Unprovoked venous thromboembolism: should we be looking for cancer?

In this guest blog, retired GP, Lynda Ware, looks at evidence for the management of an unprovoked venous thromboembolism, asking what are the benefits of intensive screening to look for an undiagnosed cancer?

Page originally published: 24 March 2015. Blog revised and republished: October 2021, to include updated evidence.

Page checked 12 July 2023

Take-home points

Venous thromboembolism (VTE) refers to blood clots in leg veins (known as deep venous thrombosis) which can travel to the lungs. Sometimes a VTE happens for no apparent reason (it is ‘unprovoked’). In a small proportion of cases, a VTE may be caused by undetected cancer. A Cochrane Review (published October 2021) explored the potential benefits and harms of testing for cancer in people with unprovoked blood clots in the legs and lungs. The results suggests that: Testing may lead to earlier diagnosis of cancer, at an earlier stage of the disease. However, it is uncertain whether testing helps reduce cancer‐ and VTE‐related deaths or illness.  It is also unclear which screening tests may be most useful.

I have vivid memories of a young man, who presented to me in surgery with bilateral calf pain. He had been on holiday in the Channel Islands and had developed painful calves. He had visited a local GP twice, who thought his discomfort was muscular, caused by long walks on rocky beaches. The tragic truth was that he had bilateral deep vein thrombosis (DVT) and, on further investigation, extensive metastatic cancer. A few weeks later he was dead.

I think of him when reading a Cochrane Review looking at venous thromboembolism (VTE) and its link to cancer: Effect of testing for cancer on cancer- or venous thromboembolism (VTE)-related mortality and morbidity in people with unprovoked VTE (updated October 2021).1

Arman
Armand highlighted the link between VTE and cancer. He died in 1867 of the very condition he had identified two years earlier.

What do we know already?

The association between VTE and cancer was first described in 1823 by Jean Baptiste Bouillaud 2. In 1865 Armand Trousseau highlighted the association again, lending his name to the condition – Trousseau Syndrome 3. Sadly, Armand died in 1867 of the very condition he had identified two years earlier.

The most common cancers associated with VTE are prostate, colon, lung and brain in men and breast, lung and ovary in women. The commonest thromboembolic events are DVT and pulmonary embolus but they can also develop in less common sites such as arm or neck veins, the vena cavae or the visceral, portal or cerebral circulation 4.

What is the optimum treatment for VTE in cancer patients?

In the case of a cancer-linked DVT, NICE recommends offering anticoagulation treatment for 3 to 6 months, sometimes longer. Choice of anticoagulation treatment for people with active cancer and confirmed proximal DVT or PE, “should take into account the tumour site, interactions with other drugs including those used to treat cancer, and the person’s bleeding risk”.6

Cancer patients are at higher risk of bleeding complications associated with vitamin K antagonists. Some studies have suggested that heparin and low-molecular-weight heparin (LMWH) may have antitumour effects. A systematic review 5 did not confirm this in patients with late-stage disease. The effect of LMWH on overall survival in patients with limited-stage disease is unknown.

Should we look for cancer in someone with a first episode of unprovoked VTE?

This has been addressed by the Cochrane Review Effect of testing for cancer on cancer- or venous thromboembolism (VTE)-related mortality and morbidity in people with unprovoked VTE. The review asked, “does testing for cancer in people with unprovoked blood clots in the legs and lungs reduce cancer- and blood clot-related death and illness?”

Here’s what the authors found:

We don't know the effect of screening on morbidity, mortality or patient satisfaction. Credit: Wellcome Images
We don’t know whether screening reduces morbidity or mortality, nor which screening tests are most useful.
Credit: Wellcome Images

The review includes four studies with 1644 participants. Two studies compared extensive cancer tests with tests carried out at the physician’s discretion and two studies compared cancer tests plus scanning with cancer tests alone.

The screening undertaken in the trials was far more extensive than the 2020 NICE guideline recommends6, particularly in the one of the studies, where the list included endoscopy, barium swallow, tumour markers, ultrasound of prostate, PAP smear – to name but a few.

The results suggest that:

  • those patients intensively screened may be more likely to have a cancer diagnosis earlier, at an earlier stage of the disease. The time to cancer diagnosis was shorter in tested patients with a mean of one month versus eleven months.
  • However, there is currently insufficient evidence to say whether screening undiagnosed cancer has an impact on cancer- or VTE-related illness or deaths. There is also not enough information about possible side effects of testing or patient satisfaction.

What is the quality of this evidence?

When comparing extensive tests versus tests at the physician’s discretion, the certainty of the evidence was low. There was bias caused by two of the studies stopping early.

When comparing tests plus PET/CT scanning with tests alone, the certainty of the evidence ranged from low to moderate. There were issues with how the studies were designed, imprecision caused by a low number of events, and bias due to lack of blinding of people assessing the effects.

Where does this leave us?

Cancer is linked to a significantly increased risk of VTE and an unprovoked episode of venous thromboembolism is associated with a 10% risk of having cancer.

Intensive screening after an episode of unprovoked VTE may identify cancer earlier and at an earlier stage. However, there is insufficient evidence to assess whether it is effective in reducing cancer- and VTE- related deaths and illness. It is also unclear which screening tests are most useful.

There are important implications for patients and clinicians in earlier cancer diagnosis and the tailored treatment of cancer-related VTE. Further large, well-designed trials are needed to shed light on the underlying uncertainties.

Links:

  1. Robertson L, Broderick C, Yeoh SE, Stansby G. Effect of testing for cancer on cancer- or venous thromboembolism (VTE)-related mortality and morbidity in people with unprovoked VTE. Cochrane Database of Systematic Reviews 2021, Issue 10. Art. No.: CD010837. DOI: 10.1002/14651858.CD010837.pub5.
  2. Bouillard JB, Bouillaud S. De l’Obliteration des veines et de son influence sur la formation des hydropisies partielles: consideration sur la hydropisies passive et general. Archives Générales de Médecine 1823;1(2):188–204. Available from: http://babel.hathitrust.org/cgi/pt?id=mdp.39015062233641;view=1up;seq=194
  3. Trousseau A. Phlegmasia alba dolens. Clinique Medicale de l’Hotel-Dieu de Paris. 2nd ed. Paris, France: The Sydenham Society;1865. p. 654–712.
  4. Lee AY, Levine MN. Venous thromboembolism and cancer: risks and outcomes. Circulation 2003:107
  5. Sandford D, Naidu A, Alizadeh N, Lazo-Langer A. The effect of LMWH on survival in cancer patients: an updated systematic review and meta-analysis of randomised trials. JTH 2014; 12 (7) 1076-1085
  6. National Institute for Health and Clinical Excellence. Venous thromboembolic diseases: diagnosis, management and thrombophilia testing. London: National Institute for Health and Clinical Excellence; 2020. (NICE NG 158). [Issued March 2020].


Unprovoked venous thromboembolism: should we be looking for cancer? by Lynda Ware

is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International

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