How Best to Assess Cancer Risk in a Man With Unprovoked Venous Thromboembolism

Author:
Ronald N. Rubin, MD—Series Editor

Citation:
Rubin RN. How best to assess cancer risk in a man with unprovoked venous thromboembolism. Consultant. 2017;57(7):418-419.

A 59-year-old previously healthy man experienced pain and swelling of his left lower extremity for several days. He had not had chest pain or episodes of dyspnea. He had seen his physician, who promptly ordered a Doppler ultrasonography study, which revealed an acute deep vein thrombosis (DVT) involving the popliteal and femoral veins. He was then admitted to the hospital for acute evaluation and management.

Further history and examination revealed an entirely negative review of symptoms. His only current condition was mild hypertension of 10 years’ duration that was well controlled with an angiotensin-converting enzyme inhibitor. He had briefly smoked cigarettes in his 20s but had not smoked since. His weight was stable and his appetite unchanged. He had a desk job for a large corporation and occasionally traveled for business, but he had not done so for several months.

Physical examination findings were normal with the exception of his left lower extremity, which featured redness and tenderness of the distal thigh and popliteal areas, as well as 2+ edema of the distal left leg and ankle, compared with the normal right lower extremity.

Results of a complete blood cell count and a comprehensive metabolic panel were completely normal. A routine chest radiograph had normal findings. Pre-anticoagulation prothrombin time and partial thromboplastin time were also normal.

Answer on next page

Answer: B, the idea that detailed and aggressive screening is mandatory is not true.

The association of cancer and thromboembolic disease has been observed for a very long time, first being described by Armand Trousseau in 1859.¹ A variety of mechanisms have been described, including the presence of procoagulant material (acting as tissue factor in the circulation) and even the presence of disseminated intravascular coagulation per se.²

A number of observational studies have estimated that unprovoked VTE is the earliest sign of cancer in as many as 10% of cases.^1,3,4 Unprovoked VTE is the sustaining of such an event in the absence of typical risk factors such as surgery, prolonged immobilization, pregnancy/puerperium, or the presence of a hereditary or acquired hypercoagulable state such as protein C deficiency or antiphospholipid syndrome. A difficult clinical question in such instances is how intense should an investigation for the presence of such an occult yet undiagnosed cancer be, and can the prognosis be meaningfully changed by such an investigation. Recent studies have offered more clarity about incidence and appropriate clinical strategies for this situation.

Aggressive Screening: Pros and Cons

The results of an open-label, randomized trial (the Screening for Occult Malignancy in Patients with Idiopathic Venous Thromboembolism [SOME] trial) comparing a more conservative age-related screening strategy with a more intensive computed tomography (CT) scanning strategy in cases of unprovoked VTE have recently been reported.⁴ In this trial enrolling 854 Canadian patients with unprovoked VTE, the more limited age-appropriate screening included mammography, breast examination, or both in women older than 50 years; a Papanicolaou test and pelvic examination in women aged 18 to 70 years; and prostate examination, a prostate-specific antigen test, or both in men older than 40 years. The more aggressive screening approach included comprehensive CT of the abdomen and pelvis, including a virtual colonoscopy and gastroscopy. Patients were treated as appropriate for their VTE event, be it DVT, PE, or both; their cases then were followed for 1 year at fixed intervals.

Findings demonstrated that 33 (3.9%) of the patients with unprovoked VTE received a new diagnosis of cancer by 1 year after the event. A variety of tumor types were found, but the occurrence rate was essentially equivalent between the 2 groups. Furthermore, there was no statistical difference in the number of occult cancer cases detected using the 2 screening strategies (4 cases missed using the limited screening strategy vs 5 cases missed using the comprehensive one).⁴

Also demonstrating the lack of utility of using more aggressive screening methods were the findings that there were no differences between the 2 groups in time to cancer diagnosis after a VTE event, overall mortality, or cancer-related mortality.^4,5 Thus, the best and most current data strongly suggest that a good history and physical examination, basic blood studies, chest radiography, and age- and sex-specific cancer screening are adequate and appropriate for patients presenting with unprovoked VTE.^4,5 To do more adds expense and unnecessary radiation exposure without providing meaningful clinical benefit.⁵ These data make Answer B above an incorrect statement and the correct choice here.

Answer C is correct in that the results of the SOME trial and other studies demonstrate that the majority of occult cancers diagnosed after an unprovoked VTE occur in the first 6 months after the VTE, with a marked diminution in incidence approaching that of an age-matched, normal population thereafter.^3,4

Answer A is also a correct statement. Current guidelines are that VTEs associated with active cancer are treated differently than VTEs not without associated cancer. Warfarin strategies are inferior to regimens using low-molecular-weight heparin (LMWH) as regards VTE recurrence, morbidity, and mortality.⁶ There is as yet insufficient data about cancer-related VTE and the use of newer oral anticoagulants, none of which have been approved in the United States for this indication.

Finally, Answer D is a correct statement (the antithesis to Answer B) as demonstrated by the SOME trial⁴ and its accompanying strong editorial.⁵

Patient Follow-Up

The patient was started on an anticoagulant regimen of LMWH. There was resolution of signs and symptoms of VTE and no recurrence in the very short term. Despite advice to the contrary, the hospitalists on the case pursued an aggressive cancer-detection evaluation, including CT of the abdomen, pelvis, and chest, as well as a broad variety of tumor marker tests, the results of which were all normal and/or nonrevealing. Rivaroxaban was eventually chosen as the patient’s long-term anticoagulant, and at 6 months he was clinically well, without VTE recurrence or any new signs or symptoms of neoplasm.

Ronald N. Rubin, MD, is a professor of medicine at the Lewis Katz School of Medicine at Temple University and is chief of clinical hematology in the Department of Medicine at Temple University Hospital in Philadelphia, Pennsylvania.

REFERENCES:

1. Carrier M, Le Gal G, Wells PS, Fergusson D, Ramsey T, Rodger MA. Systematic review: the Trousseau syndrome revisited: should we screen extensively for cancer in patients with venous thromboembolism? Ann Intern Med. 2008;149(5):323-333.
2. Khorana AA. The wacky hypercoagulable state of malignancy. Blood. 2015;​126(4):430-431.
3. 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(5):1126-1127.
4. Carrier M, Lazo-Langner A, Shivakumar S, et al; SOME Investigators. Screening for occult cancer in unprovoked venous thromboembolism. N Engl J Med. 2015;373(8):697-704.
5. Khorana AA. Cancer workup after unprovoked clot—less is more. N Engl J Med. 2015;373(8):768-769.
6. Lee AYY, Levine MN, Baker RI, et al; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349(2):146-153.