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 associationA relationship between two characteristics, such that as one changes, the other changes in a predictable way. For example, statistics demonstrate that there is an association between smoking and lung cancer. In a positive association, one quantity increases as the other one increases (as with smoking and lung cancer). In a negative association, an increase in one quantity corresponds to a decrease in the other. Association does not necessarily mean that one thing causes the other. 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

RiskA way of expressing the chance of an event taking place, expressed as the number of events divided by the total number of observations or people. It can be stated as ‘the chance of falling were one in four’ (1/4 = 25%). This measure is good no matter the incidence of events i.e. common or infrequent. 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 treatmentSomething done with the aim of improving health or relieving suffering. For example, medicines, surgery, psychological and physical therapies, diet and exercise changes. 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 reviewCochrane Reviews are systematic reviews. In systematic reviews we search for and summarize studies that answer a specific research question (e.g. is paracetamol effective and safe for treating back pain?). The studies are identified, assessed, and summarized by using a systematic and predefined approach. They inform recommendations for healthcare and research., which looked at the effect of testing for occult cancer on cancer- and VTE-linked mortalitydeath and morbidityillness or harm 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 randomizedRandomization is the process of randomly dividing into groups the people taking part in a trial. One group (the intervention group) will be given the intervention being tested (for example a drug, surgery, or exercise) and compared with a group which does not receive the intervention (the control group). controlled trialsA trial in which a group (the ‘intervention group’) is given a intervention being tested (for example a drug, surgery, or exercise) is compared with a group which does not receive the intervention (the ‘control group’). (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 studyAn investigation of a healthcare problem. There are different types of studies used to answer research questions, for example randomised controlled trials or observational studies., 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.

Editor’s note: The Cochrane Review was updated in November 2018 (searches July 2018); no new studies were included or excluded.

Links:

Robertson L, Yeoh SE, Broderick C, Stansby G, Agarwal R. Effect of testing for cancer on cancer‐ or venous thromboembolism (VTE)‐related mortality and morbidity in people with unprovoked VTE. Cochrane Database of Systematic ReviewsIn systematic reviews we search for and summarize studies that answer a specific research question (e.g. is paracetamol effective and safe for treating back pain?). The studies are identified, assessed, and summarized by using a systematic and predefined approach. They inform recommendations for healthcare and research. 2018, Issue 11. Art. No.: CD010837. DOI: 10.1002/14651858.CD010837.pub4.
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
Trousseau A. Phlegmasia alba dolens. Clinique Medicale de l’Hotel-Dieu de Paris. 2nd ed. Paris, France: The Sydenham Society;1865. p. 654–712.
Lee AY, Levine MN. Venous thromboembolism and cancer: risks and outcomesOutcomes are measures of health (for example quality of life, pain, blood sugar levels) that can be used to assess the effectiveness and safety of a treatment or other intervention (for example a drug, surgery, or exercise). In research, the outcomes considered most important are ‘primary outcomes’ and those considered less important are ‘secondary outcomes’.. Circulation 2003:107
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
Piccioli et al. Extensive screening for occult malignant disease in idiopathic venous thromboembolism: a prospective randomised clinical trialClinical trials are research studies involving people who use healthcare services. They often compare a new or different treatment with the best treatment currently available. This is to test whether the new or different treatment is safe, effective and any better than what is currently used. No matter how promising a new treatment may appear during tests in a laboratory, it must go through clinical trials before its benefits and risks can really be known.. JTH, 2004;2(6):884
Sorensen HT, Mellemkj’r L, Olsen JH et al. Prognosis of cancers associated with venous thromboembolism. N Engl J Med. 2000; 343: 1846-1850
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
Sandford D, Naidu A, Alizadeh N, Lazo-Langer A. The effect of LMWH on survival in cancer patients: an updated systematic review and meta-analysisThe use of statistical techniques in a systematic review to combine the results of included studies. Sometimes misused as a synonym for systematic reviews, where the review includes a meta-analysis. of randomised trials. JTH 2014; 12 (7) 1076-1085
National Clinical GuidelineA systematically developed statement for practitioners and participants about appropriate health care for specific clinical circumstances. 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

Page last updated: 8 May 2019