Professor Pabinger is a hematologist at the University of Vienna, where she studies cancer and thrombosis. During the 10th ICTHIC, she gave an inspiring talk about risk prediction for cancer-associated thrombosis in ambulatory patients. We had the opportunity to meet with her and discuss this topic.
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“We don’t see thrombosis in our cancer patients.”
In 2002, when Prof. Pabinger started working on thrombosis in cancer patients, the head of the oncology unit told her they did not see thrombosis in their cancer patients.
Almost 20 years later, in 2020, Martin et al. performed a survey among oncology clinicians to assess current practice patterns surrounding venous thromboembolism (VTE) .
Of the 24 participants who responded to the survey, 38% reported “usually” discussing VTE risk with their patients, while 29% each reported “sometimes” and “rarely” discussing VTE risk. A total of 58% reported “never” using validated VTE risk assessment scores in clinical practice, and only one (4%, generalist) reported “usually” doing so.
Most clinicians reported no or scarce familiarity with the Khorana score (67% “not at all” familiar, 17% “a little bit,” familiar, and 13% “somewhat” familiar). Only 4% stated to be “quite a bit” familiar with the Khorana score. Similarly, 67% reported no familiarity, and only 4% reported “quite a bit” of familiarity with the International Society on Thrombosis and Haemostasis (ISTH) recommendations .
“It is like playing bubble soccer,” says Prof. Pabinger, “the thrombosis community is in one bubble, and the oncologist is in another one; we don’t understand each other.”
The relative risk of arterial and venous thromboembolism in cancer patients
We know that the relative risk of arterial thromboembolism (ATE) and VTE in a person with cancer and without cancer is different. In a recent study, persons with a cancer diagnosis were seven-times more likely to have a diagnosis of ATE and 15-times more likely to have a diagnosis of VTE than people without cancer .
We also know that there are factors that can modulate the risk of VTE in people with cancer.
“The major risk factor for thrombosis in patients with cancer is the site of the tumor. There are differences between tumor sites and types”, says Prof. Pabinger, “The higher risk is in patients with a pancreatic tumor, and the lower risk is in patients with breast cancer, prostate, and skin cancer. In the middle are all the other types of cancers.”
Another factor is the stage of cancer. “The earliest stage has a lower risk, but late and advanced stages have a high risk, which reaches 25–30% for the more advanced. Other risk factors that can contribute are age and sex, even though we cannot identify them as risk factors.”
According to age, the relative risk of ATE and VTE increases dramatically in younger age and is higher in adolescent and young adults. It seems that no differences in risk between men and women exist instead .
Predicting factors for cancer-related VTE risk
Cancer treatments can increase the risk of thrombosis . Certain chemotherapy agents (gemcitabine, platinum-based agents) were suggested to increase the risk of VTE in cancer patients [3, 4].
A study evaluated whether treatments with these agents can be used to better predict the risk of cancer-associated VTE . Results show that treatment with gemcitabine and/or platinum-based agents have a limited predicting capability for the risk of VTE beyond known risk factors included in an established risk prediction model (such as tumor type and blood levels of D-dimer).
The univariable analyses confirmed a relative increase in the risk of VTE with platinum-based therapy and gemcitabine. Still, the multivariable analysis, comprising the tumor type and D-dimer, found an attenuated association .
The high burden of VTE in patients treated with platinum agents or gemcitabine may be the result of a correlation and not a causation. For example, gemcitabine is the main treatment for pancreatic cancer, and platinum-based agents are the standard treatments for gastric cancer, which are both tumors highly associated with VTE risk .
Another study investigated the frequency, potential risk factors, and clinical consequences of VTE and ATE in patients treated with immune checkpoint inhibitors . In this retrospective cohort study comprising 672 patients mostly with low VTE risk cancers (below 5%), the cumulative incidence of VTE was 12.9% in patients treated with checkpoint inhibitors .
“The risk of VTE was unexpectedly high, close to 13%, in that low-risk site population; so immune checkpoint is a new treatment-related risk factor for VTE,” said Prof. Pabinger.
The study also explored the association of clinical risk factors for VTE with immune checkpoint “analyzing which aspects could help identify the high risk; the study found that only history of VTE is a predictive factor. Even the Khorana score would not be helpful in that specific setting” concluded Prof. Pabinger.
The risk models
The Khorana score was first published in 2008 , and after that, many other models have been developed based on it: Vienna, ONKOTEV, COMPASS-CAT, Tic-ONCO, Pabinger et al. 2018, IMPEDE and SAVED .
“I would like to focus on the score that we published in 2018,” said Prof. Pabinger, “we borrowed the tumor site category from the Khorana, making few adjustments, and we added the D-dimer. This model showed an improvement of 30% compared to the Khorana score ,” Said Prof. Pabinger.
The Khorana score can be defined as the mother of all the risk scores for VTE, but it has some limitations to overcome, which many other scores have been implemented.
“Other scores tried to improve the Khorana one by adding additional variables, such as treatment or molecular genetic parameters. This led to some improvement but could also make it not easy to gather genetic parameters,” commented Prof. Pabinger.
“Over time, the aspects and treatments of patients change; so, it might be the case that a risk score developed 20 years ago, such as the Khorana’s one, is not good for recent therapies like checkpoint inhibitors. It is a continuous struggle to improve and adapt the risk score to current therapies.”
We now know that many biomarkers can help the prediction of VTE, such as blood count analysis with hemoglobin or white cell count. However, the biomarker that showed to be the most predictive one is the D-dimer . “D dimer is the best to improve a prediction of a score. It is predictive in many tumor sites. It is available worldwide because we use it in the diagnosis of VTE events and is well validated from the laboratory site,” said Prof. Pabinger.
Expand thrombosis awareness
In the last 20 years, we have learned a lot about thrombosis prophylaxis in cancer patients. We learned the risk factors, we developed risk assessments that have also been validated, we have many randomized trials available, we developed guidelines. For these reasons, we might think that the 2002 statement “we don’t see thrombosis in our cancer patients” is completely outdated.
Still, a gap exists. Martin’s publication in 2020 showed that almost 70% of oncologist specialists do not have any idea about the Khorana score . “This came as a surprise but indicates that we have to educate and raise awareness. The thrombosis hemostasis specialists know about thrombosis risk assessment and risk, and that thrombosis is frequent and has a large impact on quality of life,” said Prof. Pabinger.
“If we use models, we should try to make it very easy and globally available, so that can be spread through the internet. It is possible to predict the VTE, and the patients can decide with us if to implement some thrombosis prophylaxis. It is important to know the individual risk and to inform the patients.”
So how can we raise awareness among oncologists?
“We can raise awareness among oncologists by sharing information with them, catching especially those that are not interested or do not have real knowledge. We can approach them and include them in the awareness efforts,” answered Prof. Pabinger.
However, raising awareness among oncologists is not all. Direct oral anticoagulants (DOACs) are not yet approved as a strategy for primary thromboprophylaxis in cancer patients. Two recent trials investigated the use of DOACs to prevent venous thromboembolism in high-risk ambulatory patients with cancer, with risk defined by the Khorana score. DOACs showed a significant benefit in preventing venous thromboembolism, with a low incidence of major bleeding [10, 11].
“It is not easy to give DOACs off-label to prevent possible complications. We need pharmaceutical industries and agencies to approve the medication, so we can prevent VTE in patients with cancer,” concluded Prof. Pabinger.
1. Martin KA, Molsberry R, Khan SS, Linder JA, Cameron KA, Benson A 3rd. Preventing venous thromboembolism in oncology practice: Use of risk assessment and anticoagulation prophylaxis. Res Pract Thromb Haemost. 2020;4(7):1211-1215.
2. Ella Grilz, Florian Posch, Stephan Nopp, Oliver Königsbrügge, Irene M Lang, Peter Klimek, Stefan Thurner, Ingrid Pabinger, Cihan Ay, Relative risk of arterial and venous thromboembolism in persons with cancer vs. persons without cancer—a nationwide analysis. European Heart Journal, 2021; ehab171
3. Abdol Razak NB, Jones G, Bhandari M, Berndt MC, Metharom P. Cancer-associated thrombosis: an overview of mechanisms, risk factors, and treatment. Cancers (Basel). 2018;10(10):380.
4. Moik F, van Es N, Posch F, et al. Gemcitabine and platinum-based agents for the prediction of cancer-associated venous thromboembolism: results from the Vienna Cancer and Thrombosis Study. Cancers (Basel). 2020;12(9):2493.
5. Moik F, Chan WE, Wiedemann S, et al. Incidence, risk factors, and outcomes of venous and arterial thromboembolism in immune checkpoint inhibitor therapy. Blood. 2021;137(12):1669-1678.
6. Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood. 2008;111(10):4902-4907.
7. Khorana AA, DeSancho MT, Liebman H, Rosovsky R, Connors JM, Zwicker J. Prediction and prevention of cancer-associated thromboembolism. Oncologist. 2021;26(1):e2-e7.
8. Pabinger I, van Es N, Heinze G, et al. A clinical prediction model for cancer-associated venous thromboembolism: a development and validation study in two independent prospective cohorts. Lancet Haematol. 2018;5(7):e289-e298.
9. Schorling RM, Pfrepper C, Golombek T, et al. Evaluation of biomarkers for the prediction of venous thromboembolism in ambulatory cancer patients. Oncol Res Treat. 2020;43(9):414-427.
10. Khorana AA, Soff GA, Kakkar AK, et al. Rivaroxaban for thromboprophylaxis in high-risk ambulatory patients with cancer. N Engl J Med. 2019;380(8):720-728.
11. Carrier M, Abou-Nassar K, Mallick R, et al. Apixaban to prevent venous thromboembolism in patients with cancer. N Engl J Med. 2019;380(8):711-719.