Haemostasis and Malignancy

August 5, 2005
11:00 to 14:30
Sydney Convention Center
Harbourside Room

Chairman:  A. Falanga, Italy
Co-chairs:  G. Agnelli; C. W. Francis, USA; A. K. Kakkar, UK; A. Lee, Canada; M. Prins, The Netherlands;
L. Zacharski, USA .

The first part of the meeting, chaired by A. Falanga and C. Francis, addressed biological issues. A Working Party on TF standardization in cancer was presented. The panel will be composed by the following scientists, who have agreed to collaborate in the project: A. Falanga and T. Barrowcliffe (Coordinators), E. Gray , N. Key , B. Osterud, K. Mann/S. Butenas, N. Mackman , J. Morrissey, F.R. Rickles. The need for creating a task force to standardize the procedures for TF measurement in malignant tissues comes from our current knowledge on TF relevant role in cancer, not only for its procoagulant effects, but also for its involvement in angiogenesis, tumor growth and metastasis. There are many methods to measure TF in tissues as well as in circulating blood. However, the sensitivity and specificity of the available assays are variable. The specific aims and proposed activities of the TF working party are: to investigate and compare methods for measurement of TF in cancer cells, to make recommendations on methodology of TF assays, to establish one or more reference reagents. The outline work Programme for 2005-2006 has been proposed.

Along this line, N. Key showed the characteristics of three different TF assays: i.e.:1. The commercial plasma TF antigen assay (Sandwich ELISA); this test gives no information about TF activity; it measures both microparticle (MP)-bound TF and TF soluble species; 2. The capture assay for MP-associated TF Procoagulant Activity (TF-PCA) in plasma, and 3. The inhibition assay of TF/FVIIa by Antithrombin (AT) promoted by HSPGs on cell surfaces. The comparison of the results of TF measurement with the above three assays in plasma samples from subjects with hemophilia A, hemophilia B, and age-matched controls, shows no correlation between the plasma levels of TF antigen, MP-associated TF-procoagulant activity, and VIIa-AT antigen complexes.

N. Mackman presented a method for the determination of blood borne TF by a single stage clotting assay. This method can be applied to test different blood cellular fractions, i.e.: mononuclear cells, platelets, and microparticles. He presented results on TF measurement with this assay in patients with different types of cancer.

The issue of circulating thrombotic markers in malignancy was expanded to other blood components and molecules. A. Khorana presented the results of the analysis of a prospective study evaluating the predictive value of pre-chemotherapy platelet count for the development of chemotherapy-associated VTE. The results of this analysis suggest a predictive value for elevated platelet count (>350,000/mmc). A clinical risk model incorporating the pre-chemotherapy platelet count has been proposed for identifying patients at high risk for VTE at time of initiation of chemotherapy.

J. Fareed described the differential down-regulation by LMWH and warfarin of the following thrombotic and inflammatory markers: TNF-alpha , IL1-beta , CRP, MCP-1, CD 40L, TF, TFPI, ATFI, ADMA, NO, ADAMTS-13. The results indicate that LMWH can down regulate both thrombotic and inflammatory mediators in patients with cancer.

The second part of the meeting, chaired by A. Lee and G. Agnelli, was an update of clinical trials of antithrombotics in patients with cancer. It included trials still ongoing or recently completed, in addition to the designs of new clinical trials that are going to be started.

I. Pabinger updated on the CATS (Cancer And Thrombosis Study), which consists in the identification of predictive parameters of VTE and PE in patients with various malignancies. The study design is a prospective nested case-control study, which includes patients with newly diagnosed malignancy or relapsed after remission. Projected end of the study is October 2007; 497 patients have been enrolled; 58 patients died; 24 VTE events are recorded.

S. Haas updated on TOPIC I and TOPIC II trials on the prevention of VTE by LMWH certoparin in patients with metastatic breast (TOPIC 1) or lung cancer (TOPIC II). Both trials are completed.

VTE events in metastatic breast cancer were less frequent than expected (4%). The interim analysis failed to show superiority of LMWH and the enrolment of patients was stopped. VTE in metastatic non-small cell lung carcinoma was more frequent than in breast cancer. There was no significant decrease in the VTE rate in the treatment group. A post hoc analysis for the influence of disease stage provides evidence that LMWH certoparin affects significantly the VTE rate in patients with disease stage IV.

A. Kakkar presented the design of a Prospective Registry of Cancer and Events Involving Venous Thromboembolism (PERCEIVE). In this prospective multicentre study of newly diagnosed malignancy (Pancreas; Lung; Prostate; Breast;  Colon and rectum; Ovary), patients will be treated according to local best practice, no additional tests or procedures will be required. Selected data will be collected from the patients’ clinical records. Patient progress will be monitored for up to 1 year, with special attention to medical history, VTE risk factors, treatment and outcome. Primary objective is to collect data on the clinical incidence, treatment and outcome of VTE; secondary objectives are to produce evidences to help set standards of practice to improve patients’ clinical care and expected outcome in terms of both prevention and treatment of VTE, and to identify areas of interest for future studies to investigate specific related issues. 170 patients have been recruited so far.

G. Agnelli updated on the ongoing study named PROTECHT (PROphylaxis of ThromboEmbolism during ChemoTherapy). This multicenter clinical trial evaluates the efficacy of the LMWH nadroparin versus placebo in the prevention of symptomatic venous and arterial thromboembolism in advanced cancer patients during chemotherapy. Types of cancer included: Lung, Breast, Gastrointestinal, Ovarian, Head and neck. Number of patients enrolled so far: 753 (calculated sample size = 1,200). The interim analysis for efficacy and safety (400 patients) will be available on September 2005.

An update on the newest information available on the prevention of central venous catheter (CVC)-related thrombosis was presented by two groups: 1. G. Agnelli showed the analysis of risk factors for CVC-related VTE in cancer patients enrolled in the ETHICS study, recently published. The original study shows that the risk reduction by Enoxaparin prophylaxis is not statistically significant. Furthermore, the rate of CVC-related DVT was lower than expected. The inconsistency of risk for CVC-related thrombosis across the study population suggested this risk factor analysis. The results lead to the conclusion that an inadequate position of CVC tip and left-sided CVC insertion are independent risk factors for CVC-related thrombosis. Further, age >60 years and metastatic disease significantly increase the risk; 2. A. Kakkar, on behalf of A.Young and MRC nurse study, presented the latest results of the UK Multicentre Prospective Randomised, Controlled Trial of Thrombosis Prophylaxis with Warfarin in Cancer Patients with Central Venous Catheters. The data show that prophylaxis with 1 mg fixed dose warfarin is not effective in preventing CVC related thrombosis. A subsequent random between 1 mg fixed dose warfarin versus adjusted dose warfarin (INR: 1.3 -1.9) demonstrates the efficacy of the adjusted dose.

Finally, H. Buller presented the design of a new study, named IMPACT (IMproving the Prognosis in Advanced Cancer with low-molecular weight heparin Therapy). It is a prospective, randomised, open-label, multicenter study to evaluate the survival in patients with Lung (NSCLC , Stage III-B), Prostate (Hormone refractory), or Pancreatic (locally advanced) cancer. The recruitment should start on October-December 2005, approx 25 centres. Eligible patients will be randomised to: standard anti-cancer treatment, or standard anti-cancer treatment plus nadroparin. The primary outcome will be death from cancer.