Venous Thromboembolism and Cancer

Abstract & Commentary

By Harold L. Karpman, MD, FACC, FACP, Clinical Professor of Medicine, UCLA School of Medicine. Dr. Karpman reports no financial relationship to this field of study.

Synopsis: Previously undiagnosed cancer is frequent in patients with an unprovoked VTE and is more often detected with an extensive cancer screening strategy than with a limited screening strategy.

Source: Carrier M, et al. Systematic review: The Trousseau syndrome revisited: Should we screen extensively for cancer in patients with venous thromboembolism? Ann Intern Med 2008;149:323-333.

In 1865, Armand Trousseau described the association between venous thrombophlebitis (VTE) and cancer by noting, "The diagnosis in a patient with gastric pain and leg or arm phlegmasia alba dolens is the presence of cancer."1 Two years later, after suffering weeks of abdominal pain, he died of gastric cancer shortly after he declared to one of his students, "I'm lost. A thrombosis developed overnight, which doesn't leave me any doubt of the nature of my disease."1

Over the ensuing years, multiple studies have revealed that VTE manifested as deep venous thrombosis and/or pulmonary embolism can be the first manifestation of cancer.2-5 Of course, identifying a previously undiagnosed cancer in patients with VTE is important because the cancer may be curable if detected early or, if detected when no longer curable, early treatment may still prevent cancer-associated morbidity such as pathologic fractures and compression syndromes. Retrospective studies in patients with VTE suggest that a careful medical history, a thorough physical examination, and basic blood work will detect most cases of undiagnosed cancer6,7; however, more recent prospective studies have revealed that a more extensive screening strategy involving limited screening plus imaging studies and/or tumor marker measurements can increase the rate of cancer detection.7,8 Because screening and surveillance for occult cancer in patients with unprovoked VTE is poorly understood, many physicians have criticized the concept of "extensive screening" because it may provoke anxiety, may be associated with test complications, may result in unnecessary further testing for false-positive results, and, finally, may be invasive and expensive.

Carrier and his colleagues performed an intensive and systematic review of the literature to evaluate the available data on the risks and benefits of cancer screening in patients with VTE.9 They evaluated 36 studies between 1950 and 2007 to estimate the absolute risk of previously undiagnosed cancer being present in patients and patient subgroups with either provoked or unprovoked VTE, to estimate the additional cases of cancer detected by extensive screening strategies when compared with more limited screening strategies, and to estimate the potential additional morbidity or mortality risks and/or benefits of an extensive screening strategy. The primary outcome measure was detection of previously undiagnosed cancer. The combined prevalence of occult cancer was 6.1% at baseline and 10.0% at 12 months after VTE diagnosis. Limited screening detected 47.6% of all occult cancers in patients with VTE and the detection rate increased to 66.1% in the patients who were subjected to extensive screening, which included abdominal and pelvic CT examinations.

Commentary

Although Trousseau first described the association between VTE and cancer,1 Illtyd and his colleagues in 1935 more widely promulgated the idea that clinically inapparent cancer could trigger VTE.10 In fact, only small numbers of cancer cells with a procoagulant phenotype are all that is needed to initiate coagulation reactions that are amplified by host coagulation proteins to produce massive clots11-13; this reaction has often been described by the common phrase that "a nickel's worth of cancer can give a dollar's worth of clot."14 The question arises as to how extensive a workup should be performed in patients with VTE given the psychological and physical harm often produced by false-positive results and the frequency of complications secondary to investigative procedures instigated by true- and by false-positive test results. Also, it is of course important to know how frequently a cancer is detected when patients with VTE are subjected to a thorough investigation.

Carrier and his colleagues reported that the period with the highest prevalence of previously unrecognized and newly discovered cases of cancer was within the first month of an idiopathic VTE episode (6.1%) and the rate then dropped to 2% for months 1-6 and 1.4% for months 6-12.9 Limited cancer screening detected only about one-half of the total cases compared to extensive screening and it was also noted that CT scanning of the abdomen and pelvis had the most impact on improving the case findings in the extensive screening group. Even though extensive screening detected more cancer cases at baseline than usual care, at least one-third of the cases were not detected even by extensive screening. Unprovoked VTE was more commonly associated with cancer than provoked VTE. Finally, adequate data were not available to demonstrate any survival benefit associated even with extensive cancer screening in the relatively short 12-month screening period in the studies that were reviewed.

In conclusion, it must be recognized that previously undiagnosed cancer is common in patients with unprovoked VTE and that an extensive screening strategy (including CT examinations of the abdomen and pelvis) is more likely to detect the occult lesions. However, recognizing that early diagnosis may not affect the natural history of cancer,8 should the practicing clinician even screen for occult cancer in patients with VTE? This question will best be answered by the results of a large, randomized trial; however, even if the clinician does not know whether improved survival can be achieved in VTE patients with early cancer diagnosis and even though an intensive search for occult cancer may cost thousands of dollars, an intensive evaluation of the patient with unprovoked VTE will be successful in detecting occult cancer in at least 10% of patients with previously undiagnosed cancer.

Is it worth it? The outcome value of early detection will only be known after the results of an appropriate well-designed clinical trial becomes available and these results appear to be many years off. I personally would recommend continued extensive clinical evaluation of all patients with VTE, especially if it is of the unprovoked variety and, of course, vigorous treatment of all detected cancers should then be performed following the widely published guidelines.

References

1. Trousseau A. et al. Clinique Médicale de l'Hotel-Dieu de Paris. Génève-Paris-Brussels: Alliance Culturelle du Livre; 1963.

2. Baron JA, at al. Venous thromboembolism and cancer. Lancet 1998;351:1077-1080.

3. Sorensen HT, et al. The risk of a diagnosis of cancer after primary deep venous thrombosis or pulmonary embolism. N Engl J Med 1998;338:1169-1173.

4. Lee AY, et al. Venus thromboembolism and cancer: Risks and outcomes. Circulation 2003;107:I17-I21.

5. White RH, et al. Incidence of venus thromboembolism in the year before the diagnosis of cancer in 528,693 adults. Arch Intern Med 2005;165:1782-1787.

6. Lyman GH, et al; American Society of Clinical Oncology. American Society of Clinical Oncology guideline: Recommendation for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol 2007;25:5490-5505.

7. Monreal M, et al. Screening for occult cancer in patients with acute deep vein thrombosis or pulmonary embolism. J Thromb Haemost 2004;2:876-881.

8. Picciolli A, et al. Extensive screening for occult malignant disease in idiopathic venous thromboembolism: A prospective randomized clinical trial. J Thromb Haemost 2004;2:884-889.

9. Carrier M, et al. Systematic review: The Trousseau syndrome revisited: Should we screen extensively for cancer in patients with venous thromboembolism? Ann Intern Med 2008;149:323-333.

10. Illtyd JT, et al. Thrombophlebitis and cancer. Practitioner 1935;134:683-684.

11. Donati MB, Falanga A. Pathogenic mechanisms of thrombosis in malignancy. Acta Haematol 2001;106:18-24.

12. Zacharski LR, et al. Pathways of coagulation/fibrinolysis activation in malignancy. Semin Thromb Hemost 1992;18:104-116.

13. Varki A. Trousseau's syndrome: Multiple definitions and multiple mechanisms. Blood 2007;110:1723-1729.

14. Prandoni P, Piccioli A. Thrombosis as a harbinger of cancer. Curr Opin Hematol 2006;13:362-365.