Hemostasis and Malignancy
DRAFT Subcommittee Minutes
23 July 2011
14:00-18:00
Room Sakura
Chairman: Agnes YY Lee (CA)
Co-chairmen: Giancarlo Agnelli (IT), Marc Carrier (CA), Dominique Farge (FR), Alok Khorana (US), Marina Marchetti (IT), Wolfram Ruf (US), Jeffrey Zwicker (US)
Invited Speakers: J. Rak
There were 11 presentations updating subcommittee activity and discussing new proposals.
EDUCATIONAL PROGRAM
Mechanism of Coagulation in Tumour Progression and Metastasis
Janusz Rak, Canada
Dr. Janusz Rak (CA) spoke on the mechanisms of coagulation in tumor progression. Metastatic cancers emerge in the course of progressive biological changes hardwired in the cellular genome by a succession of oncogenic mutations. These changes not only affect the intrinsic properties of cancer (stem) cells, but also profoundly impact their interactions with the vascular system, through a multitude of proinflammatory, proangiogenic and procoagulant alterations, which are central to tumour dissemination. Several facets of the coagulation system participate in these events, including thrombin, fibrin, PAI-1, COX-2 and many others. However, tissue factor (TF) can be regarded as a paradigm, common denominator and a key effector of cancer-related vascular alterations. Indeed, the expression of several oncogenic proteins (e.g. K-ras, EGFR, HER2, MET, p53, PTEN and others) drives the upregulation of TF, as well as the abnormal expression of its key interacting molecular partners (FVII, PAR-1, PAR-2) in several types of cancer cells (e.g. in colorectal carcinoma or glioblastoma). This change leads to the exaggerated procoagulant and signaling activity of the TF/FVIIa pathway in transformed cells. Moreover, oncogenic pathways promote cellular vesiculation, whereby large numbers of TF-containing microparticles (microvesicles) are emitted from cancer cells into their surroundings, and may enter the systemic circulation, participate in cancer coagulopathy and mediate intercellular transfer of TF activity. Interestingly, tumor cell-derived microvesicles may also contain active oncoproteins and mediate propagation of a quasi-transformed cellular phenotype. These observations suggest that oncogenic transformation, acting in concert with microenvironmental and iatrogenic factors, may provoke a series of distinct changes in the haemostatic system of cancer patients, a process that could be biologically consequential regardless of the accompanying thrombosis. The prognostic and therapeutic implications of this linkage are a subject of active explorations.
Role of tissue factor and biomarkers: ready for prime time?
Jeffrey Zwicker (USA)
Dr. Zwicker spoke on the role of tissue factor as a potential biomarker for cancer-associated thrombosis. Although the association between cancer and thrombosis is well established, the acceptance of primary thromboprophylaxis strategies has been limited due to low overall event rates. A number of biomarkers are currently under investigation to identify those patients at highest risk including circulating tissue factor bearing microparticles, soluble p-selectin, platelet count and other markers of coagulation activation. A number of analytic issues remain and the utility of targeted thromboprophylaxis based on biomarker profiles or risk models requires investigation in prospective clinical trials.
Targeted Thromboprophylaxis Using Clinical Prediction Models
Alok A. Khorana (USA)
Dr. Khorana spoke on the role of clinical prediction models in identifying high-risk cancer patients who could potentially benefit from thromboprophylaixs. Although cancer patients are universally regarded as being at high risk for VTE, the risk varies between individual cancer patients and even in the same cancer patient over time. Multiple risk factors and biomarkers predictive of cancer-associated VTE are being evaluated. Dr. Khorana reviewed the evidence supporting the use of a clinical prediction model (Khorana et al, Blood 2008), including multiple validation studies performed in the past two years. He also reviewed data to support a proposed expansion of this model by the Vienna group (Ay et al Blood 2010) and from the PROTECHT study (Verso et al, ISTH 2011). Finally, a host of thromboprophylaxis studies have been recently reported in cancer outpatients and these data were reviewed as well.
Subcommittee Activity Updates
Dr. O’Connell updated the Subcommittee on issues related to the definition, prognosis and treatment of incidental VTE. The utilization of highly sensitive multi-row detector CT scans for staging malignancy in cancer patients has led to more frequent detection of incidental pulmonary emboli (PE). These PE are frequently symptomatic but unsuspected by the treating physician. While prospective data are lacking, it appears that incidental PE located proximal to the subsegmental branches of the pulmonary arterial tree adversely impact overall survival among cancer patients. Moreoever, patients with PE-related symptoms have poorer outcomes when compared to those with incidental PE which are truly asymptomatic. Incidental subsegmental (SS) PE may be indicative of clot burden in other anatomic locations. While truly asymptomatic and isolated SS PE probably don't adversely impact survival, it is not clear whether they can be left untreated. A unified approach to classification and terminology is necessary in order to properly include incidentally detected PE in clinical trials which report VTE as outcomes or adverse events.
Dr. Ay updated the Subcommittee on the role of D-dimer in diagnosis of malignancy-associated VTE, prediction of VTE and prognosis of cancer patients, independent of VTE. D-dimer is a well known and frequently used biomarker, which indicates the global activation of the blood coagulation system. It is a degradation product of cross-linked fibrin, and is formed after thrombin-generated fibrin has been degraded by plasmin. Increased levels of D-dimer have been observed in many conditions, including, infection, inflammation, surgery, trauma, pregnancy and cancer. As D-dimer levels are elevated after clot formation, the measurement of D-dimer is routinely used in conjunction with clinical parameters in the initial assessment of a suspected acute VTE. A few studies have investigated the usefulness of D-dimer testing for diagnosis of VTE in cancer patients. The sensitivity and negative predictive value (NPV) of a negative D-dimer for excluding the diagnosis of VTE have been found to be high and comparable to non-cancer patients. The specificity, however, is lower than in non-cancer patients. In the Vienna Cancer and Thrombosis Study (CATS), high levels of D-dimer have been associated with occurrence of VTE in cancer patients. Subsequent studies have confirmed the association of high levels of D-dimer with risk of future VTE in cancer patients. Therefore, D-dimer might be a potential biomarker for prediction of VTE and may improve risk assessment of VTE in cancer patients. Several studies have also investigated the association of activation of blood coagulation, as reflected by D-dimer, with prognosis of disease in cancer patients. The global activation of the haemostatic and fibrinolytic system has been reported to correlate with a more advanced tumor stage, unfavorable outcomes and a poor prognosis.
Dr. Carrier updated the Subcommittee on a project focusing on standardized definitions of VTE outcomes for oncology trials. The association of venous thromboembolism (VTE) and cancer therapy presents a challenge for recognition because many randomized controlled trials or clinical studies are not powered to reveal a significant relationship or safety concern. Systematic reviews and meta-analyses are required to assess the risk and have to use events reported using different “non-standard” definitions of VTE. Cancer clinical trials are using pre-established definitions from toxicity classification systems: 1) National Cancer Institute’s Common Toxicity Criteria; 2) WHO Criteria; or 3) National Cancer Institute Common Terminology Criteria for adverse events. These classification systems are widely adopted and used in cancer clinical trials and are used primarily to grade the severity of the event. None of the toxicity classification systems outline the diagnostic criteria for DVT or PE, nor the location or extent. All these VTE-associated factors are important to consider as they are associated with different risks of recurrent events, embolizations and prognosis. The primary objective of this ISTH Subcommittee activity is to propose a standardization of the symptomatic VTE definitions including the diagnostic criteria required to report a DVT or PE. Cancer clinical trials could then adequately report VTE and assess the risk and safety concerns. Secondary objectives are to suggest a standardized method for reporting symptomatic recurrent VTE and bleeding episodes.
Ongoing Studies and New Proposals
Dr. Khorana outlined ongoing studies that are evaluating tissue factor (TF) as a therapeutic target for cancer, independent of anticoagulant effect. Two drugs are currently in early phase studies. ALT-836 is an anti-TF monoclonal antibody that is currently being tested in a phase I study in advanced solid tumors, based on promising preclinical data suggesting inhibition of pancreatic and other cancers. PCI 27483 is a TF/VIIa inhibitor that has completed phase I testing and is currently in randomized phase II enrollment. Data from these studies should provide information regarding the potential of this novel anti-cancer approach.
Dr. Farge updated the activities of her proposal to establish VTE guidelines in cancer-associated thrombosis, with input from an international working group. Much work has already been done with support from the French INCa group with respect to infrastructure and methodology support. Dr. Farge outlined the systematic review and proposed grades of recommendation of these forthcoming guidelines.
Dr. Agnelli provided a perspective on new oral anticoagulants and potential use in oncology. Several agents are now available for use for a variety of non-cancer indications. However, caution needs to be exercised in relation to drug-drug interactions, compliance and monitoring. Cancer-specific studies are necessary because cancer patients comprise 10% or less of recent studies.
Updates on ongoing clinical trials were provided by several investigators. Dr. Carrier provided information regarding study design and enrollment for a) PERIOP-01, an extended duration perioperative LMWH study to evaluate recurrence-free survival in colorectal cancer, and b) SOME, a randomized study of screening strategies for occult cancer in patients presenting with unprovoked VTE. Dr. Meyer presented updated study enrollment for TILT, a randomized study of adjuvant LMWH in patients with resectable lung cancer which is three-fourths on the way to full enrollment. Dr. Kamphiusen updated the Subcommittee on a)CATCH, a trial of LMWH vs warfarin therapy for extended treatment of cancer-associated VTE which is currently in enrollment and b) LONGHEVA for post-6 month treatment of cancer-associated VTE. In this latter study, cancer patients who have received 6-12 months of anticoagulation for VTE will be randomly assigned to 6 additional months of LMWH or VKA (target INR 2.0-3.0). Allocation to treatment will be done centrally by block randomisation via a web-based system (concealed allocation) and will be stratified by center. The primary efficacy outcome is symptomatic recurrent VTE. The primary safety outcome is major bleeding.
Based on the above presentations, there was support that the subcommittee consider position papers on the following issues:
- Establishing diagnostic criteria and guidance for incidental venous thromboembolism. This is important to improve the accuracy and consistency of reporting the incidence of this outcome in clinical studies.
- Providing guidance on the role of D-dimer testing in diagnosis, prediction and prognosis of VTE in cancer.
- Encouraging the inclusion of venous thromboembolism as a standard safety outcome in oncology trials of new agents. This could potentially involve collaborating with NCI and WHO to update existing definitions of VTE which are not reflective of widely accepted clinical criteria and hinder meta-analyses of oncology clinical trials to establish linkages between specific therapeutic agents and VTE.
The meeting was adjourned at 18:00.
