Haemostasis and Malignancy

Haemostasis and Malignancy

July 13, 2003
08:00 to 12:00
Hall 8
The International Convention Center, Birmingham

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

The meeting was started by the chairman’s introduction, who briefly overviewed the progress made in the recent years in the field of Haemostasis and Malignancy from both the basic and clinical research sides. In this regard, she remarked that while basic research has been constantly progressing in the last 30 to 40 years, the clinical research has long been neglected until very recently, when there has been a blooming of prospective randomized clinical trials on prevention and treatment of VTE in the cancer patients. The SSC on Haemostasis and Malignancy has strongly promoted and implemented some of these trials. Some of them have been recently successfully accomplished and the results published will certainly impact very much our clinical practice.

The first part of the meeting was devoted to the Biological and Preclinical aspects, and was divided in two sections (A. and B). Section 1A (Chaired by A. Falanga and A. Lee) was an "Overview of methods to identify procoagulant proteins and hemostatic markers in cancer models in vitro and in vivo".

H.C. Kwaan reported on the "Measurement of the thrombogenic activity of apoptotic cells", focusing on the methods to evaluate thrombogenic activity of tumor cells undergoing chemotherapy-induced apoptosis, with particular regard to Tissue Factor Activity, Tissue Factor Antigen and Thrombin Generation Assay.
J. Francis discussed on the methods to detect Tissue Factor (TF) in tumor tissues, monocytes and biological fluids. Methods available to test for TF activity: the manual one-stage clotting assay, and the assays by the Sonoclot and the Thromboelastograph. He stressed some important issues in Tissue Factor activity evaluation, such as the relevance of using anti-TF inhibiting antibodies to increase the specificity and the importance of using a Standard curve made with recombinant TF. Of particular interest were: 1. the evaluation of Urinary TF by the Chromogenic test; 2. Cytofluorimetric analysis of monocyte TF; 3. Confocal microscopy of Tissues’ surface TF.
J. Fareed presented a number of tests to evaluate the plasma haemostatic activation markers in cancer patients, both in early stage or advanced metastatic disease, compared to healthy subjects. In particular he considered the following tests: -FVIII and vWF, Markers of thrombin generation (F1+2, TAT), PAI-1 and TAFI for fibrinolysis, ATIII and Proteins C and S, TNFalpha and Nitric Oxide (oxidative status), plasmatic TF, C-reactive Protein.

Also he showed an analysis of FII and FV genes mutations.
Section 1B (Chaired by L. Zacharski and A. Falanga) was on "Experimental models of anti-tumor effects of antithrombotics"

First, R. Ludwig reported on the P-selectin-dependent interaction between platelets and tumor cells which promotes experimental metastasis (in a mouse model injected with B16 melanoma cells). He showed data on inhibition of metastasis in this model by LMWH, suggesting a role for these molecules in interfering with the biology of the tumor.

Then, R. Sasisekharan reported on the multiple effects that heparan sulphate glycosaminoglycans (HSGAG): some of them can act as anti-tumorigenic effects while others can be pro-tumorigenic. This will depend on their sequence and dimension. He showed data with selective heparan sulphate obtained by fragmentation with different heparinase (1, 2, 3 types). HSGAGs are cryptic modulators of tumor progression and act as a reservoir, binding and storing signaling cells. They modulate growth factors activity, tumor cell adhesion and apoptosis. LMWH sequences with no anticoagulant effects and exclusively anti-tumor functions can be obtained by GAGs fragmentation

Lastly, F. Rickles reported on some inhibitors of non-procoagulant activities of Tissue Factor, among these a very promising group of molecules appear to be the curcumin and its aanalogues, the most active of which is the one named "Compound 14": this molecule seems to possess a strong anti-tumor activity in the experimental setting, including human breast cancer grown in nude mice.

Before starting the second part of the meeting, Professor MB Donati was asked to give a brief talk to celebrate the 20th anniversary of the SSC on Haemostasis and Malignancy, which had its first meeting in Stockholm in 1983 and dr. Donati was the first chairman, together with dr. Y. Nemerson. She started back from the first pioneer studies in these field and underlined the great progress in the interests in this field and the growing importance of the data coming from the clinical studies. She congratulated for the work done by the subcommittee.

The second part of the meeting was dedicated to the Clinical Investigations.(Chaired by A.K. Kakkar and M.H. Prins)

First was an Update on clinical trials ongoing or recently accomplished.

Clinical Trials on Prophylaxis of VTE in cancer:

In surgical patients: 1. M. Rassmussen presented the FAME study on prolonged thromboprophylaxis with LMWH dalteparin in major abdominal surgery. The study has enrolled 590 patients and the final results are to be presented in these days at this ISTH congress; 2. G. Agnelli presented the PEGASUS study on in-hospital prophylaxis with Fondaparinux vs Dalteparin in abdominal surgical patients (70% with cancer). This study has included more than 1000 patients per arm and the final results are to be presented in this ISTH congress.

In patients with Central Venous Catheters (CVC): 1. G. Agnelli showed the progress in the ETHICS study evaluating six week of Enoxaparin vs placebo for the prevention of upper limb CVC-associated DVT. Patients enclosed are 385 and 50 of these present with positive venography (16.1%). The results of this study are still under evaluation and will be ready for presentation in September in the Conference on "Thrombosis and Hemostasis Issues in Cancer", Bergamo, Italy (19-21 Sept. 2003); 2. A. Young gave an update on the WARP study of warfarin (two doses strategies) prophylaxis for VTE in cancer patients with CVC. Study is ongoing and results will be presented at the next SSC meeting in Venice,

In Medical patients: 1. S. Haas presented the TOPIC-I and TOPIC-II. These protocols are evaluating Certoparin against placebo in the prevention of VTE in breast (TOPIC-I ) or lung (TOPIC-II) cancer patients receiving chemotherapy. In TOPIC I the enrolment has been completed (350 patients). This study has been stopped to the first phase (primary end point was any VTE event), and there was no difference between certoparin –treated group and placebo group. Final analysis for survival will be ready by Aug. 2003. TOPIC II has been completed (540 patients enrolled). Final analysis will be available by Nov. 2003.

Clinical Trials on Treatment of VTE in cancer:

A. Lee gave a summary of the CLOT trial of prolonged Dalteparin treatment (vs standard treatment) for acute DVT: 676 patients were randomized. Results, published on July 10th issue of the NEJM show a 52%- risk reduction of DVT recurrence in the Dalteparin arm with no increase in bleeding;
R. Hull presented the results of LITE study regarding the long term LMWH Innohep vs Warfarin for secondary prevention of acute proximal DVT. No differences in VTE recurrence were found in the overall population . However, in the subset of cancer patients there was a significant reduction of DVT recurrece rate by LMWH;
S. Deitcher updated the ONCENOX trial evaluating two Enoxaparin regimens versus Enoxaparin followed by Warfarin for treatment of acute DVT in cancer. The compliance of patients was at least 90%, but no differences in DVT recurrence rate was found among the three groups.

Clinical Trials on Antithrombotics and survival:

AK Kakkar presented the data on survival of cancer patients with advanced disease receiving prophylaxis with Dalteparin versus placebo for 1 year or until death. Overall there was no difference between the two groups, however in a sub-group of patients at better prognosis (survival > 17 months) there was an advantage for those receiving Dalteparin:
H Buller presented the MALT study that evaluates Nadroparin versus placebo for prolongation of survival in advanced cancer patients not presenting VTE. Currently 302 patients have been enrolled. The results show that the median survival is 16.5 months in the Nadroparin group vs 7.4 months in placebo group (p=0.019);
Ozlem Er from Turkey reported the update of a study evaluating the impact of Dalteparin+chemotherapy on survival of small cells lung cancer patients.

To encourage exchange and new collaboration a section was devoted to: New Trials, Registries, Proposals

M. Levine presented the a clinical trial of Fragmin prophylaxis (for at least 6 months) in patients operated for malignant glioma eligible for radio- and chemo-therapy treatments (PRODIGE). Ongoing (37 patients enrolled so far).
C. Francis: Fragmin in pancreatic cancer. Ongoing.
G. Agnelli presented the PROTECHT study for the prevention of venous and arterial VTE with Nadroparin (versus placebo) in patients receiving chemotherapy for cancer of the lung, breast, GI, ovary, head and neck. To be started shortly.
M. Moia presented the Italian registry of CVC-related thrombosis in haematological patients (CATHEM). Follow-up closed on June 30, 2003. Included > 450 patients. Preliminary analysis shows a low ibcidence of symptomatic DVT. The final results will be presented at the Bergamo Conference (Sept. 2003).
A. Lee reported on the Canadian registry of CVC-related thrombosis in solid tumors. Ongoing, about 450 pts included so far. Followed up to 52 weeks (or at least 4 weeks after CVC remotion).
A.K. Kakkar presented the proposal for a Prospective global evaluation of thromboembolic disease in cancer patients (MIRACLE registry) to follow the natural history of the disease and analyze the factors leading to thrombosis; and the FAMOUS II trial to evaluate the effect on survival of dalteparin given at 2 different doses (7.500 UI/d and 10.000 UI/d vs placebo), starting 1 month after diagnosis until death.

At the end a short debate (MH Prins and MN Levine) was held to discuss what areas should be addressed next. Martin Prins highlighted the following:

regarding Prevention of VTE:1. Better definition of high risk groups, 2. Need to evaluate the oral drugs in this group; and consider the survival as secondary outcome in all trials; 3.
regarding Treatment of VTE: 1. Overcome LMWH, i.e. compare oral drugs versus LMWH, 2. Define the optimal duration of therapy in relation to type/stage of cancer.
Modifying biology: 1. Perform meta-analysis of MALT-FAMOUS and CLOT; 2. Identify cancer types/stages "promising" for studies in this area; 3. evaluate other effects of LMWH and/or anti Xa/IIa agents.
concerning Screening for malignancy in patients with idiopatic VTE: 1. Repeat SOMIT with optimal screening procedure identified (RCT), 2. Cohort registries of screening and non-screening centers.

M.N. Levine added some considerations on the unfulfilled need for defining the clinical utility of laboratory testing in order to identify whether one or more of plasma markers can predict for thrombosis in the single patient and therefore be of help in the decision making. He also commented on the recent evidence for a less relavant role of the CVC-related thrombosis. Finally he showed data on new anti-tumor regimen employing an anti-VEGF agent together with chemotherapy, which significantly improves survival, but also has a potential pro-thrombotic effect. This leaves the possibility of new drug-related thrombosis.