SOME

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Carrier M, et al. "Screening for Occult Cancer in Unprovoked Venous Thromboembolism". The New England Journal of Medicine. 2015. 373(8):697-704.
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Clinical Question

In patients with a first episode of unprovoked venous thromboembolism (VTE), does a strategy adding comprehensive CT scanning of the abdomen and pelvis to limited occult cancer screening result in detection of more occult malignancies?

Bottom Line

The addition of comprehensive CT scanning of the abdomen and pelvis to routine age-appropriate screening did not result in a difference in time to occult cancer diagnosis or cancer-related mortality in patients with unprovoked VTE.

Major Points

Malignancy is a well-recognized risk factor for VTE. Unprovoked VTE can be a presenting symptom of undiagnosed malignancy, and historically up to 10% of patients with an unprovoked VTE event are diagnosed with cancer in the following year,[1] after which period the risk of an occult cancer diagnosis is similar to the general population.

Published in 2015, the Screening for Occult Malignancy in Patients with Idiopathic Venous Thromboembolism (SOME) trial randomized 854 patients with an unprovoked VTE to age-appropriate cancer screening or age appropriate cancer screening plus CT of the abdomen and pelvis. The primary outcome was confirmed cancer diagnosis at 1 year among those with an initial negative screen. There was no difference in this outcome between groups. Cancer mortality was also similar in both groups. This is in keeping with prior smaller studies where other forms of extensive screening have shown mixed results with regards to detection of early stage cancers but consistently fail to demonstrate an effect on mortality.[2][3] A 2017 patient-level meta analysis found an initial benefit for extensive screening but no difference at 1 year.[4] This meta analysis also noted an increasing risk of occult cancer with increasing age. A 2017 Cochrane review determined that screening for cancer in this population may lead to earlier diagnosis of cancer though there is insufficient evidence to determine the effectiveness.[5]

SOME provides evidence against extended cancer screening strategy after an unprovoked VTE, focusing on age-appropriate screening. A significant percentage of cancers, however, were missed by both strategies. The most common of these were acute lymphomas, gynecologic cancers, and colorectal cancers, leaving room for future studies to inquire about alternative methods of extended cancer screening, such as peripheral blood smear, pelvic ultrasound, or FIT/FOBT. Further, whether specific age group may benefit is unclear.

Guidelines

As of August 2018, no guidelines have been published that reflect the results of this trial.

Design

  • Multicenter, open-label randomized controlled trial conducted at nine Canadian institutions
  • N=862
    • Limited cancer screening (N=431)
    • Extended cancer screening (N=423)
  • Enrollment period: 2008-2014
  • Follow-up: 1 year after diagnosis of VTE
  • Analysis: Intention-to-test (99% of those randomized included in analysis)
  • Primary outcome: Confirmed cancer within the 1-year follow up period that was missed by the screening strategy employed after VTE diagnosis

Population

Inclusion Criteria

  • New diagnosis of a first, unprovoked, symptomatic VTE (defined as proximal lower-limb DVT, pulmonary embolism, or both)
  • Age ≥18

Exclusion Criteria

  • Known active cancer or thrombophilia
  • Current pregnancy
  • Previous VTE event
  • Temporary provoking factor in last 3 months
  • Contraindications to CT scanning

Baseline Characteristics

From the limited group except where stated.

  • Demographics: Age 53 years, white race 92%
    • Sex: male 64% limited vs 71% extended (P=0.045)
  • PMH: HTN 20%, MI 3%, CVA 1%, HF 0.5%, DM 4%, prior cancer 5%, prior provoked VTE 7%, smoker 16% (former 32%)
  • VTE diagnosis: Proximal DVT 67%, PE 33%, both 12%
  • Relevant medications at diagnosis: Oral contraceptive 7%, estrogen 2%, antiplatelet 5%

Interventions

  • Randomized within 3 weeks of diagnosis of VTE to a group:
    • Limited cancer screening - Limited screening strategy including a H&P, basic bloodwork (CBC, renal evaluation, LFTs), and a CXR
      • Age- and sex-specific cancer screening if not done within 1 year (breast exam and/or mammography in women >50 years, Pap and pelvic exam in women 18-70 years if ever sexually active, prostate exam and/or PSA in men >40 years)
    • Intensive cancer screening - Comprehensive computerized tomography - CT of abdomen and pelvis with virtual colonoscopy and gastroscopy, biphasic CT scan of liver, parenchymal pancreatography and enhanced bladder CT
      • Limited screening strategy and age-specific cancer screening as in control group
  • Both groups were followed for 1 year for diagnosis of cancer or recurrent VTE

Outcomes

Comparisons are limited vs. intensive cancer screening

Primary Outcome

Newly diagnosed occult cancer (over 1 year follow-up) in those with negative screening result after VTE diagnosis
4/14 occult cancers (29%, 95% CI 8-58) vs. 5/19 (26%, 95% CI 9-51) (P=1.00)

Secondary Outcomes

Overall mortality at 1 year
1.4% vs. 1.2% (P=1.00)
Cancer-related mortality at 1 year
1.4% vs. 0.9% (P=0.75)
Time to cancer diagnosis
4.2 months vs. 4.0 months (P=0.88)
Incidence of recurrent VTE
3.3% vs. 3.4% (P=1.00)

Adverse Events

No significant adverse events were reported with either screening strategy.

Criticisms

  • CT abdomen/pelvis may not be the best additional testing for the "extensive screening" group.
  • Study likely underpowered to detect significant differences given the low rate of occult malignancy (3.9% within 1 year follow-up period)
  • Participants in the control arm may have higher quality limited screening cancer detection (in a clinical trial at a tertiary center) compared to typical community standard of care
  • Some trial participants were smokers (16%), on estrogen (8%), or had a prior VTE (6%) despite being substantially less likely to benefit from additional cancer screening
  • Excluding those with CrCL <60 mL/min limits generalizability[6]

Funding

Funding supported by the Heart and Stroke Foundation of Canada.

Further Reading

  1. 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. 149:323-33.
  2. Piccioli A et al. Extensive screening for occult malignant disease in idiopathic venous thromboembolism: a prospective randomized clinical trial. J. Thromb. Haemost. 2004. 2:884-9.
  3. Van Doormaal FF et al. Is extensive screening for cancer in idiopathic venous thromboembolism warranted?. J. Thromb. Haemost. 2011. 9:79-84.
  4. van Es N et al. Screening for Occult Cancer in Patients With Unprovoked Venous Thromboembolism: A Systematic Review and Meta-analysis of Individual Patient Data. Ann. Intern. Med. 2017. 167:410-417.
  5. Robertson L et al. Effect of testing for cancer on cancer- and venous thromboembolism (VTE)-related mortality and morbidity in people with unprovoked VTE. Cochrane Database Syst Rev 2017. 8:CD010837.
  6. Schreiber R & ACP Journal Club: adding CT to screening for occult cancer did not increase diagnosis of cancer from screening in unprovoked VTE. Ann. Intern. Med. 2015. 163:JC9.