Plasma fibrinogen and blood platelet counts are associated with response to neoadjuvant therapy in esophageal cancerBiomarkers in Medicine


Aysegül Ilhan-Mutlu, Patrick Starlinger, Thomas Perkmann, Sebastian F Schoppmann, Matthias Preusser, Peter Birner
Biochemistry, medical / Drug Discovery / Clinical Biochemistry


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Research Article 10.2217/BMM.14.111 © 2015 Future Medicine Ltd

Biomark. Med.

Research Article 9 4 2015

Aim: To investigate coagulatory factors in predicting response to neoadjuvant therapy (NeoTr) in esophageal cancer (EC). Methods: We investigated the relevance of coagulatory factors in 84 EC patients (56 adenocarcinomas, 28 squamous cell cancer) who received NeoTr. Plasma fibrinogen (PFR), peripheral blood platelet counts (PBPC) and C-reactive protein (CRP) were determined before NeoTr. Response was classified as tumor regression grades. Results: Patients with good response to NeoTr had significantly higher PFR (p = 0.006), CRP (p = 0.002) and PBPC levels (p = 0.034) when compared with others. Only, PFR remained an independent factor influencing tumor regression (p = 0.0064, coefficient of regression: -0.003). No association with survival was observed. Conclusion: PFR and to a lesser extent PBPC and CRP might be considered as a predictive marker for the response to NeoTr in EC.

Keywords: CRP • esophageal carcinoma • neoadjuvant treatment • plasma fibrinogen • platelets • tumor regression grade

Esophageal cancer (EC) is the eight most common cancer worldwide [1]. In the USA, 17,990 people are estimated to be diagnosed annually with EC and 15,210 people will ultimately die of their disease [2]. ECs are histologically classified as adenocarcinomas (AC) and squamous cell carcinomas (SCC) [3].

Preoperative chemoradiation followed by surgery is the most common neoadjuvant treatment approach for patients with resectable esophageal cancer, although this approach remains to be further investigated [4]. In order to avoid a treatment with uncertain benefit, it is of particular importance to identify the patients, who might show a better response after neoadjuvant treatment. Preoperative factors predicting the treatment response of esophageal cancer have been identified, however, clinically feasible methods to predict the response are still urgently required [5].

Activation of the coagulation cascade by cancer cells has been shown to be associated with tumor progression in a variety of cancers [6]. Accordingly, several reports have shown the association of preoperative levels of coagulation factors in lung [7,8], ovarian [9], gastric [10,11], pancreatic [12,13], hepatocellular [14] and urothelial carcinoma [15], but surprisingly only few data on its relevance in combination with neoadjuvant therapy in general exist [16,17].

With respect to the limited evidence regarding the relevance of plasma coagulatory factors in neoadjuvant therapy of EC, aim of this study was to investigate their clinical role in those patients treated with neoadjuvant therapy and subsequent surgery.


Patient cohort

All patients who received neoadjuvant therapy for esophageal cancer and underwent subsequent surgery at the Medical University of Vienna (Austria) between August 1996 and September 2011 were included in this retrospective study. Only patients without any evidence of metastases at initial diagnosis underwent surgical removal of the tumor.

After a mean period of 38 ± 20 (SD) days after completion of neoadjuvant treatment,

Plasma fibrinogen and blood platelet counts are associated with response to neoadjuvant therapy in esophageal cancer

Aysegül Ilhan-Mutlu1,5,

Patrick Starlinger2, Thomas

Perkmann3, Sebastian F

Schoppmann2,5, Matthias

Preusser1,5 & Peter Birner*,4,5 1Department of Medicine I, Clinical

Division of Oncology, Medical University of Vienna, Währinger Gürtel 18-20,

A-1090 Vienna, Austria 2Department of Surgery, Medical

University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria 3Department of Laboratory Medicine,

Medical University of Vienna, Währinger

Gürtel 18-20, A-1090 Vienna, Austria 4Department of Pathology, Medical

University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria 5Comprehensive Cancer Center Vienna,

Gastroesophageal Tumors Unit, Medical

University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria *Author for correspondence:

Tel.: +43 140 400 3650

Fax: +43 140 400 3707 328 Biomark. Med. (2015) 9(4) future science group

Research Article Ilhan-Mutlu, Starlinger, Perkmann, Schoppmann, Preusser & Birner esophagectomy was carried out. From all patients, plasma coagulatory factors including plasma fibrinogen (PFR), prothrombin time (PT), thrombin time (TT), partial thromboplastin time (aPTT), antithrombin III (AT3), peripheral blood platelet count (PBPC) and acute phase protein C-reactive Protein (CRP) before start of neoadjuvant therapy were available.

Process of blood samples & analysis of serum markers

Blood collections were performed as a routine procedure from peripheral veins in a heparin, citrat or EDTA precoated vacuumed tubes for CRP, PBPC and other coagulatory factors, respectively. These were immediately transferred to the Department of Laboratory

Medicine, Medical University of Vienna, where the analysis of the factors using standard automated hematology analyzers was carried out. During the observational period, the following hematology analyzers were applied: Until 2001 Sysmex NE-8000 (TOA Medical

Electronics, Kobe, Japan), since 2001 Sysmex XE-2100 (Sysmex Corporation, Kobe, Japan).

Histopathological investigation

Response to neoadjuvant therapy was assessed on all available H&E stained slides of esophagectomy specimens according to Mandard [18]. In brief, tumor regression grade (TRG) was quantitated in five grades:

TRG 1 (complete regression) shows no residual cancer cells and fibrosis extending through the different layers of the esophageal wall; TRG 2 is characterized by the presence of rare residual cancer cells scattered through the fibrosis; TRG 3 is characterized by an increase in the number of residual cancer cells compared with

TRG 2, but fibrosis still predominating; TRG 4 shows residual cancer outgrowing fibrosis and TRG 5 is characterized by absence of regressive changes [18]. For the evaluation of the response rate, all available slides from the tumor bed were evaluated from each surgical specimen (about 3–7/case).