The scientific community has shown increased awareness of cancer-associated thrombosis (CAT) over the past two decades. However, more must be done to educate the lay public and cancer patients about the risks, symptoms, and signs of venous thromboembolism (VTE).
We talked with Prof. Anna Falanga and Dr. Marina Marchetti about how CAT knowledge and awareness evolved in the last 20 years.
In the last 20 years, how has the medical community’s awareness of CAT changed? What were the biggest challenges, and how more is there to do?
20 years ago, solid scientific evidence was lacking in the field of CAT. Extensive epidemiological data did not exist, and studies were small with an unclear design. Much has changed since then because studies have been carried out clarifying the properties of tumor tissues to activate various components of the hemostatic system. We understood the molecular mechanisms by which tumor tissues activate coagulation and how coagulation increases tumor growth.
Important epidemiological studies have shown that patients with cancer have an increased risk of thrombosis. It has been understood that a venous thromboembolic event can affect survival and prognosis.
Also, we learned how challenging coagulation therapies are in patients with cancer and thrombosis because these patients are at higher risk of thrombotic complications, recurrence, and bleeding than non-oncological patients.
The knowledge we acquired in these past years led to the development of specific clinical trials for new therapies and has increased awareness in the scientific world. However, we must continue to produce new data and increase awareness among patients, the lay public, and healthcare professionals.
In recent years, we have seen an increase in incidental detection of VTE in cancer patients. Which benefits does this bring to the patients? How does incidental detection of VTE change the therapeutic journey of a cancer patient? And how does it change the communication with the patient?
We know that the incidence of VTE is significantly higher, by a factor of 7–11, in people with cancer compared to their counterparts without cancer. However, it can vary depending on several factors, including cancer status (active or nonactive), cancer site, disease stage (advanced or limited), concomitant cancer therapies, surgical procedures, and several patient-related risk factors. In addition, in 20% of cases, VTE events are associated with malignancy [1,2].
The incidence of VTE in cancer patients has changed over time due to several factors that influence thrombosis risk, but also due to the advances in VTE diagnosis, which have led to an increase in the incidental detection of asymptomatic PE and/or deep vein thrombosis [3].
From the patient’s point of view, a diagnosis of VTE, whether incidental or symptomatic, always has an important impact with great psychological implications. It represents a further complication, which might increase, modify, or even interrupt cancer therapies, generating distress and anxiety.
Although, detecting silent thromboses is important because they carry the same risks of complications and recurrences as symptomatic thrombosis. Diagnosing incidental VTE allows the patient to start the correct treatment as soon as possible.
The increase in incidental detection of VTE further highlights the importance of informing patients of the possibility of thrombotic complications before starting cancer treatment.
Recent patient surveys indicate a lack of awareness and education regarding CAT, including recognizing the appropriate signs and symptoms [4]. In addition, another study highlighted the importance of educating cancer patients with asymptomatic VTE about the dangers of CAT or recurrent events. In fact, people with cancer and asymptomatic VTE are prone to the risk of thrombosis, not seeing it as a threat to their health [5].
In these 20 years, in your opinion, what was the most important achievement in cancer-associated thrombosis?
One of the most important discoveries was the link between cancer and thrombosis, in particular, that the oncogenes responsible for the neoplastic cell transformation are also responsible for inducing procoagulant factors. Unveiling this mechanism opened the prospect of new cancer therapies that target the hemostatic coagulative system.
Regarding VTE prophylaxis in cancer patients, what did we learn, and what do we still need to define?
We have learned that thrombotic risk is highly variable, with some patients having a high risk and others having a low risk. Therefore, prophylaxis must be targeted, and it is important to define the right population to balance the risks and benefits.
Thromboprophylaxis is required under certain conditions, such as surgery, hospitalization for acute medical illness, and administration of antitumor therapy in the outpatient setting.
Surgery in cancer patients
Prophylaxis with low-molecular-weight heparins (LMWHs) or unfractionated heparin (UFH) should be given for at least 7–10 days after major surgical procedures. However, it is recommended that prophylaxis be extended to up to 4 weeks in patients undergoing major open or laparoscopic abdominal or pelvic surgery. LMWHs are preferred for this purpose, and the highest prophylactic dose of each heparin is recommended. In addition, direct oral anticoagulants (DOACs) are currently being evaluated for extended surgical prophylaxis in this setting [1,6].
Hospitalization
When a cancer patient is hospitalized for acute illness, prophylactic doses of LMWHs should be considered to prevent VTE. This recommendation is supported by the results of three large randomized controlled trials (RCTs), two of which examined the efficacy and safety of enoxaparin or dalteparin, whereas the other tested fondaparinux. Although these trials included a proportion of cancer patients, the evidence for the use of DOACs in this setting is still insufficient. Currently, DOACs are not recommended because efficacy is outweighed by the increased risk of bleeding, as shown by RCTs conducted in the general population of acutely ill patients [1, 7].
Outpatient cancer patients starting systemic cancer therapy
In outpatient cancer patients starting systemic cancer therapy, the risk of VTE is high, but guidelines do not recommend routine thromboprophylaxis for all patients. This is because the potential harms of anticoagulant medications may outweigh the benefits, especially in low-risk patients who may experience bleeding. However, recent studies have shown that thromboprophylaxis with LMWH or DOACs can be effective and safe in moderate- to high-risk patients [8]. The Khorana risk score is commonly used to determine patients’ risk levels, and the main guidelines recommend thromboprophylaxis for patients at high risk of VTE. The choice of thromboprophylaxis should be based on the patient’s risk level for thrombosis and bleeding, as well as clinical judgment and preference [1].
Treatment of VTE
Treatment of VTE can be divided into three phases: acute, long term, and extended. Large RCTs have tested specific protocols for acute VTE treatment, leading to the development of treatment regimens ranging from UFH, LMWH, or fondaparinux followed by VKA, to weight-adjusted doses of LMWHs, to DOACs versus FXa for long-term therapy [1]. Current guidelines recommend DOACs (edoxaban, rivaroxaban, or apixaban) or LMWHs, with VKAs approved as an alternative. When choosing between DOACs and LMWH, factors such as bleeding risk, type of cancer, and potential drug interactions should be considered. However, there are still unmet needs in this area, and research to develop drugs with minimal bleeding risk is ongoing [1].
The best modalities and safety of extending treatment beyond six months have not yet been established in these patients.
What are the main unmet needs in CAT treatment?
The high bleeding risk in cancer patients is a big challenge. For this reason, we are looking for new classes of drugs, such as factor XI, that target the intrinsic coagulation pathway and might carry fewer bleeding risks and complications. But we need to clarify if they are also effective in reducing the risk of thrombosis.
Also, much has been done, but even more about biomarkers and risk assessment models for VTE needs to be discovered.
Even without obvious thrombosis, many cancer patients experience a subclinical hypercoagulable state with hemostatic laboratory abnormalities. Fortunately, the advent of sensitive assays has allowed the detection of circulating biomarkers of coagulation activation, allowing biochemical characterization of this condition [1].
Research on biomarkers in cancer patients has shown that hemostatic abnormalities can vary across cancer types and worsen with cancer progression, suggesting a link between blood coagulation activation and tumor burden. However, determining the clinical significance of measuring these biomarkers requires further investigation [1,9].
Several studies have examined the potential utility of these biomarkers for diagnosing or predicting VTE in cancer patients [10]. There is evidence that microRNAs may be a promising new predictive marker for CAT [11].
Risk assessment models (RAMs) play an important role in identifying outpatients with cancer at high risk of VTE. However, assessing thrombosis risk is challenging because of the complexity of the interactions and effects of multiple demographic, cancer-associated, and treatment-associated risk factors [1].
The Khorana risk score (KRS) was a pioneering development in this field, validated in several prospective and retrospective studies. Based on the KRS, other RAMs have been developed to improve the prediction of CAT. Two of these RAMs, the COMPASS-CAT and the New-Vienna CATs nomogram, have been externally validated and are included in the recent ESMO guidelines for VTE prophylaxis and treatment in cancer patients [1].
In addition, specific disease-specific RAMs have been developed for hematologic malignancies, such as the IMPEDE-VTE and SAVED scores for patients with multiple myeloma and the ThroLy score for patients with lymphoma. Including biomarkers in these RAMs could further improve their accuracy in identifying patients at high risk for VTE [1].
Notably, hemostatic biomarkers are also being studied for their potential to predict cancer outcomes, including recurrence, progression, and mortality, with encouraging results.
Both arterial thromboembolism and VTE significantly impact cancer patient morbidity and mortality. They can lead to serious complications such as hospitalization, treatment interruption, a higher risk of thrombosis recurrence, and bleeding during antithrombotic therapies. Therefore, primary and secondary prevention of these events is of great importance [1].
References
- Falanga A, Marchetti M. Cancer-associated thrombosis: enhanced awareness and pathophysiologic complexity. J Thromb Haemost. 2023. doi:10.1016/j.jtha.2023.02.029. Epub ahead of print.
- Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost. 2007;5:632–4.
- Walker AJ, Card TR, West J, Crooks C, Grainge MJ. Incidence of venous thromboembolism in patients with cancer – a cohort study using linked United Kingdom databases. Eur J Cancer. 2013;49: 1404–13.
- Noble S, Prout H, Nelson A. Patients’ Experiences of LIving with CANcer-associated thrombosis: the PELICAN study. Patient Prefer Adherence. 2015;9:337–45.
- Nouhravesh N, Sindet-Pedersen C, Kümler T, Schou M, Lamberts MK, Højen AA. “No one told me anything about it and I cannot explain it”: Illness perception in symptomatic and asymptomatic patients with cancer-associated thrombosis. Thromb Res. 2022;220:125-130. doi:10.1016/j.thromres.2022.10.013
- Becattini C, Pace U, Pirozzi F, et al. Rivaroxaban vs placebo for extended antithrombotic prophylaxis after laparoscopic surgery for colorectal cancer. Blood. 2022;140(8):900-908. doi:10.1182/blood.2022015796
- Falanga A, Ay C, Di Nisio M, et al. Venous thromboembolism in cancer patients: ESMO Clinical Practice Guideline. Ann Oncol. 2023. doi:10.1016/j.annonc.2022.12.014. Epub ahead of print.
- Bosch FTM, Mulder FI, Kamphuisen PW, et al. Primary thromboprophylaxis in ambulatory cancer patients with a high Khorana score: a systematic review and meta-analysis. Blood Adv. 2020;4(20):5215-5225. doi:10.1182/bloodadvances.2020003115
- Rickles FR, Falanga A. Activation of clotting factors in cancer. Cancer Treat Res. 2009;148:31-41. doi:10.1007/978-0-387-79962-9_3
- Ay C, Pabinger I, Cohen AT. Cancer-associated venous thromboembolism: Burden, mechanisms, and management. Thromb Haemost. 2017;117(2):219-230. doi:10.1160/TH16-08-0615
- Anijs RJS, Nguyen YN, Cannegieter SC, Versteeg HH, Buijs JT. MicroRNAs as prognostic biomarkers for (cancer-associated) venous thromboembolism. J Thromb Haemost. 2023;21(1):7-17. doi:10.1016/j.jtha.2022.09.001