The Impact of Tumor Regression on Prognosis After Neoadjuvant Chemoradiotherapy in Surgically Treated Esophageal Adenocarcinoma.

BACKGROUND: The 5-year survival for patients with esophageal carcinoma remains poor despite neoadjuvant therapy and surgery. The eighth American Joint Committee on Cancer (AJCC) staging, based on the neoadjuvant treated TNM (ypTNM) stage of the resection specimen, is used for prognosis. Tumor characteristics such as tumor grade, subtype of adenocarcinoma, and tumor regression scores are not included in this classification. This study aimed to determine the impact of these tumor characteristics on overall survival (OS) and disease-free survival (DFS). METHODS: This retrospective cohort study included 228 patients with esophageal adenocarcinoma. Tumor regression was determined by the Mandard tumor regression (MTR) score. Subtype and grade of adenocarcinoma were confirmed using either the preoperative biopsy or residual tumor tissue after surgery. The MTR was modified to a three-tier classification. The study classified MTR 1 and 2 in one group as a "major response," with MTR 4 and 5 classified in one group as a "minimal response." RESULTS: The median follow-up period was 2.1 years. Combining MTR with AJCC staging did not improve the prognostic value for the prediction of OS. However, the multivariate analysis showed that the prognostic value of AJCC staging for DFS was improved by adding the three-tiered MTR (odds ratio for MTR4+5: 2.46; 95 % confidence interval, 1.07-5.67). Grade or subtype correlated with neither OS nor DFS in the univariate analyses and did not improve the prognostic value of the AJCC staging. CONCLUSION: Neither adenocarcinoma subtype nor grade influenced OS or DFS. However, the eighth AJCC staging combined with a three-tier MTR provided a better prognostic tool for DFS in esophageal adenocarcinoma treated with esophagectomy after neoadjuvant chemoradiotherapy.

Angiogenesis, hypoxia and VEGF expression during tumour growth in a human xenograft tumour model.

Tumour growth and spread of tumour cells requires angiogenesis. Incipient angiogenesis is not induced by tumour cell hypoxia but probably by proangiogenic factors. During growth tumours depend on a further induction of vascular development for adequate oxygen and nutrient supply. If the oxygen supply is insufficient, the resulting hypoxia stimulates angiogenesis through upregulation of HIF-1 alpha and VEGF. VEGF upregulation is associated with a poor response to treatment and poor prognosis. The aim of the study was to analyze the interrelationship between hypoxia and angiogenesis during tumour growth. Therefore the tumour vasculature architecture and functional properties of the vessels were studied during subsequent phases of tumour growth in relation to hypoxia and VEGF-expression. Tumours from the human glioblastoma multiforme tumour line E106 were transplanted in athymic mice. Tumours were harvested at 2 days after transplantation and when tumours reached a mean size of 2, 4, 6, 8 and 10 mm. VEGF was present early in the onset of angiogenesis independent of HIF-1 alpha. During tumour growth VEGF increased from 0.94 to 7.27 ng/mg assessed by ELISA. However, there was increasing intratumoural heterogeneity in the architecture of the tumours, even in the largest tumours small well oxygenated areas were detected resembling the relatively well organized architecture of the smallest tumours. The observation that tumour vasculature develops in early phases under normoxic and at later phases under hypoxic conditions with the presence of both conditions in the larger tumours, suggested that anti-angiogenic therapy should be directed towards HIF-1 alpha dependent and HIF 1-alpha independent pathways.