Circulating Tumor Cells as a Biomarker for Preoperative Prognostic Staging in Patients With Esophageal Cancer

Matthias Reeh, MD; Katharina E. Effenberger, PhD; Alexandra M. Koenig, MD; Sabine Riethdorf, PhD; Dominique Eichstädt, MD; Eik Vettorazzi, MSc; Faik G. Uzunoglu, MD; Yogesh K. Vashist, MD; Jakob R. Izbicki, FACS; Klaus Pantel, PhD; Maximilian Bockhorn, MD


Annals of Surgery. 2015;261(6):1124-1130. 

In This Article

Abstract and Introduction


Objective: We evaluated the prognostic significance of circulating tumor cells (CTCs) in patients with esophageal cancer (EC).

Background: Despite the availability of several preoperative diagnostic techniques, accurate pretreatment staging of EC remains challenging.

Methods: In this single-center, prospective study, peripheral blood samples for CTC analyses were obtained preoperatively from 100 patients who were judged to have resectable EC. CTC detection was performed using the CellSearch System. Data were correlated with clinicopathological parameters and patient outcomes.

Results: CTCs were detected in 18% (18/100) of all eligible patients. Patients with CTCs showed significantly shorter relapse-free (P < 0.001) and overall survival (P < 0.001) than CTC-negative patients. Even in patients with lymph node invasion and without distant metastases (pN+, M0, N = 45), CTC detection indicated significantly worse relapse-free (P < 0.001) and overall survival (P = 0.007). Multivariate analyses of eligible patients identified CTCs as a strong, independent, prognostic indicator of tumor recurrence (hazard ratio, 5.063; 95% confidence interval, 2.233–11.480; P < 0.001) and overall survival (hazard ratio, 3.128; 95% confidence interval, 1.492–6.559; P = 0.003).

Conclusions: This is the first study to report that CTCs detected by an automated immunomagnetic detection system are independent, prognostic indicators of patients' outcome in EC. Thus, implementation of CTCs may improve accuracy of preoperative staging in EC.


Esophageal cancer (EC) is one of the most aggressive tumors, with a median survival of less than 2 years and long-term survival rates below 15%.[1,2] More than two thirds of all patients with EC develop local recurrence or distant metastases and die despite complete resection of the primary tumor and multimodal treatments. Recurrence or metastasis supposedly results from clinically occult, minimal residual disease caused by circulating tumor cells (CTCs) or disseminated tumor cells.[3,4] CTCs and disseminated tumor cells can derive from the same primary tumor, either circulating in the blood stream (CTCs) or disseminating to the bone marrow (disseminated tumor cells). Both groups of tumor cells have the potential to be precursors of metastases from various tumors, including EC.[5–10] Although, most shed tumor cells may die within the circulatory system due to physical and anatomic conditions, some CTCs seem to display an especially malignant potential, acquire stem cell characteristics, and finally evolve into metastases. Large studies investigating the metastatic potential and prognostic value of CTCs in EC are yet to be conducted. CTC detection by the CellSearch system is used in patients with metastatic breast, prostate, and colon cancer.[7,8,11] The clinical relevance of this system for nonmetastatic cancers is yet to be proven.

Here we assessed CTCs as a staging tool for nonmetastatic EC to stratify patients into defined prognostic subgroups. An appropriate staging system is essential for determining treatment strategies, especially those involving neoadjuvant treatments, in patients with EC. Despite the availability of several preoperative diagnostic techniques, accurate pretreatment staging remains inconsistent.[12] Therefore, a novel tool for early tumor detection, adequate prognostic staging, and accurate therapy monitoring in EC is urgently needed. The key aim of this study was to determine whether preoperative CTC detection can accurately indicate prognosis in patients with EC and may improve preoperative staging.