Open Access Highly Accessed Research article

VEGFR-3 and CXCR4 as predictive markers for treatment with fluorouracil, leucovorin plus either oxaliplatin or cisplatin in patients with advanced esophagogastric cancer: a comparative study of the Arbeitsgemeinschaft Internistische Onkologie (AIO)

Thomas Thomaidis1, Annett Maderer1, Salah-Eddin Al-Batran2, Janis Kany1, Claudia Pauligk2, Kristina Steinmetz2, Arno Schad1, Ralf Hofheinz3, Harald Schmalenberg4, Nils Homann5, Peter Robert Galle1 and Markus Moehler1*

Author Affiliations

1 I. Medical Department, Johannes-Gutenberg University of Mainz, Langenbeckstr.1, 55131 Mainz, Germany

2 Institute of Clinical- Oncological Research at Krankenhaus Nordwest, UCT University Cancer Center, Frankfurt am Main, Germany

3 III. Medical Clinic, University Clinic, Mannheim, Germany

4 Tumor centre, University of Jena, Jena, Germany

5 II. Medical Clinic, Wolfsburg, Germany

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BMC Cancer 2014, 14:476  doi:10.1186/1471-2407-14-476

Published: 1 July 2014



Combination of fluoropyrimidines and a platinum derivative are currently standards for systemic chemotherapy in advanced adenocarcinoma of the stomach and gastroesophageal junction (GEJ). Nevertheless, individual likelihood for response to these therapeutic regimes remains uncertain. Even more, no predictive markers are available to determine which patients may benefit more from oxaliplatin versus cisplatin or vice versa. The new invasion and stem cell markers VEGFR-3 and CXCR4 have been linked prognostically with more aggressive esophagogastric cancer types. Thus, we aimed to assess correlations of VEGFR-3 and CXCR4 expression levels with clinical outcome in a randomized phase III study of patients with oxaliplatin/leucovorin/5-FU (FLO) versus cisplatin/leucovorin/5-FU (FLP).


The patients data examined in this study (n = 72) were from the collective of the FLO vs. FLP phase III AIO trial. Tumour tissues were stained via immunohistochemistry for VEGFR-3 and CXCR4 expression and results were evaluated by two independent, blinded investigators.

Outcome parameter: Survival analysis was calculated for patients receiving FLO vs. FLP in relation to VEGFR-3 and CXCR4 expression.


54% and 36% of the examined tumour tissues showed strong positive expression of VEGFR-3 and CXCR4 respectively. No superiority of each regime was detected in terms of overall survival (OS) in the whole population. Patients with strong expression of CXCR4 on their tumour tissues profited more in terms of OS under the treatment of FLP (mOS: 28 vs 15 months, p = 0.05 respectively). Patients with negative VEGFR-3 and CXCR4 expression had a trend to live longer when FLO regime was applied (mOS: 22 vs. 9 months, p = 0.099 and 20 vs. 10 months, p = 0.073 respectively). In an exploratory analysis of patients older than 60 years at diagnosis, we observed a significant benefit in overall survival for VEGFR-3 and CXCR4-positive patients when treated with FLP (p = 0.002, p = 0.021 respectively).


CXCR4 positive patients profited in terms of OS from FLP, whereas FLO proved to be more effective in CXCR4 and VEGFR-3 negative patients. Our results suggest, despite the limited size of the study, a predictive value of these biomarkers concerning chemotherapy with FLP or FLO in advanced esophagogastric cancer.

VEGFR-3; CXCR4; Advanced esophagogastric cancer; FLO; FLP; Biomarkers