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Expert Comment: Normalising cancer-associated thrombosis

In this Expert Comment, Professor Simon Noble discusses the importance of normalising cancer-associated thrombosis (CAT) among cancer patients and the steps pharmacists can take to avoid patient distress

The first time I became aware of the association between cancer and thrombosis was as a junior doctor, when I admitted a patient who had developed atrial fibrillation caused by a pulmonary embolism (PE). I noticed that the patient had painless jaundice – a tell-tale sign of pancreatic cancer, which a scan confirmed. 

As I went on to do some oncology and palliative care, I realised that cancer associated thrombosis (CAT) was a massive problem in our population that was not being managed properly. Even today, 20 years later, there is still significant work to do in raising awareness of the condition. 

With this in mind, there are two main areas I want to discuss in this piece:

  • The first is the crucial role that pharmacists can play in increasing cancer patients’ awareness of thrombosis. Pharmacists have an integral role in the administration of anti-cancer therapies and information giving ahead of cancer treatment. This is the best time to share additional information about the risk and symptoms of thrombosis. 
  • The second is to ensure the safe prescribing of anticoagulants for patients who have been diagnosed with CAT. That is, giving information on how specific drugs should be taken and ensuring that there are no significant drug–drug interactions with anti-cancer therapies.

The risk of CAT for cancer patients

Thrombosis is the second leading cause of death in cancer patients, second only to cancer progression.1 Cancer patients are at very high risk of developing thrombosis for several reasons. 

First, the tumours themselves secrete procoagulants, which makes the blood stickier. However, different cancers have different thrombotic effects. For instance, pancreatic cancer, primary brain cancer, and lung cancer can increase the risk of thrombosis twentyfold.2 Other cancers, such as breast cancer and prostate cancer, are less thrombotic but we see more of these patients with clots because these are such common cancers. 

Disease progression is another factor which makes the cancer patient at greater risk of thrombosis. Patients with metastatic disease will have a twentyfold increase in risk of developing CAT compared to someone with early-stage cancer.3 

We also have the impact of systemic anti-cancer therapies (SACT). Chemotherapies, targeted therapies, immunotherapies, and all the newer agents increase the risk of CAT.

The pharmacy community has an integral role in the management of CAT, starting with the patient who is receiving systemic treatments

A patient’s risk of developing a blood clot with stage one breast cancer is 0.2% – only double the risk of a healthy person developing a clot. However, if you give that breast cancer patient adjuvant chemotherapy, which we commonly do, that risk increases tenfold to 2%.4 Around 55,000 women and 370 men are diagnosed with breast cancer every year in the UK, so that is a lot of clots.5 

A period of immobility, dehydration or an infection can increase the thrombotic risk further. This leaves us with a patient with an underlying high risk of cancer and any illness can tip them over the threshold until they develop a clot.

The evidence for prevention of clots

Despite the prevalence of CAT, the evidence for prevention of clots in ambulant cancer patients receiving SACT is unclear. There are certain cancers known to be so thrombotic when treated that we should be giving prophylaxis. For example, haematologists will routinely give primary thromboprophylaxis to patients with myeloma receiving lenalidomide and steroids, because we know up to 25% of these patients would get a clot otherwise.6 There are also strong data to recommend the use of primary thromboprophylaxis in pancreatic cancer patients receiving chemotherapy. However, despite it being in the National Institute for Health and Care Excellence (NICE) guidelines, the uptake of this in clinical practice in the UK is still poor.

In terms of risk assessment tools, the Khorana Score can tell us which patients are at higher risk of venous thromboembolism (VTE). It assesses patients according to primary cancer, platelet count, haemoglobin, and BMI. However, when used in isolation, the numbers needed to treat, in order to prevent one clot, are too high to justify applying it to routine practice. There are some data that suggest it can be used to target those at greatest risk.

Where does this leave us practically?

This leaves us with cancer patients who are at high risk of developing clots during chemotherapy, but with no robust system for identifying those at greatest risk and who should have primary prophylaxis. 

If we are unable to prevent clots, we must increase patient awareness of clots. This means that when a cancer patient develops red flag symptoms of a clot, they are empowered to seek help immediately. 

Increasing patient awareness of clots

It makes sense to increase patient awareness of clots; the problem is, currently, we are not.

In my clinical practice, 60% of patients will have had their clot precipitated by chemotherapy or other SACT. When I speak to them, they can tell me what to do if they were to suffer any of the symptoms of sepsis because we have raised awareness of the signs to look out for. But we are not doing that for clots, patients are not aware of the risk of clots in the same way. 

This means that cancer patients are diagnosed with a deep vein thrombosis (DVT) or PE in a rushed and distressing way. Patients are either so ill they get administered to hospital, or they mention their swollen leg, for example, in passing and are hurried to a scan. Saddeningly, patients often say that their experience of being diagnosed with a clot was more distressing than their experience of being diagnosed with cancer in the first place. 

Thrombosis is a normal part of the cancer journey, and it should be treated that way. One in five cancer patients will develop a clot.7 We need to relay this message to our patients; instead of talking about cancer associated thrombosis being a complication of cancer, we need to say to patients that developing a clot is quite normal. 

The sooner a patient seeks help, the sooner they can get diagnosed, and faster diagnosis reduces the long-term impact of thrombosis. For me, the ultimate reason we should all be supporting earlier detection is patient quality of life.

Up to 40% of patients will develop post-thrombotic syndrome.8 Symptoms of this include chronic swelling of the legs, pain, and ulceration. Essentially, we are left with a patient whose life we have saved by treating their cancer, but they are not the person they used to be physically because of the subsequent impact of CAT.

Ensuring safe prescribing of anticoagulants

The next step is ensuring safe prescribing of anticoagulants to avoid further patient distress.

There are two main choices of anticoagulants that we use for CAT: low-molecular-weight heparin (LMWH) and direct acting oral anticoagulants (DOACs). For the last 15 years, we have been using LMWH, which is an injectable given subcutaneously. We encourage patients to inject themselves or have a carer do it for them. However, we can help improve their injection technique. 

The patient information leaflet suggests that the drug should be injected an inch below the belly button. However, with prolonged use, this area will get bruised and painful. The truth is, patients can inject wherever there is fat, right round to the ‘love handles’, and can rotate sites. 

We also need to warn patients that a bruise might heal with scar tissue under the skin, and that they may develop fibrosis and feel a lump. Unless we do so, cancer patients may fear they have developed secondary tumours under the skin. We should then be warning patients not to inject into that lump because it will hurt. 

These pieces of education given when the drugs are administered will improve technique and compliance, but they will also prevent avoidable distress for patients. 

More commonly now, DOACs are the first choice in the treatment of CAT. The pharmacy community has a real role here in protecting overzealous prescribers from giving DOACs indiscriminately. They are effective and they are safe in cancer patients, but they come with caveats. 

If a DOAC is given to someone with primary oesophageal cancer, and the tumour is still there, there is a 13% major haemorrhage risk.9 Similarly, 8% of patients with urothelial cancer or bladder cancer will develop haematuria.10 We should also avoid giving DOACs to patients with a high bleeding risk. 

We also need to be aware of significant drug–drug interactions. Although we are still finding our feet with this, we know that many chemotherapies and many of the new SACT will have interactions with P-glycoprotein and CYP3A4. If you have strong inhibitors or strong inducers of those drugs, there will be an interaction. 

Finally, remember that a patient’s disease changes. You might need to change the drug or the anticoagulant over the course of the patient’s cancer journey. 

Final thoughts

The pharmacy community has an integral role in the management of the patient with CAT. This starts with managing the cancer patient who is receiving systemic treatments. 

It is vital that we raise awareness of the condition among cancer patients and ensure that we are prescribing anticoagulants safely, reviewing their drug options frequently.

References

  1. Fernandes Caio J et al. Cancer-Associated Thrombosis: The When, How And Why. Eur Respir Rev 2019;28(151):180119. 
  2. Dallos MC, Eisenberger AB, Bates SE. Prevention of Venous Thromboembolism in Pancreatic Cancer: Breaking Down a Complex Clinical Dilemma. Oncologist 2020;25(2):132–9.
  3. Noble S, Pasi J. Epidemiology and pathophysiology of cancer-associated thrombosis. Br J Cancer 2010;102:S2–S9.
  4. Kirwan CC et al. Incidence of venous thromboembolism during chemotherapy for breast cancer: impact on cancer outcome. Anticancer Res 2011;31(6):2383–8. 
  5. Breast Cancer Now. Breast cancer statistics and facts. https://breastcancernow.org/about-us/media/facts-statistics (accessed July 2022).
  6. Chakraborty R et al. Venous Thromboembolism Risk With Contemporary Lenalidomide Based Regimens Despite Thromboprophylaxis In Multiple Myeloma: A Systematic Review And Meta Analysis. Cancer 2020;126(8):1640–50. 
  7. Hull University Teaching Hospitals NHS Trust. Cancer-Associated Thrombosis. www.hey.nhs.uk/patient-leaflet/cancer-associated-thrombosis/ (accessed July 2022).
  8. Cosmi B et al. The Post-thrombotic Syndrome-Prevention and Treatment: VAS-European Independent Foundation in Angiology/Vascular Medicine Position Paper. Front Cardiovasc Med 2022;9:762443. 
  9. Al-Samkari H, Connors JM. The Role of Direct Oral Anticoagulants in Treatment of Cancer-Associated Thrombosis. Cancers (Basel) 2018;10(8):271. 
  10. Ording AG et al. Hematuria in anticoagulated patients with atrial fibrillation and urologic cancer. Res Pract Thromb Haemost 2022;6(1):e12629. 





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