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Objective: To assess postoperative morbidity, disease-free survival (DFS), and overall survival (OS) in patients treated with salvage esophagectomy (SE)., Background Data: A shift toward a "surgery as needed" approach for esophageal cancer has emerged, potentially resulting in delayed esophagectomy., Methods: We identified patients with clinical stage I-III esophageal adenocarcinoma or squamous cell carcinoma who underwent chemoradiation followed by esophagectomy from 2001 to 2019. SE was defined as esophagectomy performed >90 days after chemoradiation ("for time") and esophagectomy performed for recurrence after curative-intent chemoradiation ("for recurrence"). The odds of postoperative serious complications were assessed by multivariable logistic regression. The relationship between SE and OS and DFS were quantified using Cox regression models., Results: Of 1137 patients identified, 173 (15%) underwent SE. Of those, 61 (35%) underwent SE for recurrence, and 112 (65%) underwent SE for time. The odds of experiencing any serious complication [odds ratio, 2.10 (95% CI, 1.37-3.20); P =0.001] or serious pulmonary complication [odds ratio, 2.11 (95% CI, 1.31-3.42); P =0.002] were 2-fold higher for SE patients; SE patients had a 1.5-fold higher hazard of death [hazard ratio, 1.56 (95% CI, 1.25-1.94); P <0.0001] and postoperative recurrence [hazard ratio, 1.43 (95% CI, 1.16-1.77); P =0.001]. Five-year OS for nonsalvage esophagectomy was 45% [(95% CI, 41.6%-48.6%) versus 26.5% (95% CI, 20.2%-34.8%) for SE (log-rank P <0.001)]. Five-year OS for SE for time was 27.1% [(95% CI, 19.5%-37.5%) versus 25.2% (95% CI, 15.3%-41.5%) for SE for recurrence ( P =0.611)]., Conclusions: SE is associated with a higher risk of serious postoperative complications and shorter DFS and OS., Competing Interests: M.J.B. is a consultant for AstraZeneca. D.H.I. reports research funding to Memorial Sloan Kettering from Astellas, Eli Lilly, Pieris, and Taiho and consulting for AstraZeneca, Amgen, Bayer, Bristol-Myers Squibb, and Roche. J.M.I. has stock ownership in LumaCyte and is a consultant/advisory board member for Roche Genentech. B.J.P. has served as a proctor for Intuitive Surgical and as a consultant for COTA. Y.Y.J. reports grant funding from Bayer, Bristol-Myers Squibb, Cycle for Survival, US Department of Defense, Eli Lilly, Fred’s Team, Genentech/Roche, Merck, US National Cancer Institute, and RGENIX; consulting fees from AstraZeneca, Basilea Pharmaceutica, Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, Imugene, Merck, Merck Serono, Michael J Hennessy Associates, Paradigm Medical Communications, Pfizer, RGENIX, Seagen, and Zymeworks; honoraria from AstraZeneca, Basilea Pharmaceutica, Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, Imugene, Merck, Merck Serono, Michael J Hennessy Associates, Paradigm Medical Communications, Pfizer, RGENIX, Seagen, and Zymeworks; and stock or stock options for RGENIX. G.R. has a financial relationship with Scanlan, AstraZeneca, and Medtronic. V.W.R. reports grant support (institutional) from Genelux and Genentech, travel support from Intuitive Surgical, and travel support and payments from NIH/Coordinating Center for Clinical Trials. A.J.W. reports stock and other ownership interests in Simphotek, consulting or advisory roles for AstraZeneca, MORE Health, and NanoVi, research funding from CivaTech Oncology, and travel, accommodations, and expenses from CivaTech Oncology. D.R.J. serves as a consultant for AstraZeneca and on a Clinical Trial Steering Committee for Merck. D.M. serves on a steering committee for AstraZeneca and as a consultant for Johnson & Johnson, Bristol-Myers Squibb, Merck, and Genentech. The remaining authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: We sought to evaluate the performance of 2 commonly used prediction models for postoperative morbidity in patients undergoing open and minimally invasive esophagectomy., Summary Background Data: Patients undergoing esophagectomy have a high risk of postoperative complications. Accurate risk assessment in this cohort is important for informed decision-making., Methods: We identified patients who underwent esophagectomy between January 2016 and June 2018 from our prospectively maintained database. Predicted morbidity was calculated using the American College of Surgeons National Surgical Quality Improvement Program Surgical Risk Calculator (SRC) and a 5-factor National Surgical Quality Improvement Programderived frailty index. Performance was evaluated using concordance index (C-index) and calibration curves., Results: In total, 240 consecutive patients were included for analysis. Most patients (85%) underwent Ivor Lewis esophagectomy. The observed overall complication rate was 39%; the observed serious complication rate was 33%.The SRC did not identify risk of complications in the entire cohort (C-index, 0.553), patients undergoing open esophagectomy (C-index, 0.569), or patients undergoing minimally invasive esophagectomy (C-index, 0.542); calibration curves showed general underestimation. Discrimination of the SRC was lowest for reoperation (C-index, 0.533) and highest for discharge to a facility other than home (C-index, 0.728). Similarly, the frailty index had C-index of 0.513 for discriminating any complication, 0.523 for serious complication, and 0.559 for readmission., Conclusions: SRC and frailty index did not adequately predict complications after esophagectomy. Procedure-specific risk-assessment tools are needed to guide shared patient-physician decision-making in this high-risk population., Competing Interests: Valerie W. Rusch reports grant support (institutional) from Genelux and Genentech, travel support from Intuitive Surgical, and travel support and payments from NIH/Coordinating Center for Clinical Trials. David R. Jones serves as a senior medical advisor for Diffusion Pharmaceuticals and a consultant for AstraZeneca and Merck. Gaetano Rocco has a financial relationship with Scanlan. Daniela Molena is a consultant for Intuitive Surgical, Johnson and Johnson, Urogen, and Boston Scientific. James M. Isbell has stock ownership in LumaCyte and is a consultant/advisory board member for Roche Genentech. All other authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

During the past 50 years, there has been a remarkable transformation in the management of lung and esophageal cancers. Improved methods of diagnosis, better staging and patient selection for surgery, the advent of minimally invasive approaches to resection, decreasing operative mortality, greater insights into tumor biology, and the development of effective multimodality therapies and precision medicine have contributed to this transformation. Progress has been most notable in lung cancer., (© 2022 Wiley Periodicals LLC.)

Objective: Little is known about the pattern of nodal metastases in patients with esophageal adenocarcinoma who have received neoadjuvant chemoradiation and undergone surgery. We sought to assess this pattern and evaluate its association with prognosis., Methods: All patients with esophageal adenocarcinoma who underwent neoadjuvant chemoradiation and R0 esophagectomy between 2010 and 2018 at our institution were included (n = 537). The primary objective was to evaluate the association of sites of lymph node metastases with disease-free survival. The number of nodal stations and individual sites of nodal metastases were evaluated first in univariable then in separate multivariable Cox regression models adjusted for clinical factors., Results: Of 537 patients, 193 (36%) had pathologic nodal metastases at the time of surgery; 153 (28%) had single-station disease, 32 (6.0%) had 2-station disease, and 8 (1.5%) had 3-station disease. The majority of patients with multiple positive nodal stations had positive nodes in the paraesophageal (93%) and/or left gastric stations (60%). Multivariable models controlling for clinical factors showed that an increasing number of positive nodal stations (hazard ratio, 1.59; 95% CI, 1.35-1.84; P < .01)-in particular, the subcarinal (hazard ratio, 2.78; 95% CI, 1.54-5.03; P < .01) and paraesophageal stations (hazard ratio, 2.0; 95% CI, 1.58-2.54; P < .01)-was associated with increased risk of recurrence., Conclusions: One-third of patients who have undergone R0 resection for esophageal adenocarcinoma following induction chemoradiation therapy have metastatic lymph nodes. An increasing number of nodal stations, particularly paraesophageal and subcarinal metastases, were associated with increased risk of recurrence., (Copyright © 2022 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Robotic-assisted minimally invasive esophagectomy (RAMIE) is a safe alternative to open esophagectomy (OE). However, differences in quality of life (QOL) after these procedures remain unclear. We previously reported short-term QOL outcomes after RAMIE and OE and describe here our results from 2 years of follow-up., Methods: We conducted a prospective, nonrandomized trial of patients with esophageal cancer undergoing transthoracic resection by RAMIE or OE at a single institution. The primary outcomes were patient-reported QOL, measured by the Functional Assessment of Cancer Therapy-Esophageal (FACT-E), and pain, measured by the Brief Pain Inventory (BPI). Generalized linear models were used to assess the relationship between QOL outcomes and surgery cohort. P values were adjusted (P-adj) within each model using the false discovery rate correction., Results: Esophagectomy was performed in 170 patients (106 OE and 64 RAMIE). The groups did not differ significantly by any measured clinicopathologic variables. After covariates were controlled for, FACT-E scores were higher in the RAMIE cohort than in the OE cohort (parameter estimate [PE], 6.13; P-adj = .051). RAMIE was associated with higher esophageal cancer subscale (PE, 2.72; P-adj = .022) and emotional well-being (PE, 1.25; P-adj = .016) scores. BPI pain severity scores were lower in the RAMIE cohort than in the OE cohort (PE, -0.56; P-adj = .005), but pain interference scores did not differ significantly between groups (P-adj = .11)., Conclusions: During 2 years of follow-up, RAMIE was associated with improved patient-reported QOL, including esophageal symptoms, emotional well-being, and decreased pain, compared with OE., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Minimally invasive esophagectomy may improve some perioperative outcomes over open approaches; effects on quality of life are less clear., Methods: A prospective trial of robotic-assisted minimally invasive esophagectomy (RAMIE) and open esophagectomy was initiated, measuring quality of life via the Functional Assessment of Cancer Therapy-Esophageal and Brief Pain Inventory. Mixed generalized linear models assessed associations between quality of life scores over time and by surgery type., Results: In total, 106 patients underwent open esophagectomy; 64 underwent minimally invasive esophagectomy (98% RAMIE). The groups did not differ in age, sex, comorbidities, histologic subtype, stage, or induction treatment (P = .42 to P > .95). Total Functional Assessment of Cancer Therapy-Esophageal scores were lower at 1 month (P < .001), returned to near baseline by 4 months, and did not differ between groups (P = .83). Brief Pain Inventory average pain severity (P = .007) and interference (P = .004) were lower for RAMIE. RAMIE had lower estimated blood loss (250 vs 350 cm 3 ; P < .001), shorter length of stay (9 vs 11 days; P < .001), fewer intensive care unit admissions (8% vs 20%; P = .033), more lymph nodes harvested (25 vs 22; P = .05), and longer surgical time (6.4 vs 5.4 hours; P < .001). Major complications (39% for RAMIE vs 52% for open esophagectomy; P > .95), anastomotic leak (3% vs 9%; P = .41), and 90-day mortality (2% vs 4%; P = .85) did not differ between groups. Pulmonary (14% vs 34%; P = .014) and infectious (17% vs 36%; P = .029) complications were lower for RAMIE., Conclusions: RAMIE is associated with lower immediate postoperative pain severity and interference and decreased pulmonary and infectious complications. Ongoing data accrual will assess mid-term and long-term outcomes in this cohort., (Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Introduction: Preoperative or definitive chemoradiation is an accepted treatment for locally advanced esophageal squamous cell carcinoma (ESCC). The MUNICON study showed that positron-emission tomography (PET) response following induction chemotherapy was predictive of outcomes in patients with gastroesophageal junction adenocarcinoma. We evaluated the predictive value of PET following induction chemotherapy in ESCC patients and assessed the impact of changing chemotherapy during radiation in PET nonresponders., Methods: We retrospectively reviewed all patients with locally advanced ESCC who received induction chemotherapy and chemoradiation; all patients had a PET before and after induction chemotherapy. Survival was calculated from date of repeat PET using Kaplan-Meier analysis and compared between groups using the log-rank test., Results: Of 111 patients, 70 (63%) were PET responders (defined as a 35% or more decrease in maximum standard uptake value) to induction chemotherapy. PET responders received the same chemotherapy during radiation. Of 41 PET nonresponders, 16 continued with the same chemotherapy and 25 were changed to alternative chemotherapy with radiation. Median progression-free survival (70.1 months versus 7.1 months, p < 0.01) and overall survival (84.8 months versus 17.2 months, p < 0.01) were improved for PET responders versus nonresponders. Median progression-free survival and overall survival for PET nonresponders who changed chemotherapy versus those who did not were 6.4 months versus 8.3 months (p = 0.556) and 14.1 versus 17.2 months (p = 0.81), respectively., Conclusions: PET after induction chemotherapy highly predicts for outcomes in ESCC patients who receive chemoradiation. However, our results suggest that PET nonresponders do not benefit from changing chemotherapy during radiation. Future trials should use PET nonresponse after induction chemotherapy to identify poor prognosis patients for novel therapies., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

The incidence of esophagogastric cancer is rapidly rising, but only a minority of patients derive durable benefit from current therapies. Chemotherapy as well as anti-HER2 and PD-1 antibodies are standard treatments. To identify predictive biomarkers of drug sensitivity and mechanisms of resistance, we implemented prospective tumor sequencing of patients with metastatic esophagogastric cancer. There was no association between homologous recombination deficiency defects and response to platinum-based chemotherapy. Patients with microsatellite instability-high tumors were intrinsically resistant to chemotherapy but more likely to achieve durable responses to immunotherapy. The single Epstein-Barr virus-positive patient achieved a durable, complete response to immunotherapy. The level of ERBB2 amplification as determined by sequencing was predictive of trastuzumab benefit. Selection for a tumor subclone lacking ERBB2 amplification, deletion of ERBB2 exon 16, and comutations in the receptor tyrosine kinase, RAS, and PI3K pathways were associated with intrinsic and/or acquired trastuzumab resistance. Prospective genomic profiling can identify patients most likely to derive durable benefit to immunotherapy and trastuzumab and guide strategies to overcome drug resistance. Significance: Clinical application of multiplex sequencing can identify biomarkers of treatment response to contemporary systemic therapies in metastatic esophagogastric cancer. This large prospective analysis sheds light on the biological complexity and the dynamic nature of therapeutic resistance in metastatic esophagogastric cancers. Cancer Discov; 8(1); 49-58. ©2017 AACR. See related commentary by Sundar and Tan, p. 14 See related article by Pectasides et al., p. 37 This article is highlighted in the In This Issue feature, p. 1 ., (©2017 American Association for Cancer Research.)

Objectives: To identify the associations of lymph node metastases (pN+), number of positive nodes, and pN subclassification with cancer, treatment, patient, geographic, and institutional variables, and to recommend extent of lymphadenectomy needed to accurately detect pN+ for esophageal cancer., Summary Background Data: Limited data and traditional analytic techniques have precluded identifying intricate associations of pN+ with other cancer, treatment, and patient characteristics., Methods: Data on 5806 esophagectomy patients from the Worldwide Esophageal Cancer Collaboration were analyzed by Random Forest machine learning techniques., Results: pN+, number of positive nodes, and pN subclassification were associated with increasing depth of cancer invasion (pT), increasing cancer length, decreasing cancer differentiation (G), and more regional lymph nodes resected. Lymphadenectomy necessary to accurately detect pN+ is 60 for shorter, well-differentiated cancers (<2.5 cm) and 20 for longer, poorly differentiated ones., Conclusions: In esophageal cancer, pN+, increasing number of positive nodes, and increasing pN classification are associated with deeper invading, longer, and poorly differentiated cancers. Consequently, if the goal of lymphadenectomy is to accurately define pN+ status of such cancers, few nodes need to be removed. Conversely, superficial, shorter, and well-differentiated cancers require a more extensive lymphadenectomy to accurately define pN+ status.

Background: A positron emission tomography (PET) scan after induction chemotherapy before preoperative chemoradiation and surgery for esophageal adenocarcinoma predicts outcomes. Some patients with progression on PET after induction chemotherapy had long-term overall survival (OS) when they were changed to alternative chemotherapy during radiation., Methods: This study retrospectively reviewed esophageal adenocarcinoma patients who received induction chemotherapy and chemoradiation before planned surgery; all had undergone a PET scan before and after induction chemotherapy., Results: There were 201 patients, and 113 (56%) were PET responders (≥35% decrease in the maximum standardized uptake value of the tumor). All PET responders received the same chemotherapy during radiation, whereas 38 of the 88 PET nonresponders (43%) changed chemotherapy. Among the 152 patients who underwent surgery, the pathologic complete response rate was 15% for PET responders and 3% for PET nonresponders who did not change chemotherapy (P = .046). The median progression-free survival (PFS; 18.9 vs 10.0 months, P < 0.01) and OS (37 vs 25.3 months, P = .02) were significantly better for PET responders versus PET nonresponders who did not change chemotherapy. The median PFS for PET nonresponders who changed chemotherapy was 17.9 months, and it was superior to the median PFS for PET nonresponders who did not change chemotherapy (P = .01). For PET nonresponders, the 5-year OS rates were 37% for those who changed chemotherapy and 25% for those who did not change chemotherapy (P = .18)., Conclusions: A PET scan after induction chemotherapy predicts outcomes for locally advanced esophageal adenocarcinoma patients who undergo chemoradiation and surgery. The median PFS is improved, and trends toward improved OS appear possible in PET nonresponders who change chemotherapy during radiation. The fully accrued Cancer and Leukemia Group B 80803 study (NCT01333033) is evaluating this strategy. Cancer 2016;122:2083-90. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

Objective: Robotic-assisted minimally invasive esophagectomy (RAMIE) is an emerging complex operation with limited reports detailing morbidity, mortality, and requirements for attaining proficiency. Our objective was to develop a standardized RAMIE technique, evaluate procedure safety, and assess outcomes using a dedicated operative team and 2-surgeon approach., Methods: We conducted a study of sequential patients undergoing RAMIE from January 25, 2011, to May 5, 2014. Intermedian demographics and perioperative data were compared between sequential halves of the experience using the Wilcoxon rank sum test and the Fischer exact test. Median operative time was tracked over successive 15-patient cohorts., Results: One hundred of 313 esophageal resections performed at our institution underwent RAMIE during the study period. A dedicated team including 2 attending surgeons and uniform anesthesia and OR staff was established. There were no significant differences in age, sex, histology, stage, induction therapy, or risk class between the 2 halves of the study. Estimated blood loss, conversions, operative times, and overall complications significantly decreased. The median resected lymph nodes increased but was not statistically significant. Median operative time decreased to approximately 370 minutes between the 30th and the 45th cases. There were no emergent intraoperative complications, and the anastomotic leak rate was 6% (6/100). The 30-day mortality was 0% (0/100), and the 90-day mortality was 1% (1/100)., Conclusions: Excellent perioperative and short-term patient outcomes with minimal mortality can be achieved using a standardized RAMIE procedure and a dedicated team approach. The structured process described may serve as a model to maximize patients' safety during development and assessment of complex novel procedures.

Background: Neoadjuvant therapy is commonly administered to patients with localized disease who have T3-4 esophageal disease as staged by endoscopic ultrasound (EUS). Previously, we noted that patients who present with dysphagia have a higher EUS T stage. We hypothesized that the presence of dysphagia is predictive of EUS T3-4 disease and that staging EUS could be forgone for esophageal cancer patients with dysphagia., Methods: We performed a prospective, intent-to-treat, single-cohort study in which patients with potentially resectable esophageal cancer completed a standardized four-tier dysphagia score survey. EUS was performed as part of our standard evaluation. To determine whether the presence of dysphagia predicted EUS T3-4 disease, the dysphagia score was compared with EUS T stage., Results: The study enrolled 114 consecutive patients between August 2012 and February 2014: 77% (88 of 114) received neoadjuvant therapy, 18% (20 of 114) did not, and 5% (6 of 114) pursued treatment elsewhere. In total, 70% (80 of 114) underwent esophagectomy; of these, 54% (61 of 114) had dysphagia and 46% (53 of 114) did not. Dysphagia scores were 66% (40 of 61) grade 1, 25% (15 of 61) grade 2, and 10% (6 of 61) grade 3 to 4. Among patients with dysphagia, 89% (54 of 61) had T3-4 disease by EUS; among those without dysphagia, only 53% (28 of 53) had T3-4 disease by EUS (p < 0.001)., Conclusions: The presence of dysphagia in patients with esophageal cancer was highly predictive of T3-4 disease by EUS. On the basis of this finding, approximately 50% of patients currently undergoing staging EUS at our institution could potentially forgo EUS before neoadjuvant therapy. Patients without dysphagia, however, should still undergo EUS., (Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Introduction: After definitive treatment of esophageal cancer, patients are at high risk for recurrence. Consistent follow-up is important for detection and treatment of recurrence. The optimal surveillance regimen remains undefined. We investigated posttreatment recurrence patterns and methods of detection in survivors of esophageal cancer., Methods: We retrospectively studied a cohort of patients who had undergone surgical resection for esophageal cancer at our institution between 1996 and 2010. Routine computed tomography scan and upper endoscopy were performed for surveillance., Results: In total, 1147 patients with resected esophageal adenocarcinoma or squamous cell carcinoma were included (median follow-up, 46 months). Of these, 723 patients (63%) had received neoadjuvant therapy before surgery. During follow-up, there were 595 deaths (52%) and 435 recurrences (38%) (distant [55%], locoregional [28%], or both [17%]). Half of recurrences were detected as a result of symptoms (n = 217), 45% by routine chest and abdominal computed tomography scan (n = 194), and 1% by surveillance upper endoscopy (n = 6). The recurrence rate decreased from 27 per 100 person-years in posttreatment year 1 to 4 per 100 person-years in year 6. In the first 2 years, the rate of recurrence was higher among patients who had received neoadjuvant therapy (35 per 100 person-years) than among those who had not (14 per 100 person-years) (p < 0.001)., Conclusions: The incidence of recurrence is high after esophagectomy for cancer. Surveillance endoscopy has limited value for detection of asymptomatic local recurrence. The yield from follow-up scans diminishes significantly after the sixth year; surveillance scans after that point are likely unnecessary.

Purpose/objective: To explore patterns of symptoms before and after surgery for cancer of the esophagus., Design: Longitudinal, descriptive study., Setting: An urban comprehensive cancer center in the northeastern United States., Sample: 218 patients with cancer of the esophagus undergoing esophagectomy., Methods: Symptoms were assessed by self-report before surgery, at the first postoperative visit, and at 6 and 12 months postsurgery., Main Research Variables: Symptoms and demographic and clinical variables, including stage, treatment, gender, and comorbidities., Findings: Patients with esophageal cancer reported numerous symptoms before and after esophagectomy. Several patterns of symptoms were identified. General cancer symptoms (e.g., pain, cough, shortness of breath, weight loss) were reported as worse after surgery but recovered to baseline by one year. A second pattern of esophageal-specific symptoms (feeling full too quickly, feeling bloated, nausea, and diarrhea) worsened after surgery and did not recover to baseline by one year. Reflux was the only symptom that did not worsen after surgery but did worsen significantly during the first year of recovery., Conclusions: Patients with esophageal cancer experienced multiple prolonged symptoms following surgical treatment for their disease. General cancer symptoms resolved by one year post-treatment, whereas esophageal-specific symptoms worsened after surgery and did not recover to baseline., Implications for Nursing: Identification of symptom patterns preoperatively and during recovery can assist nurses in developing intervention protocols to minimize long-term complications for patients with esophageal cancer., Knowledge Translation: Patients with esophageal cancer are at risk for multiple prolonged symptoms following surgery. Symptom assessment should occur often after surgery and include a broad range of symptoms.

Background: Mesothelin is overexpressed in several malignancies and is purportedly a specific marker of malignant transformation. In this pilot study, we investigated whether tissue and serum mesothelin are potential markers of neoplastic progression in Barrett's esophagus (BE) and in esophageal adenocarcinoma (EAC)., Methods: Mesothelin expression was retrospectively evaluated in normal, BE, and EAC tissue from surgically resected esophageal specimens (n = 125). In addition, soluble mesothelin-related peptide (SMRP) levels were measured in serum., Results: Normal esophageal mucosa did not express mesothelin. BE tissue with high-grade dysplasia specifically expressed mesothelin, whereas BE tissue with low-grade or without dysplasia did not. Fifty-seven (46%) EAC tumors were positive for mesothelin. EAC tumors with BE expressed mesothelin more often than those without BE (58% vs. 35%, P = 0.01). SMRP levels were elevated in 70% of EAC patients (mean = 0.89 nmol/L; range: 0.03-3.77 nmol/L), but not in patients with acid reflux and/or BE., Conclusions: Mesothelin is commonly expressed in BE-associated EAC. On the basis of this pilot study, a prospective study is under way to evaluate tissue and serum mesothelin which are potential markers of neoplastic progression in BE and in EAC (NCT01393483)., Impact: Current surveillance methods in Barrett's esophagus are invasive and neither cost-effective nor sensitive. This pilot study suggests that serum mesothelin is a marker of neoplastic transformation in BE and may provide a noninvasive method to improve identification of malignant transformation., (©2012 AACR.)

Background: Previous American Joint Committee on Cancer/International Union Against Cancer (AJCC/UICC) stage groupings for esophageal cancer have not been data driven or harmonized with stomach cancer. At the request of the AJCC, worldwide data from 3 continents were assembled to develop data-driven, harmonized esophageal staging for the seventh edition of the AJCC/UICC cancer staging manuals., Methods: All-cause mortality among 4627 patients with esophageal and esophagogastric junction cancer who underwent surgery alone (no preoperative or postoperative adjuvant therapy) was analyzed by using novel random forest methodology to produce stage groups for which survival was monotonically decreasing, distinctive, and homogeneous., Results: For lymph node-negative pN0M0 cancers, risk-adjusted 5-year survival was dominated by pathologic tumor classification (pT) but was modulated by histopathologic cell type, histologic grade, and location. For lymph node-positive, pN+M0 cancers, the number of cancer-positive lymph nodes (a new pN classification) dominated survival. Resulting stage groupings departed from a simple, logical arrangement of TNM. Stage groupings for stage I and II adenocarcinoma were based on pT, pN, and histologic grade; and groupings for squamous cell carcinoma were based on pT, pN, histologic grade, and location. Stage III was similar for histopathologic cell types and was based only on pT and pN. Stage 0 and stage IV, by definition, were categorized as tumor in situ (Tis) (high-grade dysplasia) and pM1, respectively., Conclusions: The prognosis for patients with esophageal and esophagogastric junction cancer depends on the complex interplay of TNM classifications as well as nonanatomic factors, including histopathologic cell type, histologic grade, and cancer location. These features were incorporated into a data-driven staging of these cancers for the seventh edition of the AJCC/UICC cancer staging manuals., (Copyright (c) 2010 American Cancer Society.)

Objective: Using Worldwide Esophageal Cancer Collaboration data, we sought to (1) characterize the relationship between survival and extent of lymphadenectomy, and (2) from this, define optimum lymphadenectomy., Summary Background Data: What constitutes optimum lymphadenectomy to maximize survival is controversial because of variable goals, analytic methodology, and generalizability of the underpinning data., Methods: A total of 4627 patients who had esophagectomy alone for esophageal cancer were identified from the Worldwide Esophageal Cancer Collaboration database. Patient-specific risk-adjusted survival was estimated using random survival forests. Risk-adjusted 5-year survival was averaged for each number of lymph nodes resected and its relation to cancer characteristics explored. Optimum number of nodes that should be resected to maximize 5-year survival was determined by random forest multivariable regression., Results: For pN0M0 moderately and poorly differentiated cancers, and all node-positive (pN+) cancers, 5-year survival improved with increasing extent of lymphadenectomy. In pN0M0 cancers, no optimum lymphadenectomy was defined for pTis; optimum lymphadenectomy was 10 to 12 nodes for pT1, 15 to 22 for pT2, and 31 to 42 for pT3/T4, depending on histopathologic cell type. In pN+M0 cancers and 1 to 6 nodes positive, optimum lymphadenectomy was 10 for pT1, 15 for pT2, and 29 to 50 for pT3/T4., Conclusions: Greater extent of lymphadenectomy was associated with increased survival for all patients with esophageal cancer except at the extremes (TisN0M0 and >or=7 regional lymph nodes positive for cancer) and well-differentiated pN0M0 cancer. Maximum 5-year survival is modulated by T classification: resecting 10 nodes for pT1, 20 for pT2, and >or=30 for pT3/T4 is recommended.

Introduction: We have previously shown that in early clinical stage esophageal adenocarcinoma, a positron emission tomography standardized uptake values (PET SUVmax) of <4.5 is associated with earlier pathologic stage and predicts better survival. In this study, we analyze the impact of the pretreatment PET SUVmax in patients with locally advanced esophageal adenocarcinoma who undergo preoperative chemoradiotherapy., Methods: We performed a retrospective analysis, selecting patients with adenocarcinoma of the esophagus who had a pretreatment PET scan and who received chemoradiotherapy before esophagectomy. Data recorded included demographics, PET SUVmax, treatment details, pathologic details, and survival data. Comparison of categorical variables was done by chi analysis, continuous variables by t test, survival analysis by the Kaplan-Meier method, and comparisons of survival using the log-rank test., Results: Between January 1996 and September 2007, 189 patients were appropriate for this analysis. The initial PET SUVmax was <4.5 in 28 patients and >or=4.5 in 161 patients. The two groups were similar with regards to demographics and treatment details. Patients in the low SUV group were less likely to show evidence of treatment response after chemoradiotherapy, including a higher likelihood of residual nodal disease and a lower likelihood of a pathologic complete response and estimated treatment response. However, both groups had similar survival., Conclusions: Although the initial PET SUVmax does not predict survival in patients with locally advanced esophageal adenocarcinoma who receive preoperative chemoradiotherapy, patients with a high initial SUVmax respond better to preoperative therapy. These results can be used to better select esophageal cancer patients for combined modality treatment.

Purpose: Endoscopic biopsy after chemoradiation therapy (CRT) for esophageal cancer has been used to determine response to treatment. We wanted to determine if endoscopic biopsy can accurately establish evidence of local pathologic complete response (pCR) in patients undergoing CRT., Methods: We queried a prospectively maintained database for patients seen at Memorial Sloan-Kettering Cancer Center from 1996 to the present who underwent, (1) CRT for local-regionally advanced esophageal cancer, (2) post-CRT endoscopic biopsy, and (3) esophagectomy. Data points included pathology of post-CRT endoscopy and surgical specimens, tumor histology, and survival. Correlations were analyzed by the chi2 test and one-way analysis of variance. Survival comparisons were assessed using the Kaplan-Meier method and log-rank analysis., Results: One hundred fifty-six patients were identified. Over 80% of patients received cisplatin-based chemotherapy and 5040 cGy of radiation. One hundred eighteen patients had no tumor identified on endoscopic biopsy. A negative biopsy at endoscopy was a poor predictor of pCR (negative predictive value: 31%), with 69% having local disease at esophagectomy. A positive biopsy was predictive of residual disease (positive predictive value: 95%). Negative endoscopic biopsy better predicted a pCR for squamous cell carcinomas versus adenocarcinomas (P[r] < 0.001). Nodal status of surgical specimens was not correlated with post-treatment endoscopic findings. Survival was equivalent after surgery in patients with a negative endoscopic biopsy versus patients with positive pathology., Conclusion: A negative endoscopic biopsy is not a useful predictor of a pCR after CRT, final nodal status, or overall survival.

Esophageal cancer with airway invasion with or without fistula presents a challenging therapeutic dilemma with no standard therapy. Recent studies in Japan have focused on the use of definitive chemoradiotherapy. However, this approach is associated with significant treatment-related morbidity and mortality. We present a case report of a patient with thoracic esophageal squamous cell carcinoma with bronchial invasion who was treated to a clinical complete response with induction chemotherapy followed by consolidation with concurrent chemoradiotherapy. The patient also underwent restaging with a positron emission tomography scan after induction chemotherapy. Such a staged approach may reduce the morbidity of upfront radiation. The use of an interim positron emission tomography scan may also identify early treatment failure.

Introduction: In a previous study of prognostic factors in patients with loco-regionally advanced adenocarcinoma of the esophagus treated with chemo-radiotherapy (CRT) followed by resection, we found that residual nodal disease was most prognostic of outcome. In this study, we evaluated prognostic factors among patients with squamous cell carcinoma (SCC) of the esophagus who have undergone a similar treatment regimen., Methods: A retrospective review of patients with SCC of the esophagus who received CRT before esophagectomy. Data collected included demographics, CRT details, pathologic findings, and survival. Statistical methods included recursive partitioning and Kaplan-Meier analyses., Results: From 1996 to 2006, 91 patients were appropriate for this analysis. Complete pathologic response in the primary tumor (pt-pCR) occurred in 49 patients (53.8%), including 10 of 91 (10.9%) who had a pt-pCR but residual nodal disease. Recursive partitioning analysis identified three prognostic groups: (1) group 1 (n = 52), patients with minimal residual local disease (pt-pCR and T1-N any); (2) group 2 (n = 28), patients with residual T2 disease (N0 and N1) and patients with T3-4N0 disease; and (3) group 3 (n = 11), patients with residual T3-4N1 disease. Three-year survival was 68.4% in group 1, 45.6% in group 2, and 0 % in group 3 (p < 0.001)., Conclusions: Unlike adenocarcinoma, in which residual nodal disease after CRT is the most significant predictor of survival, in SCC of the esophagus, pt-pCR or minimal residual local disease after CRT predicts the best survival. These findings aid the design of future clinical trials.

Background: Endoscopic ultrasound (EUS) is the most accurate locoregional staging tool for gastroesophageal junction (GEJ) adenocarcinoma, and it may allow pretreatment risk stratification. The purpose of this study was to compare preoperative EUS staging with postoperative pathologic staging and to assess the ability of EUS to predict survival after resection for GEJ adenocarcinoma., Study Design: Patients with GEJ adenocarcinoma, who had preoperative staging with EUS followed by resection, were identified from a prospectively maintained database. Patients receiving neoadjuvant therapy were excluded. EUS stage was compared with pathologic stage. Survival analyses were performed in patients who underwent complete gross resection., Results: From 1985 through 2003, 209 patients underwent preoperative EUS followed by surgery without neoadjuvant therapy for GEJ adenocarcinoma. EUS correlated with pathologic T stage in 128 of 209 (61%) patients and with pathologic nodal stage in 154 of 206 (75%) patients. EUS accurately stratified patients into "early" (T0-2 N0) or "advanced" (T3-4 or N1) disease categories in 173 (83%) patients. Curative (R0) resection was performed in 184 patients: EUS "early" (n=84) and "advanced" (n=122) stages were associated with R0 rates of 100% and 82%, respectively (p=0.001). EUS "early" versus "advanced" stage was highly predictive of outcomes (p < 0.0001). The 5-year disease-specific survival for EUS "early" patients was 65% compared with 34% for EUS "advanced" stage., Conclusions: EUS accurately predicts pathologic stage. In addition, EUS is predictive of outcomes after complete gross resection without neoadjuvant treatment for GEJ adenocarcinoma and identifies a high-risk population that might benefit from preoperative therapy.

Objective: To determine whether the length of esophageal resection or the operative approach influences outcome for patients with adenocarcinoma of the gastroesophageal junction (GEJ)., Summary Background Data: While R0 resection remains the mainstay of curative treatment of patients with GEJ cancer, the optimal length of esophageal resection remains controversial., Methods: Patients with Siewert I, II, or III adenocarcinoma who underwent complete gross resection without neoadjuvant therapy were identified from a prospectively maintained database. Proximal margin lengths were recorded ex vivo as the distance from the gross tumor edge to the esophageal transection line. Operative approaches were grouped into gastrectomy (limited esophagectomy) or esophagectomy (extended esophagectomy)., Results: From 1985 through 2003, 505 patients underwent R0/R1 gastrectomy (n = 153) or esophagectomy (n = 352) without neoadjuvant treatment. There were no differences in R1 resection rate, number of nodes examined or operative mortality between gastrectomy and esophagectomy. Univariate analysis found >3.8 cm to be the ex vivo proximal margin length (approximately 5 cm in situ) most predictive of improved survival. Multivariable analysis in patients who underwent R0 resection with >or=15 lymph nodes examined (n = 275) found the number of positive lymph nodes, T stage, tumor grade, and ex vivo proximal margin length >3.8 cm to be independent prognostic factors. Subset analysis found that the benefit associated with >3.8 cm margin was limited to patients with T2 or greater tumors and

Objectives: The American College of Surgeons Oncology Group trial Z0060 is a prospective multi-institutional trial with a primary objective to evaluate whether positron emission tomography (PET) with F-18 fluorodeoxyglucose (FDG) detects evidence of metastastic disease that precludes esophagectomy in patients with esophageal cancer who are surgical candidates after routine staging., Methods: Patients with resectable, biopsy-proven carcinoma were enrolled after computed tomography of chest and abdomen demonstrated no evidence of metastasis. FDG-PET was performed according to specified standards. FDG-PET findings suggesting metastases required confirmation and patients without metastases on PET were expected to proceed to surgery., Results: A total of 262 patients were registered. Of these, 199 were deemed eligible and of these, 189 patients were evaluable. Seventy-three patients were ineligible or unevaluable. Reasons for ineligibility included nonresectable disease by routine staging (39), missing or outdated staging procedures (12), PET technical protocol violations (10), no cancer (4), pre-PET induction therapy (3), claustrophobia (1), and other causes (4). There were 145 (78%) patients who went on to have surgery, 42 (22%) who did not, and 2 patients for whom the surgical status was not determined. The reasons for no resection included the following: M1 disease found by PET and confirmed (9), M1 disease found by PET and not confirmed (2), M1 disease at exploration not found by PET (7), decline or death before surgery (10), patient refusal of surgery (7), unresectable local tumor at exploration (5), and extensive N1 disease precluding operation (2). Eight (4.2%) patients undergoing resection had a recurrence in the first 6 months., Conclusions: Although 22% of eligible patients did not undergo esophagectomy, FDG-PET after standard clinical staging for esophageal carcinoma identified confirmed M1b disease in at least 4.8% (95% confidence interval: 2.2%-8.9%) of patients before resection. Unconfirmed PET evidence of M1 disease and regional adenopathy (N1 disease) led to definitive nonsurgical or induction therapy in additional patients.

Purpose: In patients with adenocarcinoma of the esophagus who receive preoperative chemoradiotherapy (CRT), American Joint Committee on Cancer (AJCC) stage, pathologic complete response (pCR), and estimated treatment response are various means used to stratify patients prognostically after surgery. However, none of these methods has been formally evaluated. The purpose of this study was to establish prognostic pathologic variables after CRT., Patients and Methods: A retrospective review was performed of patients with esophageal adenocarcinoma who received CRT before esophagectomy. Data collected included demographics, CRT details, pathologic findings, and survival. Statistical methods included recursive partitioning and Kaplan-Meier analyses., Results: Two hundred seventy-six patients were appropriate for this analysis. Kaplan-Meier analysis indicates that the current AJCC system poorly distinguishes between stages 0 to IIA (P = .52), IIB to III (P = .87), and IVA to IVB (P = .30). The presence of a pCR conferred improved survival over residual disease (P = .01). Recursive partitioning analysis indicates that involved lymph nodes and metastatic disease are the best predictors of survival and that depth of invasion and degree of treatment response are less predictive., Conclusion: The current AJCC staging system is not a good predictor of survival after CRT. Although patients with a pCR do have improved long-term survival relative to patients with residual disease, this method places too much emphasis on residual depth of invasion and fails to identify patients with residual disease who have good long-term survival. Recursive partitioning analysis more accurately identifies nodal disease and metastatic disease as the most important prognostic variables. Degree of treatment response is less prognostic than nodal involvement.

Introduction: Adequate staging of gastric cancer requires examination of at least 15 lymph nodes. Most resected patients are inadequately staged potentially confounding the interpretation of clinical data. The aim of this study was to determine whether adequate staging revealed different prognostic factors or improved survival compared with patients with <15 nodes examined after R0 resection for GEJ cancer., Methods: A prospectively maintained database identified 366 patients with Siewert types II and III adenocarcinoma of the GEJ who underwent R0 resection without neoadjuvant therapy at a single institution. Patients were grouped into adequately (>or=15 nodes examined) or inadequately staged (<15 nodes examined). Median follow up was 51 months., Results: From 1985 through 2003, 250/366 (68%) patients were adequately staged and 116/366 (32%) were inadequately staged. There was no difference in operative mortality between adequately staged (5.2%) and inadequately staged patients (4.3%, P = NS). Adequately staged patients had more positive lymph nodes (median 2) compared with inadequately staged patients (median 1, P < 0.01). Multivariable analysis of adequately staged patients found the number of positive lymph nodes, T stage, and lymphovascular invasion to be independent prognostic factors for overall survival (OS). For inadequately staged patients only the number of positive lymph nodes and T stage were independent prognostic factors. Adequate staging was an independent prognostic factor for patients with advanced (T >or= 2 Nany) tumors. For T1 tumors adequate staging was not associated with improved survival., Conclusions: Patients with GEJ cancer should undergo adequate lymphadenectomy to permit examination of >or=15 lymph nodes allowing the accurate identification of prognostic variables. Removal of >or=15 lymph nodes is associated with more accurate survival estimates for patients with advanced disease.

Background: As the general population ages, it becomes increasingly important to understand the potential contribution of chronologic age to mortality after esophagectomy. Because this risk is poorly defined, we sought to determine whether extreme age (>80 years) is an independent risk factor after esophagectomy., Methods: We analyzed a prospectively maintained, single-institution database of 858 consecutive patients who underwent esophagectomy between January 1996 and May 2005. Data evaluated included patient demographics, medical comorbidity, types of resections performed, length of stay, postoperative adverse events, and overall survival. We used univariate, multivariate, and Kaplan-Meier analysis to determine the influence of age on postoperative morbidity, in-hospital survival, and overall survival., Results: Of 858 patients, 31 (10 female, 21 male) were older than 80 years of age. Preliminary analysis indicated that patients younger than 50 years (n = 107) had significantly fewer comorbidities; these were excluded from the analysis. In the remaining 751 patients, the age older than 80 cohort was compared with patients aged 50 to 79. Patients aged 50 to 79 were grouped because of similar characteristics (length of stay, hospital death). There were no significant differences in comorbidities, types of resections, or postoperative complication type or severity between the two groups. Postoperative death, length of stay, and survival, however, were significantly worse in patients older than 80. In a logistic regression model controlling for comorbidity, age older than 80 was significantly associated with increased perioperative mortality (hazard-ratio, 3.9; p < 0.01)., Conclusions: Patients older than 80 years have increased mortality risk after esophagectomy, independent of comorbidity. Octogenarian status should be a consideration in the management of these patients.

Recent epidemiological shifts have led to controversy about the etiology and treatment of gastroesophageal (GE) junction adenocarcinomas. The Siewert classification conveniently describes the anatomical location of these tumors relative to the GE junction. However, available data suggest that there may be epidemiological, clinical, and molecular differences among GE junction adenocarcinomas, depending on whether they are predominantly esophageal or gastric in location. Much more investigation is required to confirm or refute these apparent differences, which can affect clinical treatment.

Background: Efforts to improve surgical outcomes have traditionally focused on improving preoperative patient selection and reducing the risk of postoperative medical complications. Strategies to optimize surgical technique have been less well studied. We sought to assess the relation between complications related to surgical technique and outcomes after esophagogastrectomy for cancer., Study Design: Medical records of 510 consecutive patients undergoing esophagogastrectomy for invasive squamous cell carcinoma or adenocarcinoma at Memorial Sloan-Kettering Cancer Center from 1996 to 2001 were reviewed. Data on diagnosis, stage of disease, therapies received, surgical approach, patient comorbidities, technical complications, and postoperative medical complications and outcomes including length of stay and overall survival were determined by one reviewer of the medical records. The primary predictor was surgical complications and the primary outcome was survival., Results: Of the 150 patients studied 138 (27%) had complications directly attributable to surgical technique, such as an anastomotic leak, a paralyzed vocal cord, or chylothorax. At 3 years 43 of 138 patients (31%) with technical complications were alive, whereas 179 of 372 patients (48%) without technical complications were alive. Technical complications were associated with increased length of stay (median 23 days versus 11 days, p < 0.001), increased in-hospital mortality (12.3% versus 3.8%, p < 0.001), and a higher rate of medical complications (77.5% versus 47.3%, p < 0.001). After controlling for age, medical comorbidities, use of induction therapy, tumor stage, histology, and location, and completeness of resection the presence of a technical complication was highly predictive of poorer overall survival; the multivariable hazard ratio was 1.41 (1.22 to 1.63, p = 0.008)., Conclusions: Technical complications have a large negative impact on survival after esophagogastrectomy for cancer. Strategies to optimize surgical technique and minimize complications should improve outcomes in this cancer operation.

Background: The oncolytic herpes simplex-1 virus, NV1066, is a replication-competent virus that has been engineered to infect and lyse tumor cells selectively and to carry a transgene for enhanced green fluorescent protein (EGFP). The purpose of this study was to determine viral cytotoxicity in an esophageal cancer cell line and to determine whether EGFP expression could be used as a marker of viral infection., Methods: BE3 esophageal adenocarcinoma cells were infected with NV1066 in vitro to determine cell kill and viral replication. EGFP expression was assessed by flow cytometry. The in vivo anti-tumor activity of NV1066 was tested in subcutaneous and intraperitoneal xenograft models. EGFP expression was localized in vivo by fluorescent microscopy and fluorescent laparoscopy., Results: NV1066 effectively replicated within and killed BE3 cells in vitro and in vivo. EGFP expression identified infected tumor cells. After NV1066 treatment in vivo, EGFP expression localized to the tumor. In an intraperitoneal tumor model, EGFP could be visualized endoscopically using a laparoscope with a fluorescent filter., Conclusions: NV1066 has oncolytic activity against the BE3 cell line and may be a useful therapy against esophageal cancer. EGFP expression localizes the virus and may help to identify tumor deposits in vivo. Oncolytic activity with NV1066 against gastrointestinal cancers may potentially be tracked by endoscopy.