Aptitude Health recently spoke with Grigoris Gerotziafas, MD, PhD, from Sorbonne University in Paris, France, to learn his views on risk assessment and prophylaxis for cancer-associated thrombosis. Prof Gerotziafas, a leading expert in the field of thrombosis and hemostasis, is the director of the Research Group “Cancer, Angiogenesis and Thrombosis” at the Centre de Research Saint Antoine, INSERM U938 at Sorbonne University and leads the Thrombosis Center in Tenon-Saint Antoine University Hospitals in Paris. His work focuses on the intricate interplay between cancer cells, blood coagulation, and endothelial cells. His leadership extends to the postgraduate thrombosis and hemostasis in hematology masters program at Sorbonne University (DU T2H, Thrombosis and Hemostasis in Hematology), guiding future specialists in this critical field. Internationally recognized, Prof Gerotziafas’ expertise spans cancer-associated thrombosis (CAT), antithrombotic treatment, and vascular complications in pregnancy and subfertility. His pioneering work includes leading the ROADMAP-Thrombosis project, which aims to identify crucial biomarkers for hypercoagulability in conditions such as solid tumors, hematologic malignancies, COVID-19, and vascular complications in pregnancy. He also heads the Comparison of Methods for Thromboembolic Risk Assessment with Clinical Perceptions and AwareneSS in Real Life Patients-Cancer Associated Thrombosis (COMPASS-CAT) Working Group, an international network of experts responsible for developing multiple risk-assessment models for diverse medical scenarios including CAT. The COMPASS-CAT score for identification of ambulatory patients with solid tumors is recommended by the recent guidelines of the European Society for Medical Oncology (ESMO). Here is a recap of our conversation.
How significant is thrombosis as a complication in patients with cancer?
Among cardiovascular diseases, venous thromboembolism (VTE), despite being a preventable disease, remains a major health problem, especially when it occurs in patients with cancer. In this setting, thrombosis is described by the term “cancer-associated thrombosis.” A hypercoagulable state is the hallmark of cancer. It is induced by specific prothrombotic properties of cancer cells that activate blood clotting, platelets, and endothelial cells. The type and stage of cancer are determinants of CAT risk. Anticancer treatments and patient-related intrinsic risk factors (eg, cardiovascular disease, hypertension) amplify the risk of CAT. Finally, the risk of CAT, as well the risk of CAT recurrence and bleeding, are associated with social inequalities, and financial and geographic barriers to access to health care services. Environmental factors (eg, climate change and air pollution) have an amplifying effect on the risk of CAT.
Despite being a preventable disease, CAT remains a major health problem and figures as the number 2 cause of mortality after cancer itself.
- The incidence of symptomatic CAT in patients who receive anticancer therapy increases up to 10% every year, with at least 600,000 VTE-related deaths annually just in Europe. Over the last 2 decades, the risk of VTE is 3- to 9-fold higher in citizens with cancer than in the general population
Therapeutic advances in oncology have transformed many cancer types into chronic diseases. In general, oncology patients live longer with a satisfactory quality of life. Sadly, the occurrence of VTE impacts both, their quality of life and life expectancy. Thrombosis in patients with cancer dramatically changes the natural history of the disease, diminishing the benefits achieved by new anticancer treatments and strategies. CAT dramatically impacts patients’ survival. The mortality rate of patients with cancer who experience CAT is 3-fold higher as compared with those without. Patients with CAT must receive long-term anticoagulant therapy, which exposes them to a significantly high risk of major bleeding, compromising the administration of anticancer treatment. Thus, CAT occurrence leads to modifications of the anticancer treatment schedule, resulting in a negative evolution of the cancer. CAT figures among the leading causes for prolonged hospitalization and re-hospitalization, causing substantially increased expenditures for healthcare systems. The direct cost of CAT to EU healthcare systems equates to €1.5–2.2 billion each year, mostly attributed to hospitalization. The average cost per stay for the first thrombotic event is about €3,611. Data from a 2-year nationwide survey in France showed that for common cancers (such as breast, lung, colon, or prostate), hospitalization due to CAT occurred in 6% to 9% of patients, while hospitalization due to CAT recurrences occurred in 16% to 28% of patients. The costs of post-hospital care (frequent medical visits, repetitive biological and imaging tests, hospital nursing, etc) raise the total expense of CAT management to levels higher than €15,000 per VTE event. These figures also include cancers considered curable today, such as breast and prostate, and some hematologic malignancies like multiple myeloma.
Another alarming feature of CAT is that its frequency is increasing and is expected to continue rising. For example, in 2000, the cumulative incidence of VTE in patients with cancer was about 1.5%. In 2024, it is about 5% to 10%, with projections suggesting an increase of more than 10% in the coming years. This rise is due to longer patient survival, and the introduction in the therapeutic armamentarium of new anticancer drugs (including targeted treatments and modern cellular treatments like chimeric antigen receptor T-cell therapy) that are effective and better tolerated compared with conventional chemotherapy, but that increase CAT risk.
These data must be communicated to oncologists, patients, and the health communication sector as well as to the political healthcare authorities. They are a solid argument for a call to action.
Has there been any advancement in prevention and treatment of cancer-associated thrombosis?
Yes, there has been progress. First of all, we know very well the periods of increased risk of CAT in patients, starting from the diagnosis of cancer and during the entire patient journey in the disease. In up to 10% of patients with unprovoked VTE, thrombosis is the first clinical manifestation of cancer. Early cancer diagnosis in these cases is vital. For this reason, extensive screening for cancer is recommended in patients with unprovoked VTE and in the absence of hereditary thrombophilia or antiphospholipid syndrome.
The risk of VTE increases 6-fold in the first 6 months after a cancer diagnosis, as well as after the confirmation of cancer progression or recurrence. This knowledge offers the opportunity to apply strategies of “targeted awareness” for prevention, early recognition of clinical signs and symptoms, application of the appropriate diagnostic imaging tests and recommended and validated diagnostic algorithms, as well as for the treatment of patients with confirmed CAT.
Regarding prevention of CAT, targeted awareness during high-risk periods allows identification of the patients at high risk of CAT via validated and accurate risk-assessment models for the particular types of cancer. Scores such as COMPASS-CAT, which is specific for patients with the most frequent types of solid cancers (breast, colon, lung, ovarian), and the Thrombosis Lymphoma (ThroLy) score for patients with lymphoma or the Vienna Cancer and Thrombosis Study score, help physicians to accurately identify ambulatory patients on anticancer treatment at high risk of CAT. Patients at high CAT risk will benefit from pharmacologic thromboprophylaxis with low-molecular-weight heparin (LMWH) or direct oral anticoagulants (mainly with specific direct inhibitors of factor Xa such as apixaban, edoxaban or rivaroxaban). Application of targeted pharmacologic thromboprophylaxis in selected high-risk patients reduces the risk of CAT by up to 90% without any significant increase in bleeding risk. Regarding this point we must be very precise and categorical. The most recent international guidelines and expert consensus statements are very clear: The risk for CAT must be evaluated as soon as the primary diagnosis of cancer is confirmed. The risk assessment must be regularly performed during the first 6 months after anticancer treatment initiation and also after confirmation of cancer progression or recurrence. In high-risk patients, identified with a validated and recommended score such as the COMPASS-CAT, who do not present any contraindications or high bleeding risk, pharmacologic thromboprophylaxis must be initiated promptly.
In addition, cancer surgery is associated with increase of CAT risk by 5 to 6 times. Accordingly, patients undergoing abdominopelvic surgery should receive thromboprophylaxis with LMWH for 1 month after surgery. Those who receive other types of surgery are recommended to be assessed for risk of VTE using the Caprini score.
Regarding diagnosis and treatment of CAT, there has been substantial progress in the development of decision-making algorithms adapted for patients with cancer who have clinical suspicion of VTE. These algorithms are based on the prompt application of accurate noninvasive imaging methods including echo Doppler, and computed tomographic angiography.
Time is a key element in the treatment of patients with clinical suspicion of VTE! According to the most recent recommendations from ESMO and the “International Consensus Statement for the Prevention and Treatment of Venous Thromboembolism”, antithrombotic treatment with therapeutic doses of LWMH or direct oral anticoagulant (DOAC) must be initiated upon clinical suspicion of thrombosis without waiting for results of imaging tests. In this case the measurement of D-dimers is not relevant. If imaging tests confirm the diagnosis, antithrombotic treatment must be continued. Otherwise, it must be stopped. Subsequently, the patient needs to be assessed for the risk of CAT.
The data available to date show that administration of antithrombotic treatment with LMWH or apixaban, edoxaban, or rivaroxaban for at least 6 months decreases by about 60% the risk of VTE recurrence. Extension of antithrombotic treatment beyond 6 months is based on individualized evaluation of the benefit of the antithrombotic treatment and the risk of bleeding. According to ESMO recommendations, “Extended anticoagulation beyond the initial 6 months with LMWH, apixaban, edoxaban, rivaroxaban, or vitamin K antagonists (VKA) should be considered for patients with active cancer in whom the risk of recurrent thrombosis is higher and may outweigh that of bleeding” (Falanga A, et al. Ann Oncol. 2023;34:452-467). Regarding the dose of anticoagulants in cases of extensive treatment, personalized tailoring is the best strategy, taking into consideration the state of the cancer, type of anticancer treatments, the patient’s mobility, and coexisting risk factors. In this regard and with the aim of optimizing management of CAT, for over 10 years in our center we have set up a specific expert consultation with outpatients, called Consultation of Thrombosis in Oncology (CoThOn). In addition, in patients with CAT it is important to test for the presence of thrombophilia and particularly of antiphospholipid syndrome. Also, regular evaluation of platelet count and renal and liver function is necessary in order to estimate the related bleeding risk with thrombocytopenia, renal insufficiency, or liver dysfunction. Last but not least, the localization of cancer is a determinant for choice of the optimal anticoagulant. Indeed, available data from phase III clinical studies show that treatment with DOAC in patients with gastrointestinal cancer is associated with higher bleeding risk as compared with treatment with LMWH.
Should oncologists have sole responsibility for diagnosis and management of VTE, or is a multidisciplinary approach necessary?
This is a very pertinent question. Patients with cancer are not seen only by oncologists. They may visit general practitioners, in some countries more often than oncologists. Increasing oncologists’ awareness is crucial. According to ESMO, “most oncologists underestimate the prevalence of CAT and its negative impact on their patients” (Mandalà M, et al. Ann Oncol. 2011;22:vi85-vi92). Less than 40% of hospital trusts have a policy for managing VTE. Less than 30% of hospitalized patients with cancer receive recommended thromboprophylaxis during hospitalization, while the corresponding rates for hospitalized patients without cancer are higher than 50%. Less than 20% of outpatients with active cancer on anticancer treatment receive some kind of thromboprophylaxis. Less than 40% of patients with cancer are aware of the risk of CAT. Less than 30% of aware patients were informed of the risk of CAT by their treating physician. Less than 20% of the general public is aware of the risk of CAT.
General practitioners, who follow patients in daily life, must also be educated to use risk-assessment models and prescribe pharmacologic thromboprophylaxis to high-risk patients. Familiarization of general practitioners with the follow-up of patients who suffer from CAT and receive antithrombotic treatment with LMWH or DOAC is also required. Additionally, dedicated outpatient consultations for thrombosis in oncology, such as the paradigm of the CoThOn in Tenon/Saint Antoine University Hospital in Paris, are vital to help manage anticoagulant treatment, ensuring compatibility with cancer drugs and patient adherence. The third critical aspect is raising public awareness of CAT. Targeted education at the societal level can prompt patients to inquire about their thrombosis risk, leading to appropriate prophylactic measures. The level of health care system development and organization and particularly of primary health care services are determining factors for the prevention and treatment of CAT.
