Dylan R. Nieman

Treatment Strategies for Esophageal Cancer

The treatment of esophageal cancer has evolved considerably in the past decade and depends largely on the extent of disease at the time of presentation. For disease confined to the esophageal mucosa, endoscopic therapy is replacing esophagectomy as the standard of care. For locoregional disease, neoadjuvant chemoradiation followed by esophagectomy is the best strategy for optimizing long-term survival. In the minority of patents who present with metastatic disease, the prognosis is poor. Palliative therapies available for these patients include chemotherapy, radiation, endoscopic therapies to ameliorate obstruction or bleeding, and surgical intervention to optimize nutritional status or to relieve obstruction.

Macrophage subtype predicts lymph node metastasis in oesophageal adenocarcinoma and promotes cancer cell invasion in vitro

Background:Currently, there is a lack of ideal biomarkers for predicting nodal status in preoperative stage of oesophageal adenocarcinoma (EAC) to aid optimising therapeutic options. We studied the potential of applying subtype macrophages to predict lymph node metastasis and prognosis in EAC.Material and Methods:Fifty-three EAC resection specimens were immunostained with CD68, CD40 (M1), and CD163 (M2). Lymphatic vessel density (LVD) was estimated with the staining of D2-40. Subsequently, we tested if M2d macrophage could promote EAC cell migration and invasion.Results:In EAC without neoadjuvant treatment, an increase in M2-like macrophage was associated with poor patient survival, independent of the locations of macrophages in tumour. The M2/M1 ratio that represented the balance between M2- and M1-like macrophages was significantly higher in nodal-positive EACs than that in nodal-negative EACs, and inversely correlated with patient overall survival. The M2/M1 ratio was not related to LVD. EAC cell polarised THP1 cell into M2d-like macrophage, which promoted EAC cell migration and invasion. Neoadjuvant therapy appeared to diminish the correlation between the M2/M1 ratio and survival.Conclusions:The ratio of M2/M1 macrophage may serve as a sensitive marker to predict lymph node metastasis and poor prognosis in EAC without neoadjuvant therapy. M2d macrophage may have important roles in EAC metastasis.

Neoadjuvant Treatment Response in Negative Nodes Is an Important Prognosticator After Esophagectomy

BACKGROUND The current American Joint Committee on Cancer Seventh Edition (AJCC7) pathologic staging for esophageal adenocarcinoma (EAC) is derived from data assessing the outcomes of patients having undergone esophagectomy without neoadjuvant treatment and has unclear significance in patients who have received multimodality therapy. Lymph nodes with evidence of neoadjuvant treatment effect without residual cancer cells may be observed and are not traditionally considered in pathologic reports, but may have prognostic significance. METHODS All patients who underwent esophagectomy after completing neoadjuvant therapy for EAC at our institution between 2006 and 2012 were reviewed. Slides of pathologic specimens were reexamined for locoregional treatment-response nodes lacking viable cancer cells but with evidence of acellular mucin pools, central fibrosis, necrosis, or calcifications suggesting prior tumor involvement. Kaplan-Meier survival functions were estimated, and Cox proportional hazards regression models were used to compare staging models. RESULTS Ninety patients (82 men) underwent esophagectomy after neoadjuvant therapy for EAC (mean age, 61.8 ± 8.9 years). All patients received preoperative chemotherapy, and 50 patients also underwent preoperative radiotherapy. Median Kaplan-Meier survival was 55.6 months, and 5-year survival was 35% (95% confidence interval, 19% to 62%). A total of 100 treatment-response nodes were found in 38 patients. For patients with limited nodal disease (62 ypN0-N1), the presence of treatment-response nodes was associated with significantly worse survival (p = 0.03) compared with patients lacking such nodes. Adjusting for patient age and AJCC7 pathologic stage showed the presence of treatment-response nodes significantly increased the risk of death (hazard ratio, 2.7; 95% confidence interval, 1.1 to 6.9; p = 0.04). When stage-adjusted survival was modeled, counting treatment-response nodes as positive nodes offered a better model fit than ignoring them. CONCLUSIONS Treatment-response lymph nodes detected from esophagectomy specimens in patients having undergone neoadjuvant chemotherapy or combined chemoradiation for EAC provide valuable prognostic information, particularly in patients with limited nodal disease. The current practice of considering lymph nodes lacking viable cancer cells, but with evidence of tumor necrosis, as pathologically negative likely results in understaging. Future efforts at revising the staging system for EAC should consider incorporating treatment-response lymph nodes in the analysis.

Eliminating a Need for Esophagectomy: Endoscopic Treatment of Barrett Esophagus With Early Esophageal Neoplasia

Over the past several years, endoscopic ablation and resection have become a new standard of care in the management of Barrett esophagus (BE) with high-grade dysplasia (HGD) or intramucosal adenocarcinoma (IMC). Risk factors for failure of endoscopic therapy and the need for subsequent esophagectomy have not been well elucidated. The aims of this study were to determine the efficacy of radiofrequency ablation (RFA) with or without endoscopic mucosal resection (EMR) in the management of BE with HGD or IMC, to discern factors predictive of endoscopic treatment failure, and to assess the effect of endoscopic therapies on esophagectomy volume at our institution. Data were obtained retrospectively for all patients who underwent endoscopic therapies or esophagectomy for a diagnosis of BE with HGD or IMC in our department between January 1, 2004, and December 31, 2012. Complete remission (CR) of BE or HGD or IMC was defined as 2 consecutive biopsy sessions without BE or HGD or IMC and no subsequent recurrence. Recurrence was defined by the return of BE or HGD or IMC after initial remission. Progression was defined as worsening of HGD to IMC or worsening of IMC to submucosal neoplasia or beyond. Overall, 57 patients underwent RFA with or without EMR for BE with HGD (n = 45) or IMC (n = 12) between 2007 and 2012, with a median follow-up duration of 35.4 months (range: 18.5-52.0 months). The 57 patients underwent 181 ablation sessions and more than half (61%) of patients underwent EMR as a component of treatment. There were no major procedural complications or deaths, with only 2 minor complications including 1 symptomatic stricture requiring dilation. Multifocal HGD or IMC was present in 43% (25/57) of patients. CR of IMC was achieved in 100% (12/12) at a median of 6.1 months, CR of dysplasia was achieved in 79% (45/57) at a median of 11.5 months, and CR of BE was achieved in 49% (28/57) at a median of 18.4 months. Following initial remission, 28% of patients (16/57) had recurrence of dysplasia (n = 12) or BE (n = 4). Progression to IMC occurred in 7% (4/57). All patients without CR continue endoscopic treatment. No patient required esophagectomy or developed metastatic disease. Overall, 6 patients died during the follow-up interval, none from esophageal cancer. Factors associated with failure to achieve CR of BE included increasing length of BE (6.0 ± 0.6 vs 4.0 ± 0.6cm, P = 0.03) and shorter duration of follow-up (28.5 ± 3.8 months vs 49.0 ± 5.8 months, P = 0.004). Shorter surveillance duration (17.8 ± 7.6 months vs 63.9 ± 14.4 months, P = 0.009) and shorter follow-up (21.1 ± 6.1 months vs 43.2 ± 4.1 months) were the only significant factors associated with failure to eradicate dysplasia. Our use of esophagectomy as primary therapy for BE with HGD or IMC has diminished since we began using endoscopic therapies in 2007. From a maximum of 16 esophagectomies per year for early Barrett neoplasia in 2006, we performed only 3 esophageal resections for such early disease in 2012, all for IMC, and we have not performed an esophagectomy for HGD since 2008. Although recurrence of BE or dysplasia/IMC was not uncommon, RFA with or without EMR ultimately resulted in CR of IMC in all patients, CR of HGD in the majority (79%), and CR of BE in nearly half (49%). No patient treated endoscopically for HGD or IMC subsequently required esophagectomy. In patients with BE with HGD or IMC, RFA and EMR are safe and highly effective. The use of endoscopic therapies appears justified as the new standard of care in most cases of BE with early esophageal neoplasia.

Mo1719 The Clinical Spectrum of Esophagogastric Junction Outflow Obstruction Identified via High Resolution Manometry

Introduction: The identification of esophagogastric junction (EGJ) outflow obstruction via high resolution manometry (HRM) is increasingly common and of unclear clinical significance. The objective of this study was to review the HRM characteristics of EGJ outflow obstruction and to assess how this diagnosis translates into clinical practice. Methods: A retrospective review was conducted of 1105 symptomatic patients who underwent HRM between 9/09 and 8/12. EGJ outflow obstruction was defined as an elevated 4 second lower esophageal sphincter integrated relaxation pressure (IRP). Patients with elevated IRP were divided into 3 groups: achalasia, mechanical obstruction (large hiatal hernia, postoperative and neoplasia) and functional obstruction (no obvious underlying cause). Clinical and demographic data, presenting symptoms, upper endoscopic findings, treatment and posttreatment outcomes were compared among the groups. Results: Of the 1105 patients studied, 237 (21%) had an elevated IRP. Sixty four percent were female with a mean age of 56.8±15.4 years. Mechanical causes of obstruction were most common (100/237, 42%) including postoperative in 50, large hiatal hernia in 48 and esophageal cancer in 2. Achalasia was present in 75 patients (32%). The remaining 62 (26%) had an elevated IRP without evidence of mechanical obstruction. Dysphagia was the primary presenting symptom in 85% of patients in the achalasia group, 31% of the mechanical group and 13% of the functional group (p,0.009). Interestingly, upper respiratory symptoms were significantly more common in patients with functional outflow obstruction (26% vs. 1% achalasia and 4% mechanical, p,0.001). The mean IRP also varied amongst the clinical groups, highest in achalasia 31.0±11.7mmHg, intermediate in mechanical obstruction (23.5 ±8.6 mmHg) and lowest in the functional group (18.7±3.8 mmHg) p,0.001. A similar pattern was seen in the mean intra-bolus pressures 28.6±15.0 mmHg, 20.1±7.4 mmHg and 14.9±4.0 mmHg, respectively. Nearly 40% (22/57) of the patents with functional outflow obstruction parameters were pH positive suggesting GE barrier failure despite the manometric findings. Fundoplication was performed in 9 of these 22 patients (41%) with good response. Five of the remaining functional patients underwent treatment; myotomy in one and Botox in 4. Conclusions: The predominant etiologies of EGJ outflow obstruction are mechanical obstruction and achalasia. Mechanical causes should be excluded before functional outflow obstruction is diagnosed and treated. HRM parameters of functional outflow obstruction may be present in a subset of patients with pH positive GERD. The ideal management of patients with symptomatic functional obstruction remains unclear.

Tu1538 Toward Improved Staging of Esophageal Adenocarcinoma in the Era of Neoadjuvant Chemotherapy; Lymph Node Harvest and Lymph Node Positivity Ratio Provide Better Survival Models

INTRODUCTION: As pre-operative chemoradiation followed by esophagectomy has become standard therapy in patients with resectable esophageal adenocarcinoma (EAC), traditional pathological staging has become a less useful prognostic tool. The 7th edition of the American Joint Commission on Cancer (AJCC7) staging system for EAC is derived from data on patients undergoing esophagectomy without neoadjuvant therapy and classifies lymph node status by the number of involved lymph nodes. Lymph node harvest (LNH) and lymph node positivity ratio (LNPR) have been suggested to be prognostic indicators but have not found widespread support. In an effort to develop a valid staging model in the era of neoadjuvant therapy, we compared the predictive value of LNH and LNPR to AJCC7 staging in a large cohort of patients undergoing resection for EAC. METHODS: The study population consisted of 316 patients who underwent R0 esophagectomy for EAC from 1/00 to 12/11 (86% male; mean age 64.0±10.3 years). Survival functions were estimated using the KaplanMeier method. Classification thresholds for both LNPR and LNH were derived by recursive partitioning using conditional inference trees comparing survival functions. Based on these analyses, LNPR was stratified and Cox proportional hazards regression models were used to compare predictive value of lymph node categorization strata. RESULTS: Median lymph node harvest was 12 (IQR 7-20). 51% of patients were N0, 29% N1, 13% N2. Median overall survival was 63.4 months (95%CI 40.6 92.3) and 5-year overall survival was 50.7% (95%CI 45.0 57.2). Eighty-three patients (26%) received neoadjuvant chemotherapy, radiation therapy or both. In patients who received neoadjuvant therapy and had no lymph node metastasis identified (40/83; 48%), recursive partitioning analysis yielded a LNH threshold of 15 for discrimination of survival functions. LNH ≥ 15 was associated with a significant survival advantage (3-year survival 95 vs. 38%; p = 0.000022). Similarly, recursive partitioning analysis yielded LNPR categories of less than 20%, 20-40%, or greater than 40% as significantly discriminant of survival functions. In patients who received neoadjuvant therapy, LNPR was more predictive of survival than number of positive lymph nodes as categorized by AJCC7 (p=0.00018 vs. 0.033). In the 256 patients who received no neoadjuvant therapy, LNH was not a significant predictor of survival after node negative resection, although LNPR was a stronger predictor of survival than the current nodal staging system (p-value 0.000015 vs. 0.05). CONCLUSION: For patients receiving neoadjuvant therapy, both LNH and LNPR are more predictive of survival than the number of lymph node metastases detected in esophagectomy specimens. A minimum LNH of 15 is necessary to establish reliable N0 staging in this cohort.