Screening for occult cancer in unprovoked venous thromboembolism (VTE)

By Erica Tsang, MD (biography and disclosures) and Iain Mackie, MD FRCPC (biography and disclosures)

No disclosures | Affiliations: Department of Medicine, University of British Columbia, Vancouver, BC, Canada

What I did before

An unprovoked venous thromboembolism (VTE), either through a deep venous thrombosis or pulmonary embolism, may be the earliest sign of malignancy.^1-2 Many clinicians will perform screening for an occult malignancy in patients with an unprovoked VTE. In a systematic review of patients with unprovoked VTE, 6% of patients were diagnosed with malignancy at the same time as their VTE diagnosis and 10% at 1-year post-VTE diagnosis.³ Early identification of malignancy may allow for earlier management, and potentially prevent cancer-associated morbidity, and improve overall survival and quality of life.

Screening methods to detect occult malignancy after an unprovoked VTE are not well standardized. Two previous prospective studies compared limited and extensive occult malignancy screening strategies.^4-5 Piccioli et al. presented a randomized controlled trial that demonstrated a higher detection rate with an extensive screening strategy.⁴ However, the study was stopped early secondary to recruitment challenges. Van Doormaal et al. presented a prospective cohort study that suggested no survival benefit with extensive screening.⁵ Extensive screening included chest and abdominal CT scans and mammography, in addition to the limited screening strategy of history, physical examination, basic lab tests, and chest x-ray. Despite these two prospective studies, there has still been a scarcity of evidence behind the type and extent of malignancy screening for patients with unprovoked VTE, as reflected in the lack of guidelines and variation of practice patterns between clinicians.

What changed my practice

The Screening for Occult Malignancy in Patients with Idiopathic Venous Thromboembolism (SOME) trial compared a limited screening strategy with and without CT imaging in patients with an unprovoked VTE.⁶ The SOME trial was a multicenter, open-label, randomized clinical trial conducted at 9 centers across Canada, and was funded by the Heart and Stroke Foundation of Canada. Inclusion criteria consisted of patients with a new diagnosis of first unprovoked symptomatic VTE, including deep vein thrombosis and/or pulmonary embolism. Patients with an active malignancy, pregnancy, hereditary or acquired thrombophilia, previous unprovoked VTE, or predisposing factors within the last 3 months were excluded.

Patients were randomized to a limited screening strategy alone or limited screening-plus-CT strategy. Limited screening included a complete history and physical, complete blood counts, serum electrolyte and creatinine levels, liver-function testing, and chest radiography. The limited screening strategy also included sex-specific screening if it had not been conducted within the previous year. The comprehensive CT of the abdomen and pelvis included virtual colonoscopy and gastroscopy, enhanced CT of the liver, pancreatography, and enhanced CT of the distended bladder. The primary endpoint was newly diagnosed cancer within the 1-year follow-up period in patients who had a negative screening result for occult cancer. Secondary endpoints included: total number of occult cancers diagnosed, total number of early cancers diagnosed by screening, 1-year cancer-related mortality, 1-year overall mortality, time to cancer diagnosis, and recurrent VTE.

854 patients were included with an unprovoked VTE, including deep vein thrombosis (67.4%), pulmonary embolism (32.6%), and both (12.3%). After 1-year of follow-up, 33 patients received a new diagnosis of cancer, including 14 in the limited screening and 19 in the limited screening-plus-CT strategy. 4 of 14 occult cancers were missed by the limited screening strategy, while 5 of 19 occult cancers were missed by the limited screening-plus-CT strategy (non-significant difference; p=1.0). There was also no significant difference between the time to cancer diagnosis within the follow-up period (p=0.87). None of the secondary endpoints yielded a significant difference between the two screening strategies.

What I do now

The SOME trial provides insight into the role of screening strategies for occult malignancy after an unprovoked VTE. Previous retrospective studies and systematic reviews had suggested a greater detection with extensive screening strategies.³ Prior to the SOME trial, Piccioli et al. performed the first randomized controlled trial to evaluate extensive screening, but the study was terminated due to poor recruitment.⁴ The SOME trial evaluated this clinical question and demonstrated no difference between limited screening and extensive screening strategies.

The SOME trial showed no significant benefit of adding CT imaging to a limited screening strategy in patients with an unprovoked VTE, consistent with the cohort study findings reported by Van Doormaal et al. There was no difference in missed occult cancers between the limited screening (29%) and limited screening-plus-CT (26%) strategies. There was also no difference in the mean time to detection of cancer between the two groups. The occult malignancy rate in the SOME trial was 3.9%, compared to previous studies with occult cancer detection rates of up to 10% after 1-year follow-up. Recent studies have also found lower rates of occult cancer detection, similar to that in the SOME trial, potentially due to improved cancer screening in developed countries.^5,7

The SOME study was limited by a lack of long-term follow-up. Retrospective studies have demonstrated that there is a higher frequency of cancer detection within the first year of VTE, but longer follow-up may be helpful in better delineating the impact of earlier detection on overall survival and recurrence rates. Furthermore, this study did not account for other factors related to an extensive screening strategy, including anxiety, radiation exposure, cost-effectiveness, and longer-term implications of incidental findings or complications of increased screening. Colorectal cancer screening, either through colonoscopies or routine fecal immunochemistry or fecal occult blood testing, was not discussed in the SOME study.

Conclusion

In patients presenting with unprovoked VTE, a limited occult malignancy screening strategy is sufficient, compared to routinely adding CT imaging of the abdomen and pelvis. We would recommend the same limited screening as employed in the SOME trial: history, physical examination, basic lab investigations (complete blood counts, electrolytes, creatinine, liver function tests), chest x-ray, and age and sex-specific screening. In women greater than 50 years, breast examination and mammography would be appropriate, while Papanicolau testing and pelvic examination should be performed for women between 18-70 years. In men older than 40 years, prostate examination with or without prostate specific antigen were done. Colorectal cancer screening should be performed as per provincial guidelines. In summary, the SOME trial demonstrated low rates of occult malignancy, with no differences in occult cancer detection rate or time to detection between the two screening strategies.

References

1. Sørensen HT, Mellemkjaer L, Steffensen FH, et al. The risk of a diagnosis of cancer after primary deep venous thrombosis or pulmonary embolism. N Engl J Med 1998;338:1169-73. (View)
2. Lee AY, Levine MN. Venous thromboembolism and cancer: risks and outcomes. Circulation 2003;107:I17-21. (View with CPSBC or UBC) DOI: 10.1161/01.CIR.0000078466.72504.AC
3. Carrier M, Le Gal G, Wells PS, et al. Systematic review: the Trousseau syndrome revisited: should we screen extensively for cancer in patients with venous thromboembolism? Ann Intern Med 2008;149:323-33. (Request with CPSBC or view UBC) DOI: 10.7326/0003-4819-149-5-200809020-00007
4. Piccioli A, Lensing AWA, Prins MH, et al. Extensive screening for occult malignant disease in idiopathic venous thromboembolism: a prospective randomized clinical trial. J Thromb Haemost 2004;2:884-9. (Request with CPSBC or view UBC) DOI: 10.1111/j.1538-7836.2004.00720.x
5. Van Doormaal FF, Terpstra W, Van Der Griend R, et al. Is extensive screening for cancer in idiopathic venous thromboembolism warranted? J Thromb Haemost 2011;9:79-84. (Request with CPSBC or view UBC) DOI: 10.1111/j.1538-7836.2010.04101.x
6. Carrier M, Lazo-Langner A, Shivakumar S, et al. Screening for Occult Cancer in Unprovoked Venous Thromboembolism. N Engl J Med. 2015 Aug 20;373(8):697-704. (Request with CPSBC or view UBC) DOI: 10.1056/NEJMoa1506623
7. Prandoni P, Casiglia E, Piccioli A, et al. The risk of cancer in patients with venous thromboembolism does not exceed that expected in the general population after the first 6 months. J Thromb Haemost 2010;8:1126-7. (Request with CPSBC or view UBC) DOI: 10.1111/j.1538-7836.2010.03797.x

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