.69 | 0.08 | 5.72 | 0.73 |
| Charlson comorbidity score, per unit |
1.13 | 0.76 | 1.67 | 0.54 |
| Education above median | 1.06 | 0.60 | 1.89 | 0.84 |
| Income above median | 1.27 | 0.68 | 2.35 | 0.45 |
| Clinical T stage | ||||
| T2 | 2.57 | 1.21 | 5.47 | 0.014 |
| T3 | 7.38 | 3.57 | 15.26 | <0.001 |
| Clinical nodal disease | 0.70 | 0.40 | 1.24 | 0.22 |
| Facility volume, per 10 cases | 0.13 | 0.03 | 0.60 | 0.009 |
CI = confidence interval.
In an exploratory analysis of patients with induction therapy, similar results were obtained with respect to clinical T status and facility volume. However, the use of induction therapy was also associated with lower odds of positive margins (OR 0.41, 95% confidence interval [CI]: 0.21 to 0.81, p = 0.01). Among patients with positive margins, 124 (36%) received postoperative combined CRT, 156 (45.6%) were observed without any postoperative therapy, 24 (7%) received isolated postoperative radiation therapy, and the remaining 38 (11%) received only postoperative chemotherapy. Patients with positive margins had substantially worse overall survival compared with their margin-negative counterparts (median survival 15 months versus 51 months, p < 0.001; Fig 1).
Fig 1.
Survival among esophageal cancer patients, by postoperative margin status: margin negative (solid blue line) versus margin positive (dotted red line).
Both microscopic residual disease (HR 1.37, 95% CI: 1.16 to 1.60, p = 0.001) and gross residual disease (HR 1.98, 95% CI: 1.62 to 2.42, p < 0.001) predicted worse survival in multivariate analysis of the entire cohort. Other independent predictors of long-term survival after multivariable adjustment were younger age, female sex, white race, lower Charlson/Deyo comorbidity score, lower T stage, and node-negative disease. Higher facility volume was associated with better long-term survival (HR 0.49 per 10 annual cases, p < 0.001) as was the use of postoperative CRT (HR 0.72, p < 0.001; Table 2).
Table 2.
Independent Predictors of Long-Term Survival in the Overall Study Population, After Cox Proportional Hazards Regression
| Risk Factor | Hazard Ratio |
Lower 95% CI |
Upper 95% CI |
p Value |
|---|---|---|---|---|
| Age, per decade | 1.25 | 1.19 | 1.31 | <0.001 |
| Female | 0.88 | 0.78 | 1.00 | 0.049 |
| Race | ||||
| Black | 1.49 | 1.22 | 1.82 | <0.001 |
| Other | 1.04 | 0.75 | 1.44 | 0.83 |
| Charlson comorbidity score (ref = 0) |
||||
| 1 | 1.30 | 1.17 | 1.45 | <0.001 |
| ≥2 | 1.43 | 1.19 | 1.71 | <0.001 |
| Pathologic T stage | ||||
| T2 | 1.86 | 1.61 | 2.15 | <0.001 |
| T3 | 3.06 | 2.68 | 3.49 | <0.001 |
| Positive lymph nodes | 2.18 | 1.95 | 2.44 | <0.001 |
| Facility volume, per 10 cases | 0.49 | 0.39 | 0.62 | <0.001 |
| Margin status (ref = R0 negative) |
||||
| R1 microscopic | 1.37 | 1.16 | 1.60 | <0.001 |
| R2 macroscopic | 1.98 | 1.62 | 2.42 | <0.001 |
| Postoperative therapy (CRT) | 0.72 | 0.64 | 0.81 | <0.001 |
CI = confidence interval; CRT = chemoradiotherapy.
Table 3 shows baseline patient, tumor, and treatment characteristics in the positive margins cohort. The subset of patients treated with adjuvant combined CRT was compared with patients undergoing surgery alone. Overall, CRT patients were younger and more likely to be male, with lower comorbidity burdens, lower 30-day readmission rates, and shorter hospital lengths of stay. They were, however, much more likely to have node-positive disease, higher T stages, and be uninsured. Patients treated with postoperative CRT had substantially better long-term survival compared with patients managed with postoperative observation alone (median survival 19 months versus 11 months, p < 0.001; Fig 2).
Table 3.
Baseline Characteristics of Patients With Positive Margins After Esophagogastrectomy, Grouped by Postoperative Management trategy of Observation Versus Combined Chemoradiation Therapy
| Variable | Total (n = 280) |
Observation (n = 156) |
Postoperative CRT (n = 124) |
p Value |
|---|---|---|---|---|
| Patient characteristics | ||||
| Age, years | 65 (57.8–73) | 67 (60–75) | 62 (55–69) | <0.001 |
| Female | 42 (15) | 31 (19.9) | 11 (8.9) | 0.017 |
| Race | 0.47 | |||
| White | 254 (92) | 138 (90.2) | 116 (94.3) | |
| Black | 20 (7.2) | 14 (9.2) | 6 (4.9) | |
| Other | 2 (0.7) | 1 (0.7) | 1 (0.8) | |
| Charlson comorbidity score | 0.007 | |||
| 0 | 189 (67.5) | 93 (59.6) | 96 (77.4) | |
| 1 | 72 (25.7) | 50 (32.1) | 22 (17.7) | |
| ≥2 | 19 (6.8) | 13 (8.3) | 6 (4.8) | |
| Education above median | 165 (62) | 82 (55.4) | 83 (70.3) | 0.018 |
| Income above median | 184 (69.2) | 97 (65.5) | 87 (73.7) | 0.19 |
| Insurance | 0.035 | |||
| Private | 96 (35.4) | 44 (29.7) | 52 (42.3) | |
| Medicare | 150 (55.4) | 93 (62.8) | 57 (46.3) | |
| Medicaid | 14 (5.2) | 8 (5.4) | 6 (4.9) | |
| Government | 2 (0.7) | 0 (0) | 2 (1.6) | |
| Uninsured | 9 (3.3) | 3 (2) | 6 (4.9) | |
| Tumor characteristics | ||||
| Tumor size | 0.17 | |||
| <1 cm | 3 (1.2) | 3 (2.1) | 0 (0) | |
| 1.9 cm | 9 (3.6) | 6 (4.2) | 3 (2.8) | |
| 4.9 cm | 139 (55.2) | 84 (58.3) | 55 (50.9) | |
| >4.9 cm | 101 (40.1) | 51 (35.4) | 50 (46.3) | |
| Facility characteristics | ||||
| Distance to cancer center | 11.7 (5.1–36.1) | 9.8 (4.2–37.4) | 12.8 (6–34.3) | 0.24 |
| Treatment facility | 0.056 | |||
| Academic/research program | 118 (43.5) | 74 (49) | 44 (36.7) | |
| Community program | 153 (56.5) | 77 (51) | 76 (63.3) | |
| Facility volume, cases/year | 0.9 (0.5–1.6) | 0.9 (0.5–1.6) | 1 (0.5–1.7) | 0.62 |
| Days to definitive surgery | 27 (13.5–43) | 30 (13.5–46) | 26.5 (13.8–38.2) | 0.01 |
| Pathologic staging | ||||
| T stage | 0.001 | |||
| T1 | 17 (6.1) | 17 (10.9) | 0 (0) | |
| T2 | 24 (8.6) | 14 (9) | 10 (8.1) | |
| T3 | 239 (85.4) | 125 (80.1) | 114 (91.9) | |
| N stage | 0.003 | |||
| N0 | 78 (27.9) | 55 (35.3) | 23 (18.5) | |
| N1 | 202 (72.1) | 101 (64.7) | 101 (81.5) | |
| Surgical endpoints | ||||
| Nodes removed | 10 (6–17) | 9 (4–17) | 11 (7–17) | 0.28 |
| Positive lymph node ratio | 0.2 (0–0.5) | 0.2 (0–0.5) | 0.2 (0.1–0.6) | 0.39 |
| Thirty-day readmission | 34 (12.8) | 25 (16.4) | 9 (7.9) | 0.06 |
| Hospital length of stay | 12 (9–21) | 14.5 (10–28) | 10 (8–14) | <0.001 |
| Adjuvant treatment | ||||
| Chemotherapy | 124 (44.3) | 0 (0) | 124 (100) | <0.001 |
| Radiation therapy | 124 (44.3) | 0 (0) | 124 (100) | <0.001 |
Values are median (interquartile range) or n (%).
CRT = chemoradiotherapy.
Fig 2.
Survival among patients with positive margins after esophagogastrectomy, grouped according to use of postoperative chemoradiation therapy (solid blue line) versus observation alone (dashed red line).
After multivariable adjustment, positive-margin patients treated with postoperative CRT maintained a significant survival benefit compared with a strategy of observation alone (HR 0.47, 95% CI: 0.35 to 0.62, p < 0.001; Table 4). However, postoperative CRT was insufficient to salvage survival rates when patients with positive margins were compared with negative-margin patients who had been treated with surgery alone (median survival 19 months versus 51 months, p < 0.001; Fig 3.)
Table 4.
Independent Predictors of Long-Term Survival Among Patients With Positive Margins After Esophagogastrectomy, Cox Proportional Hazards Regression
| Risk Factor | Hazard Ratio |
Lower 95% CI |
Upper 95% CI |
p Value |
|---|---|---|---|---|
| Age, per decade | 1.19 | 1.04 | 1.37 | 0.013 |
| Female | 0.89 | 0.60 | 1.31 | 0.55 |
| Race | ||||
| Black | 0.91 | 0.51 | 1.62 | 0.74 |
| Other | 2.03 | 0.50 | 8.28 | 0.32 |
| Charlson comorbidity score (ref = 0) |
||||
| 1 | 1.13 | 0.84 | 1.53 | 0.42 |
| ≥2 | 1.00 | 0.60 | 1.65 | 0.99 |
| Pathologic T stage | ||||
| T2 | 2.08 | 0.92 | 4.71 | 0.078 |
| T3 | 3.53 | 1.73 | 7.21 | 0.001 |
| Positive lymph nodes | 1.96 | 1.42 | 2.71 | <0.001 |
| Margin status (ref = R1 microscopic) |
||||
| R2 macroscopic | 1.67 | 1.27 | 2.21 | <0.001 |
| Postoperative therapy (CRT) | 0.47 | 0.35 | 0.62 | <0.001 |
| Facility volume, per 10 cases | 0.59 | 0.27 | 1.31 | 0.20 |
CI = confidence interval; CRT = chemoradiotherapy.
Fig 3.
Survival among patients with positive margins treated with postoperative chemoradiation therapy (dotted red line) versus patients with negative margins managed with observation alone (solid blue line). (AT = adjuvant therapy.)
Comment
This study used a population-based dataset to examine the topic of positive margins after esophagogastrectomy for esophageal cancer. In this large cohort of patients with pathologic T13N01M0 disease that was surgically resected, positive margins occurred in 10% of patients. Positive margins were more likely to be associated with higher T-status tumors and poor survival rates. Adjuvant therapy improved the prognosis of patients with positive margins, but did not restore survival to the level of those with complete surgical resection.
Although the results of this study should be carefully considered in the context of study limitations discussed below, our findings do underscore the critical principle of achieving a negative resection when performing an esophagogastrectomy for esophageal cancer [13, 14]. The results show that outcomes after treatment with adjuvant therapy in the setting of positive margins are improved, but remain rather poor as compared with patients who have an initial complete resection. Unfortunately, the alternative therapy of re-resection for positive margins is also suboptimal considering that the initial esophagogastrectomy already exposes patients to significant potential morbidity [15–19]. Owing to the complexities of restoring gastrointestinal continuity after esophagogastrectomy, re-resection for negative margins is considerably more difficult than for most cancers in other locations. Such an approach likely requires takedown of the initial conduit used for reconstruction and creation of a new conduit using a different organ. Clearly, the goal for all patients with esophageal cancer is negative margins whenever surgery is utilized.
Advances in surgical techniques and perioperative care along with more stringent patient selection criteria, have reduced the morbidity and mortality associated with esophagogastrectomy [20, 21]. However, short-term esophagogastrectomy outcomes are particularly influenced by surgeon and hospital experience [22]. Centers and surgeons performing high volumes of esophageal surgery typically report significantly lower mortality rates than those in multicenter studies or national databases [23–26]. The relationship between volume and outcomes for patients being treated for esophageal cancer has also been well described by several population-based studies [22, 27, 28]. In our study, complete resections were more likely to be performed at higher volume centers. This improvement is likely due to the availability of more experienced and specialized multimodality treatment groups. Access to surgical teams more adept at obtaining negative margins or in recognizing situations when patients may benefit from induction therapy is vital.
The role of induction therapy for esophageal cancer has been extensively investigated. Early studies were somewhat inconclusive, but in general suggested that a survival benefit exists when both chemotherapy and radiation therapy are given preoperatively [29, 30]. Recently, trials and retrospective studies have more definitively established the beneficial role of induction therapy for patients with resectable disease involving the distal esophagus [8–12, 31]. Accordingly, the popularity of induction therapy has increased 12% from 2003 to 2011, based on NCDB data [13]. Owing to limitations in the way chemotherapy data were recorded in the NCDB before 2006 and the lack of survival data thereafter, we were unable to fully explore the interaction between induction therapy, margin status, and survival. In our exploratory analysis, however, the cohort that received induction therapy had a lower positive margin rate. Being careful not to overreach, given the limited sample size, these results suggest an association between induction therapy and improved survival. This link is validated by the Dutch ChemoRadiotherapy for Oesophageal Cancer followed by Surgery Study (CROSS) and the perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer (MAGIC) trials [8, 31].
In this study, positive margin patients that received salvage therapy had a modestly increased 8-month median survival over observation alone (p < 0.001). These patients tended to be in better condition (younger and lower comorbidity index), which may have factored in their improved survival. Although it could be that medical and radiation oncologists tend to favor treating more robust postsurgical patients, only age, and not comorbidity index, was independently predictive of long-term survival (Table 4). Other independent predictors of survival in patients with positive margin include absence of advanced cancer (lack of T3 invasion or nodal involvement) and no R2 disease. The CRT cohort was not powered to discern any differences between combined chemoradiation versus radiation or chemotherapy alone.
A strength of this study is the use of a population-based, multiinstitutional database to evaluate the role that positive surgical margins have on patients undergoing esophagogastrectomy. It is unlikely that even a pooled analysis from a number of high-volume centers would have allowed creation of a cohort as large as what was extracted from the NCDB. Having a national dataset stemming from numerous institutions also promotes generalizability of conclusions drawn from the data. The study period is relatively recent but still allows time for adequate survival data to be captured. For example, survival benefits upward of 7 years were seen in the negative-margin cohort as well as in the subset of patients with positive margins who underwent postoperative therapies. It should be noted that when these two cohorts were compared, the survival benefits of obtaining a negative surgical margin remained significant (Fig 3).
Limitations of this study include its retrospective nature and relatively narrow time period. Our analysis also was limited by the nature of available data from the NCDB, the data points that it collects and the period over which the data are available. We acknowledge that medical oncologic therapies are continually evolving, and the NCDB lacks granular specifics regarding chemotherapy regimens and protocols. Contemporary patients may receive additional benefits from newer chemotherapy regimens and, accordingly, may have improved survival benefits. The lack of specifics regarding chemoradiotherapy regimens prohibits us from discerning the exact therapies given to patients after disease recurrence. The use of the AJCC sixth edition for staging is an acknowledged limitation. Unfortunately, owing to the limitations of the NCDB, it was not possible to recode to the seventh edition AJCC staging system.
Additional limitations include the NCDB’s lack of specifics regarding recurrence site: locoregional versus distal; and the specific cause of death. The NCDB does not have details regarding esophagogastrectomy techniques, including location of the anastomosis, which can have an independent impact on surgical margins and patient outcomes [21]. Moreover, the NCDB does not distinguish whether longitudinal (proximal and distal) or radial margins were involved, prohibiting our ability to assess their relative importance.
Based on this evidence and other studies, we recommend that patients with esophageal cancer be evaluated in a multidisciplinary setting where a critical component of the treatment decision process is a goal of achieving a negative surgical margin. When appropriate, induction therapy may be used to increase the chances of obtaining a durable cure. In instances where the resection margin is involved, adjuvant therapy may offer a modest survival benefit. Referral to a high-volume center should be considered for cases of locally advanced tumors when complete resection may be particularly difficult. Future studies are needed to further evaluate the association of induction therapy and the incidence of negative margins.
Footnotes
Presented at the Poster Session of the Fifty-first Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Jan 24–28, 2015.
References
- 1.Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol. 2006;24:2137–2159. doi: 10.1200/JCO.2005.05.2308. [DOI] [PubMed] [Google Scholar]
- 2.Brown LN, Devesa SS, Chow W-H. Incidence of adenocarcinoma of the esophagus among white Americans by sex, stage and age. J Natl Cancer Inst. 2008;100:1184–1187. doi: 10.1093/jnci/djn211. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Trivers KF, Sabatino SA, Stewart SL. Trends in esophageal cancer incidence by histology, United States, 1998–2003. Int J Cancer. 2008;123:1422–1428. doi: 10.1002/ijc.23691. [DOI] [PubMed] [Google Scholar]
- 4.Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9–29. doi: 10.3322/caac.21208. [DOI] [PubMed] [Google Scholar]
- 5.Kelsen DP, Winter KA, Gunderson LL, et al. Long-term results of RTOG trial 8911 (USA Intergroup 113): a random assignment trial comparison of chemotherapy followed by surgery compared with surgery alone for esophageal cancer. J Clin Oncol. 2007;25:3719–3725. doi: 10.1200/JCO.2006.10.4760. [DOI] [PubMed] [Google Scholar]
- 6.Paulson EC, Ra J, Armstrong K, et al. Underuse of esophagectomy as treatment for resectable esophageal cancer. Arch Surg. 2008;143:1198–1203. doi: 10.1001/archsurg.143.12.1198. [DOI] [PubMed] [Google Scholar]
- 7.Abrams JA, Buono DL, Strauss J, et al. Esophagectomy compared with chemoradiation for early stage esophageal cancer in the elderly. Cancer. 2009;115:4924–4933. doi: 10.1002/cncr.24536. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.van Hagen P, Hulshof MCCM, van Lanschot JJB, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012;366:2074–2084. doi: 10.1056/NEJMoa1112088. [DOI] [PubMed] [Google Scholar]
- 9.Burmeister BH, Smithers BM, Gebski V, et al. Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: a randomised controlled phase III trial. Lancet Oncol. 2005;6:659–668. doi: 10.1016/S1470-2045(05)70288-6. [DOI] [PubMed] [Google Scholar]
- 10.Kountourakis P, Correa AM, Hofstetter WL, et al. Combined modality therapy of cT2N0M0 esophageal cancer: the University of Texas M. D. Anderson Cancer Center experience. Cancer. 2011;117:925–930. doi: 10.1002/cncr.25651. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Worni M, Castleberry AW, Gloor B, et al. Trends and outcomes in the use of surgery and radiation for the treatment of locally advanced esophageal cancer: a propensity score adjusted analysis of the Surveillance, Epidemiology, and End Results registry from 1998 to 2008. Dis Esophagus. 2014;27:662–669. doi: 10.1111/dote.12123. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Speicher PJ, Wang X, Englum BR, et al. Induction chemoradiation therapy before esophagectomy is associated with superior long-term survival for esophageal cancer. Dis Esophagus. 2014 Sep 12; doi: 10.1111/dote.12285. [E-Pub ahead of print] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Speicher PJ, Englum BR, Ganapathi AM, et al. Adjuvant chemotherapy is associated with improved survival after esophagectomy without induction therapy for node-positive adenocarcinoma. J Thorac Oncol. 2015;10:181–188. doi: 10.1097/JTO.0000000000000384. [DOI] [PubMed] [Google Scholar]
- 14.Ng T, Vezeridis MP. Advances in the surgical treatment of esophageal cancer. J Surg Oncol. 2010;101:725–729. doi: 10.1002/jso.21566. [DOI] [PubMed] [Google Scholar]
- 15.Wright CD, Kucharczuk JC, O’Brien SM, Grab JD, Allen MS. Predictors of major morbidity and mortality after esophagectomy for esophageal cancer: a Society of Thoracic Surgeons general thoracic surgery database risk adjustment model. J Thorac Cardiovasc Surg. 2009;137:587–595. doi: 10.1016/j.jtcvs.2008.11.042. [DOI] [PubMed] [Google Scholar]
- 16.Ra J, Paulson EC, Kucharczuk J, et al. Postoperative mortality after esophagectomy for cancer: development of a preoperative risk prediction model. Ann Surg Oncol. 2008;15:1577–1584. doi: 10.1245/s10434-008-9867-4. [DOI] [PubMed] [Google Scholar]
- 17.Connors RC, Reuben BC, Neumayer LA, Bull DA. Comparing outcomes after transthoracic and transhiatal esophagectomy: a 5-year prospective cohort of 17,395 patients. J Am Coll Surg. 2007;205:735–740. doi: 10.1016/j.jamcollsurg.2007.07.001. [DOI] [PubMed] [Google Scholar]
- 18.Dimick JB, Wainess RM, Upchurch GR, Iannettoni MD, Orringer MB. National trends in outcomes for esophageal resection. Ann Thorac Surg. 2005;79:212–218. doi: 10.1016/j.athoracsur.2004.06.044. [DOI] [PubMed] [Google Scholar]
- 19.Swanson SJ, Batirel HF, Bueno R, et al. Transthoracic esophagectomy with radical mediastinal and abdominal lymph node dissection and cervical esophagogastrostomy for esophageal carcinoma. Ann Thorac Surg. 2001;72:1918–1924. doi: 10.1016/s0003-4975(01)03203-9. [DOI] [PubMed] [Google Scholar]
- 20.D’Amico TA. McKeown esophagogastrectomy. J Thorac Dis. 2014;6(Suppl 3):322–324. doi: 10.3978/j.issn.2072-1439.2014.03.28. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Berry MF, Atkins BZ, Tong BC, Harpole DH, D’Amico TA, Onaitis MW. A comprehensive evaluation for aspiration after esophagectomy reduces the incidence of postoperative pneumonia. J Thorac Cardiovasc Surg. 2010;140:1266–1271. doi: 10.1016/j.jtcvs.2010.08.038. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Birkmeyer JD, Siewers AE, Finlayson EV, et al. Hospital volume and surgical mortality in the United States. N Engl J Med. 2002;346:1128–1137. doi: 10.1056/NEJMsa012337. [DOI] [PubMed] [Google Scholar]
- 23.Orringer MB, Marshall B, Chang AC, Lee J, Pickens A, Lau CL. Two thousand transhiatal esophagectomies: changing trends, lessons learned. Ann Surg. 2007;246:363–372. doi: 10.1097/SLA.0b013e31814697f2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Atkins BZ, Shah AS, Hutcheson KA, et al. Reducing hospital morbidity and mortality following esophagectomy. Ann Thorac Surg. 2004;78:1170–1176. doi: 10.1016/j.athoracsur.2004.02.034. [DOI] [PubMed] [Google Scholar]
- 25.Davies AR, Forshaw MJ, Khan AA, et al. Transhiatal esophagectomy in a high volume institution. World J Surg Oncol. 2008;6:88. doi: 10.1186/1477-7819-6-88. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Luketich JD, Pennathur A, Awais O, et al. Outcomes after minimally invasive esophagectomy: review of over 1000 patients. Ann Surg. 2012;256:95–103. doi: 10.1097/SLA.0b013e3182590603. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Begg CB, Cramer LD, Hoskins WJ, Brennan MF. Impact of hospital volume on operative mortality for major cancer surgery. JAMA. 1998;280:1747–1751. doi: 10.1001/jama.280.20.1747. [DOI] [PubMed] [Google Scholar]
- 28.Birkmeyer JD, Sun Y, Goldfaden A, Birkmeyer NJ, Stukel TA. Volume and process of care in high-risk cancer surgery. Cancer. 2006;106:2476–2481. doi: 10.1002/cncr.21888. [DOI] [PubMed] [Google Scholar]
- 29.Bosset JF, Gignoux M, Triboulet JP, et al. Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell cancer of the esophagus. N Engl J Med. 1997;337:161–167. doi: 10.1056/NEJM199707173370304. [DOI] [PubMed] [Google Scholar]
- 30.Walsh TN, Noonan N, Hollywood D, Kelly A, Keeling N, Hennessy TP. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med. 1996;335:462–467. doi: 10.1056/NEJM199608153350702. [DOI] [PubMed] [Google Scholar]
- 31.Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355:11–20. doi: 10.1056/NEJMoa055531. [DOI] [PubMed] [Google Scholar]