SCIENTIFIC SUBCOMMITTEE SESSION
6 July 2007 Palexpo, Geneva, Switzerland
Hemostasis and Malignancy
Chair: M. Prins (The Netherlands)
Co-chairs: G. Agnelli (Italy), A. Falanga (Italy), C. Francis (USA), A. Lee (Canada), L. Zacharski (USA)
M. Prins opened the meeting and the first session on laboratory aspects was chaired b y A. Falanga and L. Zacharski.
E. Gray (UK) Reported on the progress of the Working Party on TF standardization in cancer. A first set of 6 samples has been sent to 5 laboratories. There was a considerable variation, in part related to the type of samples sent to the laboratories (cell lysates vs recombinant) and assays used. E. Gray presented an update for the Working Group on TF standardization in cancer. The panel of this Group is composed by: 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 the knowledge of TF relevant role in cancer. 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 group are: 1. To compare measurements of TF with a variety of methods in different laboratories; and, 2. To improve intra- and inter- laboratory reproducibility by development of standardised protocols, appropriate reagents and reference materials. Gray presented the results of the pilot collaborative study aimed to investigate the suitability of a panel of candidate TF reference materials (freeze-dried): purified tissue factor, recombinant, cell lysates (THP-1, NB4). The participants of the pilot study were the 7 Working Party laboratories. Assay methods utilised were: clotting, chromogenic and antigen. So far 6 out of 7 participating labs have returned results. A report of the pilot study to participants will be done by August 2006. Future plans ( Time frame – 2007/2008): 1- to a ssess suitability of current batch of purified recombinant TF (may be able to share a batch with Working Party on Thrombin Generation Tests), assess suitability of freeze-dried cell lysates: cell numbers, stimulated or unstimulated, excipient. Prepare large scale batches of tissue factor and cell lysate; 2- to initiate main international collaborative study on proposed candidates; 3- dependent on collaborative study results, establish candidates as ISTH/SSC references –; and 4. standardise assay methods.
N. Key (USA) reported on the measurements of circulating TF. It is possible to measure both antigens and activity and to measure this in different compartment of the blood (plasma, microparticles, cells). He concluded that measurement of activity of whole blood components would be most ideal.
M. Marchetti (Italy) reported, also on behalf of and A. Falanga on testing for the non-anticoagulant effects of heparins. She described several assays used to quantify and assess differences between specific types low molecular weight heparins.
S. Osanto (The Netherlands) reported on MP-associated TF activity in cancer patients. She showed that there was a clear link between MP-associated TF activity and cancer stage and between the development of VTE complications in cancer and higher MP-associated TF activity. Finally MP-associated TF activity seemed highly related to cancer survival.
L. Zacharski (USA) forwareded a hypothesis Iron stores as a link between malignancy and coagulation disorders. Based on a common epidemiology in realtion to age and mechanisms, excess iron incducing procoagulant as well a mutagenic potential iron stores were hypothesized to be a common link by triangulation. Several studies on flebotomy to lower ferritin concentration provide evidinece that indeed this is linked to a lower incidence of arterial thrombosis and cance.
The next part of the meeting addressed clinical issues in the relation between cancer and thrombosis.
G. Meyer and P.Girard (France) gave on behalf on the steering committee of the TILT study a presentation of the design of this study that assesses the Effect of low molecular weight heparin on survival of stage I,II or IIIA non small cell lung cancer. A multicenter, open, randomized controlled trial. Low molecular weight heparin will be given during the entire period of chemotherapy. The primary outcome is survival . It is planned to include 800 patients.
A. Lee (Canada) gave an update on the FOCUS study. The general objective is to identify a potentially efficacious and safe dose of dalteparin as an adjuvant agent in women receiving standard chemotherapy for newly diagnosed ovarian cancer, for phase III investigation . The study wants t o determine the effect of 3 selected doses of dalteparin on CA-125 response in women receiving standard chemotherapy for extended ovarian cancer, in addition to the determine incidence of symptomatic VTE in this group of women and establish the safety (bleeding) of dalteparin when given with chemotherapy over a 3-month period. Finally the study will determine the feasibility of once daily sc injections and women compliance with self-injections over a 3-month period. Also a substudy to explore the relationships between tumour biology and activation of coagulation will be performed. Currently 60 patients are included.
H. Büller (The Netherlands) gave an update on the INPACT study. ). 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. Eligible patients will be randomised to: standard anti-cancer treatment, or standard anti-cancer treatment plus nadroparin. All patients will have standard anti-cancer treatment: 14 days weight-adjusted “full therapeutic” dose, followed by 4 weeks half dose, then a 4-week wash out period, finally 2-week once daily full dose + 4-week wash-out period for several cycles. This last cycle can be repeated up to 6 times in the absence of contraindications. The primary outcome is death from cancer. Currently 200 patients are included.
A. Kakkar (UK) presented a study on LMWH in gastric cancer. This trial will be conducted in India and will include patients with stage III/IV gastric cancer. Patient are randomized to usuasl care with or withiout added LMWH. The trial is open and plans to include 600 patients.
H.M. Otten provided an update on the Trousseau study (Screening for Occult Malignancy in patients with idiopathic VTE). Trousseau study: “Screening on malignancy in patients with an idiopathic VTE: Effect on mortality”. It is a prospective, multicenter, cohort study. The objective is to see the effect on mortality of screening with CT chest/abdomen + mammography versus routine in patients with idiopathic VTE. Inclusion criteria are: Objectified VTE, No risk factor, 40 years, First VTE, No signs of malignancy at routine examination. Trousseau is ongoing and reached approximately 500 patients and an interim anterim analysis will be presented at the ISTH 2007.
A. Falanga (Italy) presented a study on the incidence of VTE in cancer patients receiving adjuvant chemotherapy. Trghwe overal incidence of VTE during chemotherapy was 8.0%. There were no additional risk identificators.
A. Khorana and C. Francis (USA) reported on the development and validation of a predictive model for chemotherapy-associated thrombosis. Leucocyte count, platelet count age, high BMI and cancer types were included in the model. Based on the risk score the incidence of thrombosis was as low as 2% in the lowest risk group and reached 7% in the highest risk groups in the validation stage.
M. Monreal (Spain) reported on potential differences in efficacy and safety of different LMWH’s for the s econdary prevention of VTE in cancer patients. The data were based on the RIETE registry. It was remarked that the study was not randomized and that dosing regimens between these LMWH’s differed consderably.
I. Pabinger updated on the CATS (Cancer And Thrombosis Study). Aims of this study are to evaluate the incidence of venous thromboembolism in cancer patients and to identify predictive parameters for the development of venous thrombosis and pulmonary embolism in patients with malignancies. It is a prospective nested case control study. Patients with newly diagnosed cancer of the central nervous system, breast, lung, kidney, the gastrointestinal or genitourinary system, sarcoma or haematological malignancies (multiple myeloma, high and low grade lymphoma) or progression of disease after complete or partial remission, are enrolled into the study.
At today enrollment has been completed. Dr. Pabinger reported that surgry, radiotherapy and high platelet count at baseline were risk factors for VTE. Full results are presented at the ISTH 2007.
A. Kakkar presented the first results 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. PERCEIVE registry. The overall incidence of thombosis was somewhat lower than expected (approx. 3%), and mainly occurring close to the diagnosis of cancer.
S. Schulman called for acive participation in the registry of Recurrent VTE in cancer patients. This registry rapresents a collaborative project of the two subcommittee, on “Control of anticoagulation” and on “Haemostais and Malignancy”. Recurrence of VTE occurs in spite of adequate anticoagulation in 7-27% of cancer patients per years. There is also a high risk of major bleeding on vitamine K antagonists in patients with cancer (5-13%/year). There is no guideline for the treatment of such recurrences. This registry collects data on 200 events of this type, the treatment provided and the effect and safety thereof. The data will create a basis for future trials. Currently there are onl 10 reported events enparticipation was highly recommended