Abstract
Background:
Isolated local recurrence after curative esophagectomy for esophageal cancer is a rare event. Although it is potentially curable, management can be challenging.
Methods:
We performed a retrospective review of all patients undergoing esophagectomy for esophageal adenocarcinoma (EAC) from 2000 to 2019. Date of recurrence was defined as the date at which the initial abnormal surveillance study or symptomatic presentation led to further workup and subsequent pathologic diagnosis of recurrence. Overall survival after recurrence was estimated using Kaplan-Meier methods and compared between treatment groups using the log-rank test.
Results:
Of the 1370 patients with EAC who underwent esophagectomy in our cohort, 531 (39%) developed recurrence of their disease. The 5-year cumulative incidence of recurrence was 2.7% (95% confidence interval [CI], 2.0%−3.6%) for local, 6.3% (95% CI, 5.2%−7.8%) for regional, and 22.0% (95% CI, 20.0%−24.4%) for distant recurrences. On univariable and multivariable competing-risk regression analysis, advanced pT stage, signet ring histology, and serious complication were independently associated with local recurrence. Patients with local recurrence treated with definitive therapy had a median survival after recurrence of 19.1 months (95% CI, 11.4–33.2 months), compared with 10.6 months (95% CI, 8.5–14.2 months) for chemotherapy or radiotherapy alone and 1.73 months (95% CI, 0.23–15.6 months) for no treatment (P<0.001).
Conclusions:
Isolated local recurrence occurred in only 3% of patients. Advanced T stage, signet cell histology, and serious complication were risk factors for recurrence. Although complex surgical resection is required, in very select cases, more-aggressive treatment may be warranted.
Esophageal cancer is the sixth leading cause of cancer-related death worldwide, responsible for 509,000 estimated deaths globally in 2018.1–3 Esophageal adenocarcinoma (EAC) is the most common histologic subtype in Western countries, and incidence of EAC has increased dramatically, making it one of the most rapidly increasing cancers in the US.2 Surgical resection is the cornerstone of treatment and offers the only potential for cure. Despite optimal resection, recurrence occurs in approximately 35%−45% of patients.4–14 However, isolated local recurrence is a rare event, and although this presentation may be potentially curable, clinical management can be difficult. The primary aim of the present study was to evaluate cases of isolated local recurrence, potential predictors, and options for treatment.
Patients and Methods
Following institutional review board approval (IRB #16–1631), we retrospectively queried our prospectively maintained database to identify all patients with histologically confirmed EAC treated surgically from 2000 to 2019. The need for individual patient consent was waived by the IRB. Patients with histologic tumor types other than EAC and dysplasia or carcinoma in situ without tumor invasion were excluded. All relevant clinical and pathologic variables, including baseline demographic characteristics, preoperative staging, tumor histologic characteristics and location, specific treatment regimens, and postoperative disease status, were extracted from this database. Records were requested for patients who underwent staging at an outside institution. All pathologic reports were reviewed for pathologic staging. Patients were staged according to the 8th edition of the American Joint Committee on Cancer Staging Manual of the tumor-node-metastasis classification,15 including those who underwent resection before the use of this edition. All patients underwent esophagectomy performed with curative intent. Patients undergoing surgery as salvage treatment and those with pathologic evidence of an incomplete (R1/R2) resection were excluded.
Type of esophagectomy was broadly classified according to surgical approach and reconstruction method. All postoperative complications were graded according to the Clavien-Dindo severity grading system.16 Using this classification, we defined any complication grade III or greater as serious, whereas complications grade I or II were considered minor. After esophagectomy, patients were followed up regularly in the outpatient setting by the operating surgeon and/or medical oncologist. Follow-up was performed most commonly at 3- to 6-month intervals for the first 2 years and then every 6 to 12 months for the remaining 3 years. Patients who died or were lost to follow-up within 90 days of surgery were excluded. Visits typically involved medical history, physical examination, laboratory tests, and radiographic imaging. Further diagnostic workup was indicated in patients with concerning clinical exam findings or unexpected abnormalities on any of the performed tests. Use of annual endoscopic surveillance was surgeon-specific. Date of recurrence was defined as the date of the initial abnormal surveillance study or symptomatic presentation that led to further workup and subsequent histological confirmation of recurrence. Following pathologic confirmation of metastatic EAC, patients with recurrence were divided into 3 groups on the basis of pattern of recurrence: (1) local recurrence (disease isolated to the esophageal lumen or conduit, with no evidence of any other regional or distant metastatic disease); (2) regional recurrence (disease limited to the regional lymph nodes); and (3) distant recurrence (hematogenous metastasis to nonregional lymph nodes, visceral organs, bone, pleura, and/or peritoneum).
Patients were categorized according to the farthest location of disease metastasis and the first anatomical site of recurrence—patients with both local and regional metastasis were classified as having regional recurrence, whereas patients with both locoregional and distant metastasis were classified as having distant recurrence. As in previous studies, when metastasis to an additional site was discovered within 1 month of the first detection of recurrence, recurrences were presumed to have occurred concurrently, and patients were classified accordingly.17 To ascertain optimal management strategies for local recurrence, treatment was analyzed retrospectively. Broadly, treatment regimens for recurrence were classified into 3 groups: no treatment, local or systemic therapy, and combined local and systemic therapy (definitive treatment). Definitive treatment was defined as surgery alone, chemotherapy and surgery, or chemoradiation and surgery.
Statistical Analysis
Relevant demographic, staging, pathologic, and treatment characteristics were summarized using descriptive statistics. Categorical variables were summarized as frequencies and percentages; continuous variables were summarized as medians and interquartile ranges (IQRs). Cumulative incidence of recurrence at local, regional, and distant sites was estimated from the time of curative-intent surgery, using cumulative incidence functions, with death without recurrence considered a competing event. Patients were otherwise censored at the time of last follow-up.
For the primary aim, risk factors for local recurrence were evaluated using univariate and multivariate competing-risk analyses using the Fine and Gray model. Death without recurrence, regional recurrence, and distant recurrence were considered competing-risk events. Variables with P<0.1 on univariable analysis were considered for multivariable analysis. Relationships between factors and regional recurrence were quantified using hazard ratios (HRs) and 95% confidence intervals (95% CIs).
When constructing the multivariable model, because of the limited number of local recurrences in our cohort, clinical T stage and pathologic grade were not included, because of a high correlation with pathologic T stage, to prevent overfitting of the model. All potential covariates contributing to prognosis and incidence of recurrence were included in the multivariable model.
Overall survival (OS) after local recurrence was visualized using Kaplan-Meier curves and compared by groups using the log-rank test among the subset of patients who experienced recurrence. Among patients with local recurrence, survival after recurrence was compared by treatment type. Cox regression was used to quantify the relationship with OS. All P values reported were 2-tailed, and P<0.05 was considered to indicate statistical significance. Statistical analyses were performed using STATA version 16 (College Station, TX).
Results
A total of 1370 patients with EAC who underwent esophagectomy were included in our cohort (Supplemental Figure 1). Follow-up was performed until December 2020. Median follow-up from surgery was 36 months (IQR, 18–71 months) for all patients and 53 months (IQR, 24–88 months) for the 670 patients who remain alive. Relevant baseline characteristics, operative data, and pathologic variables are displayed in Table 1. Median age was 64 years (IQR, 57–70 years). Most patients were men (84%) and white (94%). Within our cohort, 382 patients underwent surgery alone (27.9%), 49 patients received neoadjuvant chemotherapy (3.6%), and 939 patients received concurrent neoadjuvant chemoradiation (68.5%). Resection was most commonly accomplished using an open approach (76.5%), and the most common procedure performed was Ivor Lewis esophagectomy (88.2%).
Table 1.
Relevant baseline demographic, operative, and histopathological characteristics of included patients with and without locally recurrent disease after esophagectomy with curative intent
| Characteristic | All (N=1370) | No Local Recurrence (N=1324) | Local Recurrence (N=46) |
|---|---|---|---|
| Median age, years | 64 (57–70) | 64 (57–70) | 63 (57–70) |
| Sex | |||
| Male | 1151 (84.0) | 1109 (83.8) | 42 (91.3) |
| Female | 219 (16.0) | 215 (16.2) | 4 (8.7) |
| Race | |||
| White | 1292 (94.3) | 1247 (94.2) | 45 (97.8) |
| Black | 10 (0.7) | 10 (0.8) | 0 (0.0) |
| Asian | 33 (2.4) | 32 (2.4) | 1 (2.2) |
| Other | 35 (2.6) | 35 (2.6) | 0 (0.0) |
| Baseline grade | |||
| Well/Moderate | 812 (59.3) | 794 (60.0) | 18 (39.1) |
| Poor | 521 (38.0) | 493 (37.2) | 28 (60.9) |
| Clinical stage | |||
| I | 228 (16.6) | 227 (17.1) | 1 (2.2) |
| II | 172 (12.6) | 162 (12.2) | 10 (21.7) |
| III | 856 (62.5) | 825 (62.3) | 31 (67.4) |
| IVA | 105 (7.7) | 101 (7.6) | 4 (8.7) |
| Neoadjuvant therapy | |||
| None | 382 (27.9) | 372 (28.1) | 10 (21.7) |
| Chemo | 49 (3.6) | 45 (3.4) | 4 (8.7) |
| Chemoradiation | 939 (68.5) | 907 (68.5) | 32 (69.6) |
| ASA | |||
| 2 | 272 (19.9) | 258 (19.5) | 14 (30.4) |
| 3–4 | 950 (69.3) | 925 (69.9) | 25 (54.3) |
| Esophagectomy type | |||
| Ivor Lewis | 1209 (88.2) | 1171 (88.4) | 38 (82.6) |
| Other | 161 (11.8) | 153 (11.6) | 8 (17.4) |
| Surgical approach | |||
| Open | 1048 (76.5) | 1010 (76.3) | 38 (82.6) |
| Minimally invasive | 322 (23.5) | 314 (23.7) | 8 (17.4) |
| Tumor location | |||
| Distal esophagus | 175 (12.8) | 171 (12.9) | 4 (8.7) |
| Gastroesophageal | 1195 (87.2) | 1153 (87.1) | 42 (91.3) |
| junction | |||
| Pathologic T stage | |||
| pT0 | 240 (17.5) | 237 (17.9) | 3 (6.5) |
| pT1 | 479 (35.0) | 468 (35.3) | 11 (23.9) |
| pT2 | 240 (17.5) | 233 (17.6) | 7 (15.2) |
| pT3/4 | 411 (30.0) | 386 (29.2) | 25 (54.3) |
| Pathologic N stage | |||
| pN0 | 893 (65.2) | 868 (65.6) | 25 (54.3) |
| pN1 | 281 (20.5) | 26 (20.0) | 16 (34.8) |
| pN2 | 146 (10.7) | 144 (10.9) | 2 (4.3) |
| pN3 | 50 (3.6) | 47 (3.5) | 3 (6.5) |
| Pathologic grade | |||
| No residual tumor | 249 (18.2) | 245 (18.5) | 4 (8.7) |
| Well/moderate | 622 (45.4) | 605 (45.7) | 17 (37.0) |
| Poor | 408 (29.8) | 384 (29.0) | 24 (52.2) |
| Lymphovascular invasion | 332 (24.2) | 313 (23.6) | 19 (41.3) |
| Signet ring histology | 226 (17) | 199 (15) | 27 (59) |
| Serious complication | 236 (17.2) | 218 (16.5) | 18 (39.1) |
| Adjuvant therapy | 130 (9.5) | 124 (9.4) | 6 (13.0) |
Data are number (%) or median (interquartile range). P values were not provided since recurrence is a time-to event endpoint that was analyzed using competing-risk regression.
Recurrence
As of December 2020, 531 patients (38.8%) developed recurrence of their disease, which was distant/systemic in 376 patients, regional in 109 patients, and isolated to the esophagogastric anastomosis in 46 patients. The 5-year cumulative incidence of recurrence was 2.7% (95% CI, 2.0%−3.6%) for local, 6.3% (95% CI, 5.2%−7.8%) for regional, and 22.0% (95% CI, 20.0%−24.4%) for distant recurrences. The majority of recurrences occurred within 2 years of surgery (82.9%). Median time to recurrence was 9.8 months (95% CI, 8.7–10.7 months) for distal recurrence, 11.9 months (95% CI, 9.7–13.8 months) for regional recurrence, and 12.4 months (95% CI, 9.9–19.2 months) for local recurrence. When stratified by type, there was no statistically significant difference in time to recurrence between groups (P=0.10).
All cases of local recurrence occurred in the proximity of the esophagogastric anastomosis. In 25 patients with local recurrence, diagnosis was made on routine screening endoscopy or on endoscopy performed after suspicious findings on routine imaging. In the remaining 21 patients, diagnosis of local recurrence was made on endoscopy performed as a result of symptoms of obstruction or dysphagia.
Risk Factors Associated with Local Recurrence
Results of univariable and multivariable analyses for factors predictive of local recurrence are shown in Table 2. Univariable competing-risk regression analysis demonstrated that poor baseline differentiation, higher clinical tumor stage, worse ASA status, signet ring histology, serious complication (Clavien-Dindo grade 3 or higher), lymphovascular invasion, and advanced pathologic T stage were predictors of isolated local recurrence. Variables with P<0.10 on univariable analysis were selected for inclusion. The initial model included baseline differentiation, smoking history, ASA status, pathologic T stage, signet ring histology, serious complication, and lymphovascular invasion. The final model was determined using backwards selection. On multivariable competing-risk regression analysis, advanced pathologic T stage (HR, 2.18 [95% CI, 1.13–4.19]; P=0.02), signet ring histology (HR, 7.13 [95% CI, 3.63–14.01]; P<0.001), and serious complication (HR, 2.80 [95% CI, 1.44–5.43]; P=0.002) were independently associated with isolated local recurrence. Of the 18 patients with local recurrence who suffered a major postoperative complication, 17 experienced anastomotic complications, including anastomotic leak, stricture, or conduit necrosis.
Table 2.
Univariable and multivariable analysis of potential predictive factors for local recurrence of esophageal cancer after curative esophagectomy
| Univariable | Multivariable | |||||||
|---|---|---|---|---|---|---|---|---|
|
| ||||||||
| Factor | At Risk | Events | HR | 95% CI | P | HR | 95% CI | P |
| Age, years | — | — | 1.00 | 0.97–1.03 | 0.91 | |||
| Sex | ||||||||
| Male | 1151 | 42 | 1 | — | — | |||
| Female | 219 | 4 | 0.49 | 0.18–1.38 | 0.18 | |||
| Race | ||||||||
| White | 1292 | 45 | 1 | — | — | |||
| Other | 78 | 1 | 0.38 | 0.05–2.40 | 0.34 | |||
| Baseline grade | ||||||||
| Well/moderate | 813 | 18 | 1 | — | — | 1 | — | — |
| Poor | 521 | 28 | 1.56 | 1.16–2.10 | <0.001 | 1.07 | 0.71–1.60 | 0.76 |
| Clinical stage | ||||||||
| I | 228 | 1 | 1 | — | — | |||
| II | 172 | 10 | 13.66 | 1.74–107.02 | 0.01 | |||
| III | 856 | 31 | 8.39 | 1.14–61.64 | 0.04 | |||
| IVA | 105 | 4 | 9.02 | 1.00–81.29 | 0.05 | |||
| Neoadjuvant | ||||||||
| No neoadjuvant | 382 | 10 | 1 | — | — | |||
| Chemo +/− radiation | 988 | 36 | 1.42 | 0.71–2.86 | 0.32 | |||
| ASA | ||||||||
| 2 | 272 | 14 | 1 | — | — | 1 | — | — |
| 3–4 | 950 | 25 | 0.53 | 0.27–1.01 | 0.06 | 0.57 | 0.29–1.10 | 0.10 |
| Procedure | ||||||||
| Ivor Lewis | 1209 | 38 | 1 | — | — | |||
| Other | 161 | 8 | 1.09 | 0.94–1.27 | 0.27 | |||
| Approach | ||||||||
| Open | 1048 | 38 | 1 | — | — | |||
| Minimally invasive | 322 | 8 | 0.79 | 0.36–1.70 | 0.42 | |||
| Tumor location | ||||||||
| Distal esophagus | 175 | 4 | 1 | — | — | |||
| Gastroesophageal | ||||||||
| junction | 1195 | 42 | 1.52 | 0.55–4.25 | 0.42 | |||
| Lymphovascular invasion | 332 | 19 | 2.13 | 1.19–3.83 | 0.01 | |||
| Signet histology | 226 | 27 | 7.48 | 4.17–13.44 | <0.001 | 7.13 | 3.63–14.01 | <0.001 |
| Pathologic T stage | ||||||||
| pT0 | 243 | 3 | 1 | — | — | 1 | — | — |
| pT1 | 476 | 11 | 1.78 | 0.50–6.39 | 0.35 | |||
| pT2 | 240 | 7 | 2.23 | 0.58–8.65 | 0.24 | |||
| pT3/T4 | 411 | 25 | 4.78 | 1.44–15.85 | 0.01 | 2.18 | 1.13–4.19 | 0.02 |
| Pathologic N stage | ||||||||
| pN0 | 893 | 25 | 1 | — | — | |||
| pN+ | 477 | 21 | 1.57 | 0.88–2.80 | 0.13 | |||
| Pathologic grade | ||||||||
| No residual tumor | 259 | 4 | 1 | — | — | |||
| Well/moderate | 623 | 17 | 1.63 | 0.55–4.68 | 0.38 | |||
| Poor | 407 | 24 | 3.55 | 1.23–10.23 | 0.02 | |||
| Serious complication | 235 | 18 | 2.94 | 1.61–5.32 | <0.001 | 2.80 | 1.44–5.43 | 0.002 |
| Adjuvant therapy | 130 | 6 | 1.54 | 0.65–3.62 | 0.33 | |||
Analysis was performed using competing-risk regression. Bold values indicate P<0.05. All variables with P<0.1 from the univariable analysis were included in the initial multivariable model, and a backwards selection was performed such that only variables with P<0.05 were retained in the final model. CI, confidence interval; HR, hazard ratio.
Treatment of Local Recurrence
Patients were classified in terms of the treatment they received for local recurrence: no treatment, local or systemic therapy alone, or combined local and systemic therapy. A total of 4 patients were excluded from analysis because of a lack of information on treatment of recurrence, owing to loss to follow-up in 2 patients and discovery of diffuse metastatic disease intraoperatively during surgical resection in the remaining 2 patients. Of the 42 patients with local recurrence and adequate follow-up, 9 received no treatment (21%) due to reduced performance status (n=2), patient refusal (n=2), or death soon after recurrence detection or during workup before treatment of recurrence (n=5). Local or systemic therapy alone was used in 16 patients (38%), which consisted of chemotherapy alone in 14 patients and radiotherapy alone in 2 patients. The remaining 17 patients (41%) received definitive therapy, which consisted of chemotherapy plus radiation in 7 patients and completion esophagogastrostomy and reconstruction in 10 patients. Surgery was performed either alone (2 patients), with chemotherapy (5 patients), or with chemoradiation (3 patients). Of these patients, reconstruction was accomplished with colon interposition in 7, jejunal interposition in 1, and reanastomosis of the residual gastric conduit to the proximal esophagus in 2.
Median OS after local recurrence was 1.73 months (95% CI, 0.23–15.6 months) in patients receiving no treatment, which was significantly worse compared with 10.6 months (95% CI, 8.5–14.2 months) in patients treated with chemotherapy or radiotherapy alone and 19.1 months (95% CI, 11.4–33.2 months) in patients treated with definitive therapy (P<0.001) (Figure 1). Of note, median OS after local recurrence in patients treated with surgery was 12.8 months (95% CI, 8.6–43.4 months).
Figure 1.
Overall survival (OS) after recurrence among the 46 patients with isolated local recurrence, according to the specific treatment approach used for recurrence. Treatment of local recurrence was classified into three groups so that patients were stratified as receiving no treatment, isolated local or systemic treatment, or combined local and systemic treatment.
Comment
Recurrence of esophageal cancer after curative esophagectomy occurs in approximately 35% to 50% of patients, contributing to the dismal survival outcomes seen in these patients.5,8,11–14 Consistent with previous estimates, the incidence of recurrence in our cohort was 38.8%, and most cases occurred within 2 years of surgery.18–20 Most cases of recurrence were classified as distant. Isolated local recurrence at the anastomotic site or in the esophageal conduit after resection occurred in only 3.4% of patients, corresponding to previous reports.17,21-23
The exact mechanisms responsible for recurrence of esophageal cancer remain poorly understood. However, it is generally believed that systemic spread of metastatic disease is the result of the complex lymphatic supply of the esophagus, and often patients develop distant metastatic disease in the absence of locoregional recurrence.18–20 While regional and distant recurrences often coincided, in our patient cohort, local recurrence was present in only 15 of the 484 cases of regional and distant recurrences.
In the present study, advanced T stage, signet cell histology, and serious complication were independent risk factors for local recurrence. It is not surprising that higher tumor stage corresponds to an increased risk of local recurrence. Positive lymph node status has repeatedly been demonstrated to be associated with an increased risk of recurrence.24–26 However, in the present study, positive lymph node status was not associated with an increased risk of local recurrence, which has been previously reported.22 This is most likely because patients with node-positive disease develop regional or distant recurrence. It is possible that different mechanisms are responsible for local recurrence.
Several other retrospective studies have demonstrated increased risk of recurrence in patients undergoing resection for esophageal cancer who developed intrathoracic anastomotic leakage or other serious postoperative complication.27–29 A total of 18 patients with local recurrence had suffered a major postoperative complication, and of these patients, 17 experienced anastomotic complications, including anastomotic leak, stricture, or conduit necrosis. Additionally, 4 patients with local recurrence without serious postoperative complication had minor anastomotic leaks. It has been proposed that the stronger inflammatory and oxidative stress responses occurring with postoperative complications may contribute to recurrence development and has been described in other cancers.30 Supporting this theory is a study showing that complicated hypertension, hyperlipidemia, and diabetes mellitus are relevant and independent risk factors for the postoperative recurrence of esophageal cancer.31 Moreover, local recurrence was not associated with any other factors predictive of regional and distant recurrence, such as baseline differentiation and lymphovascular infiltration.
Management of local recurrence can be challenging, and currently there are no guidelines that can aid treatment decisions. Within our cohort, patients receiving definitive treatment had significantly better survival outcomes. In patients who received neoadjuvant chemoradiation (n=32), reirradiation was only given if recurrence occurred outside of the radiation field (n=4) or to treat episodes of tumor-related hematemesis or dysphagia (n=3). Patients who were treated with salvage surgical resection lived for years following treatment of their recurrence, with a median survival time of 12.8 months (95% CI, 8.6–43.4 months). In a previous report by Schipper et al. published in 2005, complete re-resection performed for locally recurrent esophageal carcinoma led to a 2-, 3-, and 5-year survival of 62%, 44%, and 35%.32
The limitations of our study include that it is a retrospective analysis of a single-center experience and, therefore, is susceptible to selection bias. Our study included only 46 patients with isolated local recurrence, and our results may not be generalizable to other populations. Additionally, no algorithm or general guide is available to describe how specific decisions were made regarding treatment of these recurrences, as each patient is discussed individually at a multidisciplinary meeting before treatment begins. Ultimately, our analysis was limited by the heterogeneous patient population, the small number of cases of isolated local recurrence, and likely unmeasured confounding in the study.
In summary, whereas a significant proportion of patients develop recurrence of esophageal cancer after resection, isolated local recurrence is exceedingly rare. Advanced T stage, signet cell histology, and serious complication were independent risk factors for local recurrence. More-aggressive treatment approaches that combine local and systemic therapies may improve survival after local recurrence in select patients.
Supplementary Material
Acknowledgment:
In memory of Rebecca A. Carr, MD, February 24, 1988, to January 19, 2021. The authors thank Robert Carr for extensive revisions to the manuscript. This work was supported, in part, by NIH/NCI Cancer Center Support Grant P30 CA008748.
Footnotes
Conflicts of Interest: Matthew J. Bott is a consultant for AstraZeneca. James M. Isbell has stock ownership in LumaCyte and is a consultant/advisory board member for Roche Genentech. Bernard J. Park has served as a proctor for Intuitive Surgical and a consultant for COTA. David R. Jones serves as a consultant for AstraZeneca and on a Clinical Trial Steering Committee for Merck. Daniela Molena serves as a consultant for Johnson & Johnson, Urogen, and Boston Scientific. There are no other conflicts.
Publisher's Disclaimer: 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.
References
- 1.Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. [DOI] [PubMed] [Google Scholar]
- 2.Pohl H, Welch HG. The role of overdiagnosis and reclassification in the marked increase of esophageal adenocarcinoma incidence. J Natl Cancer Inst. 2005;97(2):142–146. [DOI] [PubMed] [Google Scholar]
- 3.Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7–34. [DOI] [PubMed] [Google Scholar]
- 4.Meguid RA, Hooker CM, Taylor JT, et al. Recurrence after neoadjuvant chemoradiation and surgery for esophageal cancer: does the pattern of recurrence differ for patients with complete response and those with partial or no response? J Thorac Cardiovasc Surg. 2009;138(6):1309–1317. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Mariette C, Balon JM, Piessen G, Fabre S, Van Seuningen I, Triboulet JP. Pattern of recurrence following complete resection of esophageal carcinoma and factors predictive of recurrent disease. Cancer. 2003;97(7):1616–1623. [DOI] [PubMed] [Google Scholar]
- 6.Dorth JA, Pura JA, Palta M, et al. Patterns of recurrence after trimodality therapy for esophageal cancer. Cancer. 2014;120(14):2099–2105. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Wang Y, Zhang L, Ye D, et al. A retrospective study of pattern of recurrence after radical surgery for thoracic esophageal carcinoma with or without postoperative radiotherapy. Oncol Lett. 2018;15(3):4033–4039. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Oppedijk V, van der Gaast A, van Lanschot JJ, et al. Patterns of recurrence after surgery alone versus preoperative chemoradiotherapy and surgery in the CROSS trials. J Clin Oncol. 2014;32(5):385–391. [DOI] [PubMed] [Google Scholar]
- 9.Peyre CG, Hagen JA, DeMeester SR, et al. Predicting systemic disease in patients with esophageal cancer after esophagectomy: a multinational study on the significance of the number of involved lymph nodes. Ann Surg. 2008;248(6):979–985. [DOI] [PubMed] [Google Scholar]
- 10.Batool S, Khan M, Akbar SA, Ashraf I. Risk factors and patterns of recurrence after curative resection in Gastroesophageal Junction Adenocarcinoma. Pak J Med Sci. 2019;35(5):1276–1283. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Shapiro J, van Lanschot JJB, Hulshof MCCM, et al. Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. The Lancet Oncology. 2015;16(9):1090–1098. [DOI] [PubMed] [Google Scholar]
- 12.du Rieu MC, Filleron T, Beluchon B, et al. Recurrence risk after Ivor Lewis oesophagectomy for cancer. Journal of Cardiothoracic Surgery. 2013;8(1):215. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Butter R, Lagarde SM, van Oijen MGH, et al. Treatment strategies in recurrent esophageal or junctional cancer. Dis Esophagus. 2017;30(9):1–9. [DOI] [PubMed] [Google Scholar]
- 14.Kunisaki C, Makino H, Takagawa R, et al. Surgical outcomes in esophageal cancer patients with tumor recurrence after curative esophagectomy. J Gastrointest Surg. 2008;12(5):802–810. [DOI] [PubMed] [Google Scholar]
- 15.Amin MB, Edge SB. AJCC cancer staging manual. Eighth edition. ed. Switzerland: Switzerland: Springer; 2017. [Google Scholar]
- 16.Clavien PA, Barkun J, de Oliveira ML, et al. The Clavien-Dindo classification of surgical complications: five-year experience. Ann Surg. 2009;250(2):187–196. [DOI] [PubMed] [Google Scholar]
- 17.Kato H, Fukuchi M, Miyazaki T, et al. Classification of recurrent esophageal cancer after radical esophagectomy with two- or three-field lymphadenectomy. Anticancer Res. 2005;25(5):3461–3467. [PubMed] [Google Scholar]
- 18.Lou F, Sima CS, Adusumilli PS, et al. Esophageal cancer recurrence patterns and implications for surveillance. J Thorac Oncol. 2013;8(12):1558–1562. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Xi M, Yang Y, Zhang L, et al. Multi-institutional Analysis of Recurrence and Survival After Neoadjuvant Chemoradiotherapy of Esophageal Cancer: Impact of Histology on Recurrence Patterns and Outcomes. Ann Surg. 2019;269(4):663–670. [DOI] [PubMed] [Google Scholar]
- 20.Abate E, DeMeester SR, Zehetner J, et al. Recurrence after esophagectomy for adenocarcinoma: defining optimal follow-up intervals and testing. J Am Coll Surg. 2010;210(4):428–435. [DOI] [PubMed] [Google Scholar]
- 21.Moorcraft SY, Fontana E, Cunningham D, et al. Characterising timing and pattern of relapse following surgery for localised oesophagogastric adenocarcinoma: a retrospective study. BMC Cancer. 2016;16:112. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Blackham AU, SM HN, Schell MJ, et al. Recurrence patterns and associated factors of locoregional failure following neoadjuvant chemoradiation and surgery for esophageal cancer. J Surg Oncol. 2018;117(2):150–159. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Lin CL, Meredith K, Klapman J. Rate of Recurrent Luminal Esophageal Cancer in Asymptomatic Patients After Curative Treatment for Esophageal Cancer. J Clin Gastroenterol. 2015;49(8):e71–75. [DOI] [PubMed] [Google Scholar]
- 24.Belmouhand M, Svendsen LB, Kofoed SC, Normann G, Baeksgaard L, Achiam MP. Recurrence following curative intended surgery for an adenocarcinoma in the gastroesophageal junction: a retrospective study. Dis Esophagus. 2018;31(4). [DOI] [PubMed] [Google Scholar]
- 25.BlackhaU, YuB, AlmhannK, et al. The prognostic value of residual nodal disease following neoadjuvant chemoradiation for esophageal cancer in patients with complete primary tumor response. J Surg Oncol. 2015;112(6):597–602. [DOI] [PubMed] [Google Scholar]
- 26.Groth SS, Burt BM, Farjah F, et al. Prognostic value of neoadjuvant treatment response in locally advanced esophageal adenocarcinoma. J Thorac Cardiovasc Surg. 2019;157(4):1682–1693 e1681. [DOI] [PubMed] [Google Scholar]
- 27.Kofoed SC, Calatayud D, Jensen LS, et al. Intrathoracic anastomotic leakage after gastroesophageal cancer resection is associated with increased risk of recurrence. J Thorac Cardiovasc Surg. 2015;150(1):42–48. [DOI] [PubMed] [Google Scholar]
- 28.Lerut T, Moons J, Coosemans W, et al. Postoperative complications after transthoracic esophagectomy for cancer of the esophagus and gastroesophageal junction are correlated with early cancer recurrence: role of systematic grading of complications using the modified Clavien classification. Ann Surg. 2009;250(5):798–807. [DOI] [PubMed] [Google Scholar]
- 29.Saunders JH, Yanni F, Dorrington MS, Bowman CR, Vohra RS, Parsons SL. Impact of postoperative complications on disease recurrence and long-term survival following oesophagogastric cancer resection. Br J Surg. 2020;107(1):103–112. [DOI] [PubMed] [Google Scholar]
- 30.Matsubara D, Arita T, Nakanishi M, et al. The impact of postoperative inflammation on recurrence in patients with colorectal cancer. Int J Clin Oncol. 2020;25(4):602–613. [DOI] [PubMed] [Google Scholar]
- 31.Zheng L, Jiang J, Liu Y, Zheng X, Wu C. Correlations of recurrence after radical surgery for esophageal cancer with glucose-lipid metabolism, insulin resistance, inflammation, stress and serum p53 expression. J buon. 2019;24(4):1666–1672. [PubMed] [Google Scholar]
- 32.Schipper PH, Cassivi SD, Deschamps C, et al. Locally recurrent esophageal carcinoma: when is re-resection indicated? Ann Thorac Surg. 2005;80(3):1001–1005; discussion 1005–1006. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.