Unprovoked venous thromboembolism: should we be looking for cancer?

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

A recent Cochrane Review 1 looking at venous thromboembolism (VTE) and its link to cancer revived 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 DVTs and, on further investigation, extensive metastatic cancer. A few weeks later he was dead.

Trousseau, who gave his name to this condition and later diagnosed it in himself. Credit: Wellcome Library, London

Trousseau, who gave his name to this condition and later diagnosed it in himself.
Credit: Wellcome Library, London

 What do we know already?

The association between 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 4. 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.

The scale of the problem

  • Risk of developing VTE in patients with cancer is 20-30% 5
  • Risk of undiagnosed cancer in a person with an unprovoked VTE (no obvious predisposing factor such as recent surgery or long-haul flight, immobility or family history of clots) is 10% 6
  • Poor prognosis in those with cancer and associated VTE, with 12% one year survival from date of VTE diagnosis 7
  • Threefold higher risk of recurrent VTE in patients with cancer 8

What is the optimum treatment for VTE in cancer patients?

The treatment of cancer-linked VTE is different to that for non-cancer-linked cases. For example, in the case of a cancer-linked DVT, Low Molecular Weight Heparin (LMWH) is given daily for at least six months, sometimes indefinitely. In a DVT not linked to cancer, warfarin is prescribed for three months after initial brief LMWH cover. Cancer patients are at higher risk of bleeding complications associated with vitamin K antagonists. Some studies have suggested that heparin and LMWH may have antitumour effects. A recent updated systematic review 9 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 a new Cochrane review, which looked at the effect of testing for occult cancer on cancer- and VTE-linked mortality and morbidity in this group.

Here’s what they 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 two randomised controlled trials (RCTs) in 2004 and 2012 with 396 participants. They looked at the effect of testing for occult cancer on cancer- and VTE -related mortality and morbidity in patients with a first episode of unprovoked VTE. A third RCT, not included, is ongoing and will be published later this year.

The screening undertaken in the trials was far more extensive than the 2012 NICE guideline 10 recommends, particularly in the 2004 study, where the list included endoscopy, barium swallow, tumour markers, ultrasound of prostate, PAP smear – to name but a few.

The results showed that those patients intensively screened were more likely to have a cancer diagnosis earlier (the time to cancer diagnosis was shorter in tested patients with a mean of one month versus eleven months) and were likely to be at a less advanced stage. Testing did not appear to have any effect on cancer-related deaths. Neither study addressed all-cause mortality, VTE-related mortality and morbidity, side-effects of testing or patient satisfaction.

What is the quality of this evidence?

Evidence from the 2004 study was of moderate quality. The later 2012 study was included as a conference abstract and therefore it was not possible to comment on its methodological detail. Numbers of studies and participants were small.

Where does this leave us?

Cancer is linked to a significant 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 can identify cancer earlier and at an earlier stage but there is insufficient evidence to assess whether it is effective in reducing cancer- and VTE- related mortality and morbidity. 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 RCTs are needed to shed light on the underlying uncertainties.

Links:

  1. Robertson L, Yeoh SE, Stansby G, Agarwal R. Effect of testing for cancer on cancer- and venous thromboembolism (VTE)-related mortality and morbidity in patients with unprovoked VTE. Cochrane Database of Systematic Reviews 2015, Issue 3. Art. No.: CD010837. DOI: 10.1002/14651858.CD010837.pub2.
  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. Falanga A, Zacharski L. Deep vein thrombosis in cancer: the scale of the problem and approaches to management. Annals of Oncology 2005: 16 (5): 696-701
  6. Piccioli et al. Extensive screening for occult malignant disease in idiopathic venous thromboembolism: a prospective randomised clinical trial. JTH, 2004;2(6):884
  7. Sorensen HT, Mellemkj’r L, Olsen JH et al. Prognosis of cancers associated with venous thromboembolism. N Engl J Med. 2000; 343: 1846-1850
  8. Levitan N, Dowlati A, Remick SC, et al. Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy. Med (Baltimore) 1999; 78: 285-291
  9. 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
  10. National Clinical Guideline Centre, National Institute for Health and Clinical Excellence (commissioner). Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing. London: National Clinical Guideline Centre, Royal College of Physicians; 2012. (NICE CG144). [Issued June 2012]. Available from: http://www.nice.org.uk/guidance/cg144/evidence/cg144-venous-thromboembolic-diseases-full-guideline3

 

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Lynda Ware

About Lynda Ware

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Lynda Ware is a Senior Fellow in General Practice with Cochrane UK. She retired from General Practice in September 2014, having been a partner in rural Oxfordshire for over 31 years. Lynda's particular interests are in women's health and psychological medicine.

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