Haemostasis and Malignancy

June 30, 2006
Oslo Kongressenter, Norway

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

The first part of the meeting, chaired by A. Falanga and L. Zacharski, addressed biological issues. 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.

The issue of circulating thrombotic markers in malignancy has expanded to a number of blood components and molecules. C. Francis presented the predictive factors for thrombosis in pancreatic cancer, particularly he presented data regarding TF expression in resected and metastatic pancreatic cancer patients, TF levels in peripheral circulation in metastatic pancreatic cancer and correlation with angiogenic factors and DVT/PE . Tissue specimens were obtained from 109 patients with resected pre-neoplastic lesions and 122 patients with resected pancreatic cancers. In addition, 10 normal pancreas specimens were evaluated. A pancreatic tumor microarray of resected pancreatic cancer specimens was constructed. Tissue sections from these microarrays were deparaffinized, rehydrated, washed and stained for TF, VEGF, and CD31 for microvessel density. Overall results of TF immunostaining showed a high percentage of positive staining in pre-neoplastic and neoplastic pancreatic tissue, whereas TF expression was not observed in the 10 normal pancreas. VEGF expression was observed in 56% tumors. Tumors with high TF expression were much more likely to also express VEGF. TF expression also correlated with microvessel density. The association of TF expression with development of clinical VTE was evaluated in a subgroup of 33 patients with resected pancreatic cancer for whom data regarding VTE was available. In this group, a strong association of TF expression with VTE was found. Finally, median survival of subjects with tumors with low TF was higher than in those with high TF expression, however this difference was not statistically significant.

S. Haas presented the analysis of predictive factors from TOPIC I and TOPIC II studies on the prevention of VTE by LMWH certoparin in patients with metastatic breast (TOPIC 1) or lung cancer (TOPIC II). VTE events in the breast cancer group were less frequent than expected (4%). Indeed TOPIC I was discontinued at the interim analysis because the incidence of thrombosis was very low (4%) and showed an equal rate in the LMWH certoparin and placebo groups. In contrast, in TOPIC II, the incidence of VTE events was 4.5% in the certoparin arm compared to 8.3% in the placebo arm. In these non small cell lung cancer patients an elevated pre-chemotherapy platelet count (>350,000 plts /mm^3) was associated with an increased rate of VTE and in these patients prophylaxis with LMWH was very effective, in fact certoparin reduced VTE rate from 11% of placebo to 2%.

T.E. Warkentin reported on venous limb ischemia in cancer patients in relation to warfarin administration. In 98 cancer patients who were treated with heparin, 9 developed lower limb ischemia. In these patients (assuming heparin followed by warfarin, started from the 2 nd day of heparin treatment to reach a therapeutic INR range), a sudden decrease of platelet count was observed when heparin was stopped and patients developed limb ischemia. Tests for HIT were negative, TAT complex elevated and levels of protein C and Factor VII were low. In conclusion, cancer-associated venous limb ischemia can be associated with warfarin administration and the p athogenesis may be attributed to disturbed procoagulant-anticoagulant balance , with increased t hrombin generation (warfarin fails to inhibit thrombin generation) , and decreased p rotein C and FVII, which are particularly prone to depletion with warfarin in cancer hypercoagulability.

CLINICAL RESEARCH UPDATE

The second part of the meeting chaired by M. Prins, C. Francis and A. Lee, included an update of the ongoing clinical trials of antithrombotics in patients with cancer. In addition the designs of new clinical trials and registries was presented.

ONGOING CLINICAL TRIALS

H.M. Otten described 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 380 patients and interim analysis will be performed within 2006.

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, 709 patients have been enrolled. Dr. Pabinger reported preliminary results on cumulative probability of VTE according to tumor type. In addition, in the group of glioma cancer patients a cohort study was performed in 63 consecutive patients high grade glioma. Observation started at time of surgery (patients that presented with VTE prior to surgery were not included). A 26% probability of VTE was found. Patients undergoing total tumor resection had a lower probability to develop VTE compared to partial resection, while the occurrence of VTE had no impact on survival compared to non-VTE group.

A. Falanga on behalf of G. Agnelli presented the PROTECHT trial (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 is 956 (estimated sample size: 1,200 patients). The interim analysis of the 400 pts was completed in November 2005 and no issues were raised, therefore the study continued. The interim analysis of 800 pts will be completed in September 2006. Last patient included in March 2007, preliminary data may be available in October 2007.

A. Falanga on behalf of M. Kovacs presented the catheter study. This is “ A Pilot Study of Central Venous Catheter Survival in Cancer Patients Using Low Molecular Weight Heparin (Dalteparin) for the Treatment of Deep Vein Thrombosis of the Upper Extremity” (The Catheter Study). The hypothesis of this study is that treatment (dalteparin + warfarin) of upper limb DVT secondary to central venous catheters can salvage the line and allow chemo to proceed without significant VTE complications or need for a new line. Seventy four cancer pts with symptomatic acute upper limb DVT associated with central venous catheter (with or without pulmonary embolism, objectively documented) have been enrolled in the study, 64 of 74 (86%) completed 3 months follow-up. Results: DVT Outcome = 0, PE Outcome = 0, Major Bleeds = 3 (1 death). The catheter outcome results show that 63 (85%) patients could be treated with no incidents and catheters were in and remained functional. This study suggests that treatment of catheter-associated DVT can allow the line to be salvaged in the majority of patients until it is no longer needed.

R. Lecumberri updated on the ongoing study named BECAT (prophylaxis of catheter-related DVT in cancer patients). This is a multicentric, randomized, placebo-controlled and double-blind study for the evaluation of the efficacy and safety of antithrombotic profilaxis with Bemiparin (3,500 IU/day) in cancer patients with a central venous catheter. Oncohematologic pts with central venous catheter and platelets above 30,000/mm^3 are enrolled at CVC insertion and randomized to receive placebo or Bemiparin 3,500 IU/d. At days 45 and 90 Ecodoppler is performed and combined incidence of DVT-CVC related recorded.

Dr. Lecumberri also presented the CANBESURE STUDY: Cancer, Bemiparin and Surgery Evaluation, a multicentric, randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of the prophylaxis with Bemiparin 3,500 IU/d for 28 days compared to 8 days, in venous thromboembolic disease in patients undergoing oncological abdominal or pelvic surgery. It is a phase III, double-blind, multicentre study conducted in Spain.

NEW STUDIES

A. Kakkar presented the design of a the study OVANOX ( OVarian cANcer and enOXaparin). This is a randomized, Phase III-b placebo-controlled study of extended VTE prophylaxis with LMWH enoxaparin given pre and post-operatively and continued concomitantly with chemotherapy in patients with operable epithelial ovarian cancer. The principal objective of the study is to demonstrate the superiority of extended post-operative VTE prophylaxis with enoxaparin 40 mg subcutaneous once-daily for 3 weeks, compared to placebo, both following 1 week of initial treatment with enoxaparin 40 mg sc once-daily. The main secondary objective is to demonstrate the superiority of enoxaparin 40 mg sc for 3 weeks followed by 1.2 mg/kg in addition to chemotherapy for 18 weeks, over placebo for 3 weeks followed by no treatment, in improving disease free survival at 180 days. Other secondary objectives are: 1) compare overall survival up to 5 years between enoxaparin and placebo, in addition to chemotherapy up to 6 cycles; 2) assess the incidence of total documented VTE (symptomatic / asymptomatic, distal / proximal) up to Day 21; 3) assess the incidence of documented symptomatic VTE (proximal/distal) up to 6 chemotherapy cycles; 4) evaluate the safety (hemorrhage, death, SAE) of enoxaparin in patients with operable ovarian cancer.

M. Prins on behalf of H. Buller presented the design of the study INPACT (INproving 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. 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.

A. Lee presented the study design of FOCUS ( Fragmin in Ovarian Cancer: Utility on Survival) . 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.

R. Lecumberri presented the design of a phase II prospective, randomized, open and sequential study to evaluate the efficacy and safety of Bemiparin administration on the response to treatment in patients diagnosed with limited small cell lung cancer (ABEL study). Patients with limited SCLC will be randomized to received the standard chemotherapy treatment versus standard treatment plus bemiparin 3500 IU/d for 6 months. A follow up of 5 years will be performed and the following parameters will be evaluated: Survival (1, 2, 3 and 5 years), Response rates (complete/partial/global) after first-line therapy, Incidence of VTE, Haemorrhages, Biological markers.

S. Noble presented the design of a study, named FRAGMATIC. A randomised phase III clinical trial investigating the effect of FRAGMin® Added to standard Therapy I n patients with lung Cancer . Aim of the study is to assess the effect of adding 6 months of daily dalteparin (Fragmin) to standard treatment for patients with lung cancer. The primary outcome is the overall survival. Multicentre randomised phase III trial, 2200 patients will be randomised to one of two groups with a 1:1 randomisation. The c ontrol Group will receive anti cancer treatment according to local practice for the patient’s histology, stage and performance status. The i ntervention group will be treated as control plus once daily subcutaneous dalteparin for 6 months at a prophylactic dose.

REGISTRIES

S. Schulman and A. Falanga presented 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.

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.

H.M. Otten presented the design of the TEACH survery (Thrombo-Embolism And CHemotherapy). This is a prospective survey on the incidence of venous thrombo-embolic events during chemotherapy for solid tumors. TEACH will start in May or June 2007. Objectives are to evaluate the Incidence of DVT (symptomatic and asymptomatic) and of VTE/PE (symptomatic) in patients receiving chemotherapy by a prospective multi-center survey ( Europe ). Patients needed are 2000 with negative baseline US with a maximum of 600 pts per disease entity. They should have no prior major surgery within 4 weeks, no prior chemotherapy within 6 weeks, no anticoagulant scheduled treatment or prophylaxis, an a live expectancy > 3 months.

JOINT SESSION ON D-DIMER

This session was organized in collaboration with the Subcommittees on “Fibrinolysis” and “DIC”. It was well attended and very successful. Carl-Erik Dempfle updated on current state of play for D-dimer and fibrin-related markers determination in DIC. Cheng Hock Toh talked on diagnostic potential of D-dimer and fibrin-related markers in DIC. Finally, Marielle Beckers (on behalf of K. Hamulyak, H. ten Cate and M. Prins)showed the diagnostic pitfalls of D-dimer analysis in patients with cancer suspected from venous thrombosis. Promising results may come from study evaluating the predictive value of D-Dimer for occult cancer or for cancer survival, but better standardized clinical studies are required.