[Show abstract][Hide abstract] ABSTRACT: Previously regarded as a rare neoplasm, the incidence of esophageal adenocarcinoma has risen rapidly in recent decades. It is often discovered late in the disease process and has a dismal prognosis. Current prognostic markers including clinical, radiographic, and histopathologic findings have limited utility and do not consider the biology of this deadly disease. Genome-wide analyses have identified SMAD4 inactivation in a subset of tumors. Although Smad4 has been extensively studied in other gastrointestinal malignancies, its role in esophageal adenocarcinoma remains to be defined. Herein, we show, in a large cohort of esophageal adenocarcinomas, Smad4 loss by immunohistochemistry in 21 of 205 (10%) tumors and that Smad4 loss correlated with increased postoperative recurrence (P=0.040). Further, patients whose tumors lacked Smad4 had shorter time to recurrence (TTR) (P=0.007) and poor overall survival (OS) (P=0.011). The median TTR and OS of patients with Smad4-negative tumors was 13 and 16 months, respectively, as compared with 23 and 22 months, respectively, among patients with Smad4-positive tumors. In multivariate analyses, Smad4 loss was a prognostic factor for both TTR and OS, independent of histologic grade, lymphovascular invasion, perineural invasion, tumor stage, and lymph node status. Considering Smad4 loss correlated with postoperative locoregional and/or distant metastases, Smad4 was also assessed in a separate cohort of 5 locoregional recurrences and 43 metastatic esophageal adenocarcinomas. In contrast to primary tumors, a higher prevalence of Smad4 loss was observed in metastatic disease (44% vs. 10%). In summary, loss of Smad4 protein expression is an independent prognostic factor for TTR and OS that correlates with increased propensity for disease recurrence and poor survival in patients with esophageal adenocarcinoma after surgical resection.
American Journal of Surgical Pathology 01/2015; 39(4). DOI:10.1097/PAS.0000000000000356 · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The primary aim of this trial was to assess the feasibility of minimally invasive esophagectomy (MIE) in a multi-institutional setting.
Esophagectomy is an important, potentially curative treatment for localized esophageal cancer, but is a complex operation. MIE may decrease the morbidity and mortality of resection, and single-institution studies have demonstrated successful outcomes with MIE.
We conducted a multicenter, phase II, prospective, cooperative group study (coordinated by the Eastern Cooperative Oncology Group) to evaluate the feasibility of MIE. Patients with biopsy-proven high-grade dysplasia or esophageal cancer were enrolled at 17 credentialed sites. Protocol surgery consisted of either 3-stage MIE or Ivor Lewis MIE. The primary end point was 30-day mortality. Secondary end points included adverse events, duration of hospital-stay, and 3-year outcomes.
Protocol surgery was completed in 95 of the 104 patients eligible for the primary analysis (91.3%). The 30-day mortality in eligible patients who underwent MIE was 2.1%; perioperative mortality in all registered patients eligible for primary analysis was 2.9%. Median intensive care unit and hospital stay were 2 and 9 days, respectively. Grade 3 or higher adverse events included anastomotic leak (8.6%), acute respiratory distress syndrome (5.7%), pneumonitis (3.8%), and atrial fibrillation (2.9%). At a median follow-up of 35.8 months, the estimated 3-year overall survival was 58.4% (95% confidence interval: 47.7%-67.6%). Locoregional recurrence occurred in only 7 patients (6.7%).
This prospective multicenter study demonstrated that MIE is feasible and safe with low perioperative morbidity and mortality and good oncological results. This approach can be adopted by other centers with appropriate expertise in open esophagectomy and minimally invasive surgery.
[Show abstract][Hide abstract] ABSTRACT: Objectives
Prognosis for locally advanced esophagogastric adenocarcinoma (EAC) is poor with surgery alone and adjuvant therapy after open esophagectomy is frequently not tolerated. After minimally invasive esophagectomy (MIE), however, earlier return to normal function may render patients better able to receive adjuvant therapy. This study examined whether primary MIE followed by adjuvant chemotherapy impacted survival compared to propensity-matched patients treated with neoadjuvant therapy.
Patients with stage II or higher EAC treated with MIE (n=375) were identified. Using 30 pretreatment covariates, propensity for assignment to either neoadjuvant followed by MIE (n=183; 54%) or MIE as primary therapy (n=156; 46%) was calculated, generating 97 closely-matched pairs. Hazard ratios were adjusted for age, sex, BMI, smoking, comorbidity and final pathologic stage.
In propensity-matched pairs, adjusted hazard ratio for death did not differ significantly for primary MIE compared to neoadjuvant (HR 0.83; 95% CI 0.60-1.16). Recurrence patterns were similar between groups and 65% of patients with IIb or greater pathologic stage received adjuvant therapy. Clinical staging was inaccurate in 37/105 (35%) patients who underwent primary MIE (n=18 upstaged and n=19 downstaged).
Primary MIE followed by adjuvant chemotherapy guided by pathologic findings did not negatively impact survival and allowed for accurate staging of the patient compared to clinical staging. Our data suggest that primary MIE in patients with resectable EAC may be a reasonable approach, improving stage-based prognostication and potentially minimizing overtreatment in patients with early-stage disease through accurate stage assignments. A randomized controlled trial testing this hypothesis is needed.
Journal of Thoracic and Cardiovascular Surgery 10/2014; 149(2). DOI:10.1016/j.jtcvs.2014.10.044 · 3.99 Impact Factor