Gefitinib in definitive management of esophageal or gastroesophageal junction cancer: a retrospective analysis of two clinical trials.

The role of epidermal growth factor receptor inhibition in resectable esophageal/gastroesophageal junction (E/GEJ) cancer is uncertain. Results from two Cleveland Clinic trials of concurrent chemoradiotherapy (CCRT) and surgery are updated and retrospectively compared, the second study differing only by the addition of gefitinib (G) to the treatment regimen. Eligibility required a diagnosis of E/GEJ squamous cell or adenocarcinoma, with an endoscopic ultrasound stage of at least T3, N1, or M1a (American Joint Committee on Cancer 6th). Patients in both trials received 5-fluorouracil (1000 mg/m(2) /day) and cisplatin (20 mg/m(2) /day) as continuous infusions over days 1-4 along with 30 Gy radiation at 1.5 Gy bid. Surgery followed in 4-6 weeks; identical CCRT was given 6-10 weeks later. The second trial added G, 250 mg/day, on day 1 for 4 weeks, and again with postoperative CCRT for 2 years. Preliminary results and comparisons have been previously published. Clinical characteristics were similar between the 80 patients on the G trial (2003-2006) and the 93 patients on the no-G trial (1999-2003). Minimum follow-up for all patients was 5 years. Multivariable analyses comparing the G versus no-G patients and adjusting for statistically significant covariates demonstrated improved overall survival (hazard ratio [HR] 0.64, 95% confidence interval [CI] = 0.45-0.91, P = 0.012), recurrence-free survival (HR 0.61, 95% CI = 0.43-0.86, P = 0.006), and distant recurrence (HR 0.68, 95% CI = 0.45-1.00, P = 0.05), but not locoregional recurrence. Although this retrospective comparison can only be considered exploratory, it suggests that G may improve clinical outcomes when combined with CCRT and surgery in the definitive treatment of E/GEJ cancer.

Clinicopathologic features and treatment outcomes of patients with human epidermal growth factor receptor 2-positive adenocarcinoma of the esophagus and gastroesophageal junction.

Human epidermal growth factor receptor 2 (HER2) is overexpressed in 21% of gastric and 33% of gastroesophageal junction (GEJ) adenocarcinomas. Trastuzumab has been approved for metastatic HER2-positive gastric/GEJ cancer in combination with chemotherapy. This retrospective analysis was undertaken to better define the clinicopathologic features, treatment outcomes, and prognosis in patients with HER2-positive adenocarcinoma of the esophagus/GEJ. Pathologic specimens from 156 patients with adenocarcinoma of the esophagus/GEJ treated on clinical trials with chemoradiation and surgery were tested for HER2. Seventy-six patients also received 2 years of gefitinib. Baseline characteristics and treatment outcomes of the HER2-positive and negative patients were compared both in aggregate and separately for each of the two trials. Of 156 patients, 135 had sufficient pathologic material available for HER2 assessment. HER2 positivity was found in 23%; 28% with GEJ primaries and 15% with esophageal primaries (P= 0.10). There was no statistical difference in clinicopathologic features between HER2-positive and negative patients except HER2-negative tumors were more likely to be poorly differentiated (P < 0.001). Locoregional recurrence, distant metastatic recurrence, any recurrence, and overall survival were also statistically similar between the HER2-positive and the HER2-negative groups, in both the entire cohort and in the gefitinib-treated subset. Except for tumor differentiation, HER2-positive and negative patients with adenocarcinoma of the esophagus and GEJ do not differ in clinicopathologic characteristics and treatment outcomes. Given the demonstrated benefit of trastuzumab in HER2-positive gastric cancer and the similar incidence of HER2 overexpression in esophageal/GEJ adenocarcinoma, further evaluation of HER2-directed therapy in this disease seems indicated.

Pyloric gland metaplasia and pouchitis in patients with ileal pouch-anal anastomoses.

BACKGROUND: Diagnosis and management of chronic antibiotic-refractory pouchitis and Crohn's disease of the pouch can be challenging. Pyloric gland metaplasia is a histological feature indicative of chronic mucosal inflammation. Its value in diagnosis and prognosis of pouch disorders has not been investigated. AIM: To assess the prevalence, diagnostic and prognostic value, and risk factors of pyloric gland metaplasia in pouch patients. METHODS: Patients were identified from our prospectively maintained Pouchitis Database. Pouch biopsy specimens were re-reviewed for pyloric gland metaplasia and other histological features. Two cohorts of patients were studied: a historical cohort (n = 111) and the second, a validation cohort (n = 100). Univariate and multivariate analyses were performed to assess risk factors for pyloric gland metaplasia. RESULTS: The prevalence of pyloric gland metaplasia in the historical cohort and validation cohort was 45 (40.1%) and 24 (24.0%), respectively. The sensitivity and specificity of pyloric gland metaplasia for the diagnosis of chronic antibiotic-refractory pouchitis or Crohn's disease were 70.7% and 92.5%, respectively, for the first cohort and 39.0% and 86.4%, respectively, for the 2nd validation cohort. In multivariate analysis of the first cohort, patients with refractory pouchitis or Crohn's disease were 28 times (95% CI, 7.3-107.1) more likely to have pyloric gland metaplasia than those with a normal pouch or irritable pouch syndrome. The factor of refractory pouchitis or Crohn's disease remained in the model for the 2nd validation cohort with odds ratio of 4.58 (95% CI, 1.6-13.4). CONCLUSIONS: Pyloric gland metaplasia is associated with diagnosis of chronic antibiotic-refractory pouchitis or Crohn's disease of the pouch and appears to be a specific marker for both disease entities.