A 57-year-old woman presents to the emergency department after two days of pain and swelling in her left thigh. She denies any recent surgery, infection, hospitalization, or prolonged immobilization. She denies any recent trauma to her left lower extremity. She has no personal history of malignancy. She takes no medications. She has no family history of deep venous thrombosis (DVT) or pulmonary embolism (PE), and no family history of malignancy. She is up to date with screening colonoscopy, having had a normal study within the last year, and is up to date with cervical cancer screening, having had a pap smear within the last two years that revealed no intraepithelial lesion. She has not had a mammogram in three years.
On exam, she is afebrile, with a heart rate of 72 beats per minute, a blood pressure of 120/70 mm Hg, a respiratory rate of 16 bpm, and an oxygen saturation of 98% on room air. Her jugular venous pressure is seen at 7 cm H20. Cardiac auscultation reveals a regular rate and rhythm with a normal S1 and S2. Her lower extremities are notable for erythema in the left lower extremity, as well as pitting edema. On measurement, her left calf diameter is 3 cm greater than her right calf diameter.
Initial laboratory testing is notable for a creatinine of 0.65, a white blood cell count of 7,300, a hematocrit of 39%, a platelet count of 239,000, an international normalized ratio (INR) of 1.0, and a partial thromboplastin time of 29 seconds. A D-dimer test is deferred. Compression venous ultrasonography reveals absence of compressibility in the left femoral vein, consistent with DVT. The patient is diagnosed with unprovoked proximal DVT.
The patient is prescribed apixaban 10 mg twice daily for seven days, followed by 5 mg twice daily. Her pain subsides over the following two days.
Which of the following is the appropriate cancer screening in this patient?
The correct answer is: B. Mammography and chest radiograph.
This patient presents with a first episode of venous thromboembolism (VTE). Given the absence of recent surgery, trauma, immobilization, or known malignancy, her VTE is unprovoked. Apixaban 10 mg twice daily for seven days followed by apixaban 5 mg twice-daily is a safe and efficacious therapeutic option for treating her VTE.1 Furthermore, long term therapy with apixaban will reduce her risk of recurrent thromboembolism without an increased rate of bleeding.2
Typical evaluation for the first episode of unprovoked VTE includes a search for both inherited and acquired thrombophilias, including malignancy. The Factor V Leiden mutation and prothrombin gene mutations account for the majority of inherited hypercoaguable states.3 Other inherited thrombophilias include protein C deficiency and protein S deficiency, though these are less common. Rare inherited thrombophilias include antithrombin deficiency and dysfibrogenemia. Acquired thrombophilias include the antiphospholipid antibody syndrome, acquired protein C or S deficiencies, and many other conditions.3 Given that many of these tests will not affect the choice or duration of therapy, expert opinion recommends a limited thrombophilia workup for unprovoked VTE in the absence of strong family history, including Factor V Leiden screening, prothrombin gene mutation screening, and anticardiolipin antibodies to evaluate for antiphospholipid antibody syndrome.3
VTE is often the first sign of cancer.4 As such; many clinicians become concerned about the possible diagnosis of malignancy in a patient with VTE. Forty percent of VTE cases are unprovoked, making this a common clinical scenario.5 Many clinicians feel compelled to search for occult malignancy following VTE in the hopes that an earlier diagnosis will prevent morbidity and mortality. This question was studied systematically in the Screening for Occult Malignancy in Patients With Idiopathic Venous Thromboembolism (SOME) trial, a large, multicenter, randomized controlled trial of 854 patients with a first episode of proximal VTE or PE.6 The patients were randomized either to limited screening including basic blood work, a chest radiograph, and screening for breast, cervical, and prostate cancer, or the above limited screening in combination with abdominal and pelvic computed tomography (CT). Notably, the CT scans included a bowel prep and virtual colonoscopy, and only 6.7% of the limited screening group had undergone any colon cancer screening (fecal occult blood testing, sigmoidoscopy, or colonoscopy).
The incidence of occult malignancy was low in both groups, with 3.2% of patients in the limited screening group, and 4.5% of the limited screening plus CT group (p=0.28). In the year after randomization, five occult malignancies were detected in the limited screening group, versus four in the limited screening plus CT group (p>0.99). Furthermore, given the fact that so few of the limited screening group underwent recommended colon cancer screening, routine clinical practice would be even more likely to detect malignancy than the limited screening group in this trial, further diminishing the potential benefit of more aggressive screening.
For this patient, who has no known cancer, the use of cancer biomarkers to establish a diagnosis of cancer (Answer A) is inappropriate. While Carbohydrate Antigen 19-9 (CA19-9) is both sensitive and specific for pancreatic cancer, the positive predictive value of a positive test is only 0.9% due to the low prevalence in an asymptomatic population.7 Carcinoembryonic antigen (CEA) may have a role in monitoring response to therapy in colon cancer but low sensitivity limits the utility of CEA as a screening test.8 Based on the SOME trial results described above, CT scanning would be unlikely to identify many additional cancers and does expose patients to radiation and the risks associated with false positive findings and subsequent invasive procedures, hence Answer D is incorrect. Answer C is not optimal, since age-appropriate cancer screening (in this patient this would include mammography, pap smear, and colon cancer screening via either colonscopy, computed tomographic colonography, or flexible sigmoidoscopy) has been shown to be a cost-effective approach to detect clinically silent cancers.9,10,11 Thus, the correct approach is ensuring that this patient gets routine mammography, as well as a chest radiograph (Answer B).
Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboemobolism. N Engl J Med 2013;369:799-808.
Agnelli G, Buller HR, Cohen A, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013;368:699-708.
Goldhaber SZ. Risk factors for venous thromboembolism. J Am Coll Cardiol 2010;56:107.
Sørensen HT, Mellemkjaer L Steffensen FH, Olsen JH, Nielsen GL.The risk of a diagnosis of cancer after primary deep venous thrombosis or pulmonary embolism. N Engl. J Med 1998;338:1169-73.
Ageno W, Samperiz A, Caballero R, et al. Duration of anticoagulation after venous thromboembolism in real world clinical practice. Thromb Res 2015;135:666-72.
Carrier M, Lazo-Langner A, Shivakumar S, et al. Screening for Occult Cancer in Unprovoked Venous Thromboembolism. N Engl. J Med 2015;373:697-704.
Kim JE, Lee KT, Lee JK, Paik SW, Rhee JC, Choi KW. Clinical usefulness of carbohydrate antigen 19-9 as a screening test for pancreatic cancer in an asymptomatic population. J Gastroenterol Hepatol 2004;19:182-6.