Rational for new promising studies on occult cancer screening for patients with unprovoked venous thromboembolism

 

Venous thromboembolism (VTE), comprising deep vein thrombosis and pulmonary embolism, can be the first sign of an occult cancer. It is therefore appealing for clinicians to screen for occult cancers among patients with unprovoked VTE. In order counsel patients about the pros and cons of occult cancer detection, clinicians need precise estimate of occult cancer detection among this patient population. An old systematic review of the literature previously reported that up to 10% of patients with unprovoked VTE would be diagnosed with an occult cancer within 12 months of their diagnosis[1]. However, this period prevalence seems to be overestimated. A recent individual patient data meta-analysis using contemporary studies demonstrated that the 12-nonth prevalence is closer to 5%[2]. The reasons for a lower prevalence of occult cancer detection over time (10% in 2008 vs. 5.2 in 2017) are unclear. Nonetheless, this lower prevalence of occult cancer detection in patients with unprovoked VTE is reassuring for patients and clinicians, and is important to consider for researchers planning new studies on this topic.

In addition to precise estimates of occult cancer detection, clinicians need to know if a more extensive occult cancer screening strategy is beneficial to patients. Two recently published randomized controlled trials have failed to show that an extensive occult cancer screening increases the number of occult cancer detection or leads to an improvement in patient important outcomes (e.g. morbidity or mortality) for these patients[3, 4]. The SOME trial, a Canadian multicenter study comparing a limited cancer screening to a comprehensive computed tomography and the MVTEP trial, a French multicenter randomized controlled trial comparing a limited screening strategy to a 18F-Fluorodesoxyglucose Positron Emission Tomography/Computed Tomography (FDG PET/CT), both failed to show that extensive occult cancer screening detected a higher rate of occult cancers at initial screening[3, 4]. Therefore, current recent guidance suggests that only a limited screening for cancer consisting of a medical history, a physical examination, basic blood work, a chest X-ray, and age-and gender specific testing per national guidelines should be considered in these patients, since current evidence does not show a clear benefit of an extensive cancer screening strategy[5]. However, about one-third of cancer cases are still missed at initial screening. Similarly, the recently published individual patient level data meta-analysis showed that patients that underwent an extensive screening had a 2-fold higher probability of occult cancer detection at screening compared to those undergoing a limited screening only (p=0.012)[2]. These observations prompted more research for better cancer screening diagnostic tools in higher-risk patients with unprovoked VTE to detect cancer at an earlier stage.

Recently, platelet mRNA sequencing has been introduced as a promising, highly accurate test for cancer. Upon confrontation with tumor cells, the mRNA profile of platelets is altered and becomes fundamentally different from the mRNA profiles of individuals without cancer. A recent case-control study has reported a very high sensitivity (97%) and specificity (94%) for diagnosing various tumor types. This pan-cancer detection tool provides a potentially unique opportunity to improve cancer screening in patients with unprovoked VTE. Professor Harry Büller and Dr. Noémie Kraajpoel are currently leading the on-going PLATO-VTE study, a multi-national prospective cohort study, aiming to evaluate the diagnostic accuracy of platelet mRNA sequencing for occult cancer in the setting of unprovoked VTE (Total sample size = 463; NCT02739867). 

The most promising diagnostic modality for extensive occult cancer screening might be the FDG PET/CT. FDG-PET/CT. The MVTEP trial demonstrated that the incidence of occult cancers missed by screening was significantly lower in patients undergoing the FDG PET/CT strategy. Additionally, age seems to be the most important risk factor[4]. The 12-month prevalence of cancer ranges from 0.5% in patients younger than 40 years to 9% in patients older than 80 years[2]. Therefore, Drs. Philippe Robin and Pierre-Yves Salaun are currently planning the MVTEP2 trial which will evaluate the efficacy using FDG PET/CT for occult cancer detection in older patients with unprovoked VTE.

The PLATO-VTE study and MVTEP2 trials are exciting endeavors that will better define the risks and benefits of an extensive occult cancer screening strategy in high risk patients with unprovoked VTE and their results are highly anticipated.


REFERENCES

  1. Carrier M, Le Gal G, Wells PS, Fergusson D, Ramsay 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: 323–333
  2. van Es N, Le Gal G, Otten HM, 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 Aug 22. doi: 10.7326/M17-0868. [Epub ahead of print]
  3. Carrier M, Lazo-Langner A, Shivakumar S, et al. Screening for occult cancer in unprovoked venous thromboembolism. N Eng J Med. 2015; 373: 697–704.
  4. Robin P, Le Roux PY, Planquette B, et al. Limited screening with versus without 18F-fluorodeoxyglucose PET/CT for occult malignancy in unprovoked venous thromboembolism: an open-label randomised controlled trial. Lancet Oncol.2016; 17:193-9.
  5. Delluc A, Antic D, Lecumberri R, Ay C, Meyer G, Carrier M. Occult cancer screening in patients with venous thromboembolism: guidance from the SSC of the ISTH. J Thromb Haemost. 2017 Aug 5. doi: 10.1111/jth.13791. [Epub ahead of print]
  • Marc Carrier

    Marc Carrier

    Associate Professor in the Faculty of Medicine, Departments of Medicine and Epidemiology at the University of Ottawa and a Senior Scientist in the Clinical Epidemiology Program of the Ottawa Hospital Research Institute
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