title: 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).
abstract: BACKGROUND
  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).
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors: Thomas
authors: T
authors: Thomaidis
authors: Annett
authors: A
authors: Maderer
authors: Salah-Eddin
authors: SE
authors: Al-Batran
authors: Janis
authors: J
authors: Kany
authors: Claudia
authors: C
authors: Pauligk
authors: Kristina
authors: K
authors: Steinmetz
authors: Arno
authors: A
authors: Schad
authors: Ralf
authors: R
authors: Hofheinz
authors: Harald
authors: H
authors: Schmalenberg
authors: Nils
authors: N
authors: Homann
authors: Peter Robert
authors: PR
authors: Galle
authors: I, Medical Department, Johannes-Gutenberg University of Mainz, Langenbeckstr,1, 55131 Mainz, Germany. moehler@mail.uni-mainz.de.
authors: Markus
authors: M
authors: Moehler
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage; D004943:Esophagogastric Junction / Q000473:pathology*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007150:Immunohistochemistry; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D011379:Prognosis; D019718:Receptors, CXCR4 / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality; D016896:Treatment Outcome; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism*
chemical_list: D009944:Organoplatinum Compounds; D019718:Receptors, CXCR4; D000077150:Oxaliplatin; D040321:Vascular Endothelial Growth Factor Receptor-3; D002945:Cisplatin; D002955:Leucovorin; D005472:Fluorouracil